Inspiring a convergent engineering approach to measure and model the tissue microenvironment.

Understanding the molecular and physical complexity of the tissue microenvironment (TiME) in the context of its spatiotemporal organization has remained an enduring challenge. Recent advances in engineering and data science are now promising the ability to study the structure, functions, and dynamics of the TiME in unprecedented detail; however, many advances still occur in silos that rarely integrate information to study the TiME in its full detail. This review provides an integrative overview of the engineering principles underlying chemical, optical, electrical, mechanical, and computational science to probe, sense, model, and fabricate the TiME. In individual sections, we first summarize the underlying principles, capabilities, and scope of emerging technologies, the breakthrough discoveries enabled by each technology and recent, promising innovations. We provide perspectives on the potential of these advances in answering critical questions about the TiME and its role in various disease and developmental processes. Finally, we present an integrative view that appreciates the major scientific and educational aspects in the study of the TiME.

Successful dietary changes correlate with weight-loss outcomes in a new dietary weight-loss program.

Background: Currently available behavioral and dietary weight-loss programs lack magnitude and sustainability compared with bariatric surgery. A novel dietary weight-loss program was developed to assist participants in achieving sustainable diet changes by building knowledge and skills in food self-selection. Although the approach worked, a large variation was observed in outcome among participants. Objective: Determine factors affecting weight-loss outcomes among participants to further improve the efficacy of the program. Methods: Participants attended 19 dietary educational sessions during a 1-year intervention which included prescribed homework. Changes in weight, diet, and body composition were assessed. Results: Participants (n = 22) achieved mean body weight loss of -6.49(8.37%, p < 0.001) from baseline at 12 months. Nine participants (41%) achieved weight loss >5% of initial bodyweight; two reached a Body Mass Index 25 kg/m2. A large divergence in weight loss among participants was observed; successful (n = 9) achieved -12.9(9.6)% while unsuccessful achieved -2.03(2.78)%. Dietary protein and fiber density by 24-h records showed a significant and inverse correlation with weight loss (%) throughout the program. Weight loss at 3 months and 12 months showed a strong correlation (r = 0.84). Participants with self-reported depression lost significantly less weight than those without depression at 12 months (p < 0.03). Conclusions: Divergence in weight-loss outcomes among the participants is likely due to a difference in successful dietary implementation. Intra-cohort analysis indicates early weight-loss success and early dietary implementation was predictive of long-term success.

RAGE as a Novel Biomarker for Prostate Cancer: A Systematic Review and Meta-Analysis.

The receptor for advanced glycation end-products (RAGE) has been implicated in driving prostate cancer (PCa) growth, aggression, and metastasis through the fueling of chronic inflammation in the tumor microenvironment. This systematic review and meta-analysis summarizes and analyzes the current clinical and preclinical data to provide insight into the relationships among RAGE levels and PCa, cancer grade, and molecular effects. A multi-database search was used to identify original clinical and preclinical research articles examining RAGE expression in PCa. After screening and review, nine clinical and six preclinical articles were included. The associations of RAGE differentiating benign prostate hyperplasia (BPH) or normal prostate from PCa and between tumor grades were estimated using odds ratios (ORs) and associated 95% confidence intervals (CI). Pooled estimates were calculated using random-effect models due to study heterogeneity. The clinical meta-analysis found that RAGE expression was highly likely to be increased in PCa when compared to BPH or normal prostate (OR: 11.3; 95% CI: 4.4-29.1) and that RAGE was overexpressed in high-grade PCa when compared to low-grade PCa (OR: 2.5; 95% CI: 1.8-3.4). In addition, meta-analysis estimates of preclinical studies performed by albatross plot generation found robustly positive associations among RAGE expression/activation and PCa growth and metastatic potential. This review demonstrates that RAGE expression is strongly tied to PCa progression and can serve as an effective diagnostic target to differentiate between healthy prostate, low-grade PCa, and high-grade PCa, with potential theragnostic applications.

Yellow Mealworm (Tenebrio molitor) and Lesser Mealworm (Alphitobius diaperinus) Proteins Slowed Weight Gain and Improved Metabolism of Diet-Induced Obesity Mice.

BACKGROUND: High-protein diets not only meet amino acid needs but also modulate satiety and energy metabolism. Insect-based proteins are sustainable, high-quality proteins. Mealworms have been studied, but limited information is known about their ability to impact metabolism and obesity. OBJECTIVE: We determined the effects of defatted yellow mealworm (Tenebrio molitor)- and whole lesser mealworm (Alphitobius diaperinus)-based proteins on the body weight (BW), serum metabolites, and liver and adipose tissue (AT) histology and gene expression of diet-induced obesity mice. METHODS: Male C57BL/6J mice were fed a high-fat diet (HFD; 46% kcal) to induce obesity and metabolic syndrome. Obese mice were then assigned to treatments (n = 10/group) and fed for 8 wk: HFD: HFD with casein protein; B50: HFD with 50% protein from whole lesser mealworm; B100: HFD with 100% protein from whole lesser mealworm; Y50: HFD with 50% protein from defatted yellow mealworm; Y100: HFD with 100% protein from defatted yellow mealworm. Lean mice (n = 10) fed a low-fat-diet (LFD; 10% kcal) were included. Longitudinal food intake, BW, body composition, and glucose response were measured. At time of killing, serum metabolites, tissue histopathology and gene expression, and hepatic triglycerides were analyzed. RESULTS: After 8 wk, HFD, B50, and B100 had greater (P < 0.05) weight gain than LFD, whereas Y50 and Y100 did not. Y50, B100, and Y100 had a lower (P < 0.05) BW change rate than HFD. Mealworm-based diets led to increased (P < 0.05) serum high-density lipoprotein (HDL) and reduced (P < 0.05) serum low-density lipoprotein (LDL) concentrations and reduced (P<0.05) LDL/HDL ratio. Mealworm-based diets led to increased (P < 0.05) hepatic expression of genes related to energy balance, immune response, and antioxidants and reduced (P < 0.05) AT expression of genes associated with inflammation and apoptosis. Mealworm-based diets altered (P < 0.05) hepatic and AT expression of glucose and lipid metabolism genes. CONCLUSIONS: In addition to serving as an alternative protein source, mealworms may confer health benefits to obese patients.

Evaluation of high-protein diets differing in protein source in healthy adult dogs.

Given the dynamic market for protein-based ingredients in the pet food industry, demand continues to increase for both plant- and animal-based options. Protein sources contain different amino acid (AA) profiles and vary in digestibility, affecting protein quality. The objective of this study was to evaluate the apparent total tract digestibility (ATTD) of canine diets differing in protein source and test their effects on serum metabolites and fecal characteristics, metabolites, and microbiota of healthy adult dogs consuming them. Four extruded diets were formulated to be isonitrogenous and meet the nutrient needs for adult dogs at maintenance, with the primary difference being protein source: 1) fresh deboned, dried, and spray-dried chicken (DC), 2) chicken by-product meal (CBPM), 3) wheat gluten meal (WGM), and 4) corn gluten meal (CGM). Twelve adult spayed female beagles (body weight [BW] = 9.9 ± 1.0 kg; age = 6.3 ± 1.1 yr) were used in a replicated 4 × 4 Latin square design (n = 12/treatment). Each period consisted of a 22-d adaptation phase, 5 d for fecal collection, and 1 d for blood collection. Fecal microbiota data were analyzed using QIIME 2.2020.8. All other data were analyzed using the Mixed Models procedure of SAS version 9.4. Fecal scores were higher (P < 0.05; looser stools) in dogs fed DC or CBPM than those fed WGM or CGM, but all remained within an appropriate range. Dry matter ATTD was lower (P < 0.05) in dogs fed CBPM or CGM than those fed DC or WGM. Crude protein ATTD was lower (P < 0.05) in dogs fed DC or CGM than those fed WGM. Dogs fed CBPM had lower (P < 0.05) organic matter, crude protein, and energy ATTD than those fed the other diets. Fecal indole was higher (P < 0.05) in dogs fed CBPM than those fed WGM. Fecal short-chain fatty acids were higher (P < 0.05) in dogs fed DC than those fed CGM. Fecal branched-chain fatty acids were higher (P < 0.05) in dogs fed DC or CBPM than those fed WGM. Fecal ammonia was higher (P < 0.05) in dogs fed DC or CBPM than those fed WGM or CGM. The relative abundances of three bacterial phyla and nine bacterial genera were shifted among treatment groups (P < 0.05). Considering AA profiles and digestibility data, the DC diet protein sources provided the highest quality protein without additional AA supplementation, but the animal-based protein diets resulted in higher fecal proteolytic metabolites. Further studies evaluating moderate dietary protein concentrations are needed to better compare plant- and animal-based protein sources.

Pet food trends are constantly changing. Because consumers are often focused on dietary proteins, with ingredient sources, dietary inclusion levels, and processing methods being important, they are a popular research topic. Protein sources contain different amino acid (AA) profiles and vary in digestibility, affecting protein quality. Our objective was to evaluate the apparent total tract digestibility of canine diets differing in protein source and test their effects on serum metabolites and fecal characteristics, metabolites, and microbiota of healthy adult dogs. Test diets were formulated to be similar nutritionally, but differed in protein source: fresh deboned, dried, and spray-dried chicken (DC), chicken by-product meal (CBPM), wheat gluten meal (WGM), and corn gluten meal (CGM). Fecal scores were higher in dogs fed chicken-based diets, but remained within an appropriate range. Dogs fed CBPM had lower nutrient and energy digestibilities than those fed the other diets, with protein digestibility also being lower in dogs fed DC or CGM than those fed WGM. Fecal metabolites and microbiota were shifted among diets, with animal-based protein diets increasing fecal protein metabolites. All diets were complete and balanced and performed well. When considering AA profiles and digestibility, however, the DC diet provided the highest protein quality.

Effects of a Saccharomyces cerevisiae fermentation product-supplemented diet on fecal characteristics, oxidative stress, and blood gene expression of adult dogs undergoing transport stress.

Previously, a Saccharomyces cerevisiae fermentation product (SCFP) was shown to positively alter fecal microbiota, fecal metabolites, oxidative stress, and circulating immune cell function of adult dogs. The objective of this study was to measure the effects of SCFP on fecal characteristics, serum oxidative stress biomarkers, and whole blood gene expression of dogs undergoing transport stress. Sixteen adult pointer dogs [8M, 8F; mean age = 6.7 ± 2.1 yr; mean body weight (BW) = 25.5 ± 3.9 kg] were used in a randomized crossover design study. All dogs were fed a control diet for 4 wk, then randomly assigned to a control or SCFP-supplemented diet (formulated to include approximately 0.13% of the active SCFP ingredient) and fed to maintain BW for 11 wk. A 6-wk washout preceded the second 11-wk experimental period with dogs receiving opposite treatments. After 11 wk, fresh fecal and blood samples were collected before and after transport in a van for 45 min. Change from baseline data (i.e., before and after transport) were analyzed using the Mixed Models procedure of SAS 9.4, with P < 0.05 being significant and P < 0.10 being trends. Change in serum malondialdehyde concentrations increased (P < 0.05) and serum 8-isoprostane concentrations tended to increase (P < 0.10) in dogs fed SCFP, but decreased (P < 0.05) in control dogs after transport. Other serum markers were unaffected by diet during transport stress. Fecal dry matter percentage tended to be affected (P < 0.10) by diet during transport stress, being reduced in control dogs, but stable in dogs fed SCFP. Other fecal characteristics were unaffected by diet during transport stress. Genes associated with activation of innate immunity were impacted by diet in response to transport stress, with blood cyclooxygenase-2 and malondialdehyde mRNA expression being increased (P < 0.05) in control dogs, but stable or decreased in dogs fed SCFP. Expression of other genes was unaffected by diet during transport stress. These data suggest that the benefits of feeding a SCFP during transport stress may be mediated through suppression of innate immune cell activation.

Saccharomyces cerevisiae fermentation product (SCFP) is a yeast product containing bioactive fermentation metabolites, residual yeast cells, and yeast cell wall fragments. In this study, SCFP was investigated for its impacts on fecal characteristics and oxidative stress of dogs undergoing transport stress. Using a randomized crossover study design, 16 adult pointer dogs were used to compare changes in fecal characteristics, oxidative stress marker concentrations, and gene expression when fed a SCFP-supplemented diet or control diet. After transport, change in serum malondialdehyde concentrations increased and serum 8-isoprostane concentrations tended to increase in dogs fed SCFP, but decreased in control dogs. Fecal moisture percentage tended to be affected by diet during transport stress, being reduced in control dogs, but stable in dogs fed SCFP. Blood cyclooxygenase-2 and myeloperoxidase mRNA gene expression was affected by diet during transport stress, being increased in control dogs, but stable or decreased in dogs fed SCFP. In conclusion, these data suggest that the benefits of feeding a SCFP during transport stress may be mitigated through suppression of innate immune cell activation rather than through suppressing oxidative damage to lipids.

Effects of a mildly cooked human-grade dog diet on gene expression, skin and coat health measures, and fecal microbiota of healthy adult dogs.

Purported benefits of human-grade pet foods include reduced inflammation, enhanced coat quality, and improved gut health, but research is scarce. Therefore, we compared gene expression, skin and coat health measures, and the fecal microbiome of dogs consuming a mildly cooked human-grade or extruded kibble diet. Twenty beagles (BW = 10.25 ± 0.82 kg; age = 3.85 ± 1.84 yr) were used in a completely randomized design. Test diets included: 1) chicken and brown rice recipe [feed-grade; extruded; blue buffalo (BB)]; and 2) chicken and white rice [human-grade; mildly cooked; Just Food for Dogs (JFFD)]. The study consisted of a 4-week baseline when all dogs ate BB, and a 12-week treatment phase when dogs were randomized to either diet (n = 10/group). After the baseline and treatment phases, fresh fecal samples were scored and collected for pH, dry matter (DM), and microbiome analysis; blood samples were collected for gene expression analysis; hair samples were microscopically imaged; and skin was analyzed for delayed-type hypersensitivity (DTH), sebum concentration, hydration status, and transepidermal water loss (TEWL). Data were analyzed as a change from baseline (CFB) using the Mixed Models procedure of SAS (version 9.4). At baseline, fecal pH was higher (P < 0.05) and hair surface score, superoxide dismutase (SOD) expression, and tumor necrosis factor-α (TNF-α) expression was lower (P < 0.05) in dogs allotted to JFFD. The decrease in CFB fecal pH and DM was greater (P < 0.05) in dogs fed JFFD, but fecal scores were not different. The increase in CFB hair surface score was higher (P < 0.05) in dogs fed JFFD. The decrease in CFB TEWL (back region) was greater (P < 0.05) in dogs fed JFFD, but TEWL (inguinal and ear regions), hydration status, and sebum concentrations in all regions were not different. Hair cortex scores and DTH responses were not affected by diet. The increase in CFB gene expression of SOD, COX-2, and TNF-α was greater (P < 0.05) in dogs fed JFFD. PCoA plots based on Bray-Curtis distances of bacterial genera and species showed small shifts over time in dogs fed BB, but dramatic shifts in those fed JFFD. JFFD increased (adj. P < 0.05) relative abundances of 4 bacterial genera, 11 bacterial species, 68 KEGG pathways, and 167 MetaCyc pathways, and decreased (adj. P < 0.05) 16 genera, 25 species, 98 KEGG pathways, and 87 MetaCyc pathways. In conclusion, the JFFD diet dramatically shifted the fecal microbiome but had minor effects on skin and coat measures and gene expression.

This study tested the effects of a mildly cooked human-grade diet and a feed-grade extruded kibble diet on the fecal microbiome, skin and coat health measures, and expression of genes related to inflammation and oxidative stress in healthy adult dogs. During a 4-week baseline, 20 beagles consumed the kibble diet. After baseline, 10 dogs continued to consume that diet, while 10 dogs consumed the mildly cooked diet for 12 weeks. After baseline and treatment phases, fresh fecal, blood, and hair samples were collected and skin was analyzed. The mildly cooked diet led to lower fecal pH and dry matter percentage, but fecal scores were not affected. The mildly cooked diet dramatically altered the fecal microbiome, shifting the relative abundances of over 30 bacterial species and 165 bacterial metabolic pathways. Measures of skin sebum content and hydration status were not different between groups, but skin water loss was lower in dogs consuming the mildly cooked diet. Baseline and post-treatment gene expression and hair surface scores were noted, but hair cortex and delayed-type hypersensitivity testing were not altered by diet. Our results demonstrate that mildly cooked diets dramatically change the fecal microbiome, but may not impact skin and coat in healthy adult dogs over a short time period.

Effects of a Saccharomyces cerevisiae fermentation product-supplemented diet on circulating immune cells and oxidative stress markers of dogs.

Feeding Saccharomyces cerevisiae fermentation product (SCFP) has previously altered fecal microbiota, fecal metabolites, and immune function of adult dogs. The objective of this study was to investigate measures of skin and coat health, changes in circulating immune cell numbers and activity, antioxidant status, and oxidative stress marker concentrations of healthy adult dogs fed a SCFP-supplemented extruded diet. Sixteen adult English Pointer dogs (8 M, 8 F; mean age = 6.7 ± 2.1 yr; mean BW = 25.9 ± 4.5 kg) were used in a randomized crossover design study. All dogs were fed a control diet for 4 wk, then randomly assigned to either the control or SCFP-supplemented diet (0.13% of active SCFP) and fed to maintain BW for 10 wk. A 6-wk washout preceded the second 10-wk experimental period with dogs receiving opposite treatments. After baseline/washout and treatment phases, skin and coat were scored, and pre and postprandial blood samples were collected. Transepidermal water loss (TEWL), hydration status, and sebum concentrations were measured (back, inguinal, ear) using external probes. Oxidative stress and immune cell function were measured by ELISA, circulating immune cell percentages were analyzed by flow cytometry, and mRNA expression of oxidative stress genes was analyzed by RT-PCR. Change from baseline data was analyzed using the Mixed Models procedure of SAS 9.4. Sebum concentration changes tended to be higher (P < 0.10; inguinal, ear) in SCFP-fed dogs than in controls. TEWL change was lower (P < 0.05) on the back of controls, but lower (P = 0.054) on the ear of SCFP-fed dogs. Delayed-type hypersensitivity response was affected by diet and time post-inoculation. Other skin and coat measures and scores were not affected by diet. Changes in unstimulated lymphocytes and stimulated IFN-γ secreting T cells were lower (P < 0.05) in SCFP-fed dogs, while changes in stimulated T cells were lower (P < 0.05) in control-fed dogs. Upon stimulation, the percentage of cytotoxic T cells delta trended lower (P < 0.10) in SCFP-fed dogs. Change in serum superoxide dismutase concentrations was higher (P < 0.05) and change in catalase mRNA expression was lower (P < 0.05) in SCFP-fed dogs. All other measurements of immune cell populations, oxidative stress markers, and gene expression were unaffected by treatment. In conclusion, our data suggest that SCFP positively impacts indicators of skin and coat health of dogs, modulates immune responses, and enhances some antioxidant defense markers.

Saccharomyces cerevisiae fermentation product (SCFP) is a yeast product containing bioactive fermentation metabolites, residual yeast cells, and yeast cell wall fragments. In this study, SCFP was investigated for its impacts on immune health, oxidative stress, and skin and hair coat health in dogs. Using a randomized crossover study design, 16 adult pointer dogs were used to compare changes in immune cell numbers and activity, antioxidant status and oxidative stress marker concentrations, and skin and coat health markers when fed a SCFP-supplemented diet or control diet. Skin sebum concentrations increased in dogs fed SCFP, but transepidermal water loss changes depended on body location (ear, inguinal, or back). Delayed-type hypersensitivity response was affected by diet and time. Changes in unstimulated lymphocytes and stimulated IFN-γ secreting T cells were lower in SCFP-fed dogs, while changes in stimulated T cells were lower in control dogs. Changes in stimulated cytotoxic T cells tended to be lower in SCFP-fed dogs. Change in serum superoxide dismutase concentrations were higher, while change in catalase mRNA expression was lower in SCFP-fed dogs. In conclusion, our data suggest that SCFP positively impacts indicators of skin and coat health of dogs, modulates immune responses, and enhances some key antioxidant defense markers.

A feasibility study to test a novel approach to dietary weight loss with a focus on assisting informed decision making in food selection.

Obesity is a significant contributor to the development of chronic diseases, some of which can be prevented or reversed by weight loss. However, dietary weight loss programs have shortcomings in the success rate, magnitude, or sustainability of weight loss. The Individualized Diet Improvement Program's (iDip) objective was to test the feasibility of a novel approach that helps individuals self-select a sustainable diet for weight loss and maintenance instead of providing weight loss products or rigid diet instructions to follow. The iDip study consisted of 22 dietary improvement sessions over 12 months with six months of follow-up. Daily weights were collected, and a chart summarizing progress was provided weekly. Six 24-hour dietary records were collected, and dietary feedback was provided in the form of a protein-fiber plot, in which protein/energy and fiber/energy of foods were plotted two-dimensionally together with a target box specific to weight loss or maintenance. An exit survey was conducted at 12 months. Twelve (nine female, 46.3±3.1 years (mean±SE)) of the initial 14 participants (BMI>28 kg/m2) completed all sessions. Mean percent weight loss (n = 12) at six and 12 months was -4.9%±1.1 (p = 0.001) and -5.4%±1.7 (p = 0.007), respectively. Weight loss varied among individuals at 12 months; top and bottom halves (n = 6 each) achieved -9.7%±1.7 (p = 0.0008) and -1.0%±1.4 weight loss, respectively. The 24-hour records showed a significant increase in protein density from baseline to final (4.1g/100kcal±0.3 vs. 5.7g/100kcal±0.5; p = 0.008). Although mean fiber density showed no significant change from the first month (1.3g/100kcal±0.1), the top half had significantly higher fiber/energy intake than the bottom half group. The survey suggested that all participants valued the program and its self-guided diet approach. In conclusion, half of the participants successfully lost >5% and maintained the lost weight for 12 months without strict diet instructions, showing the feasibility of the informed decision-making approach.

Impact of administration route on nanocarrier biodistribution in a murine colitis model.

The incidence of inflammatory bowel disease (IBD) is increasing worldwide. Although current diagnostic and disease monitoring tests for IBD sensitively detect gut inflammation, they lack the molecular and cellular specificity of positron emission tomography (PET). In this proof-of-concept study, we use a radiolabeled macrophage-targeted nanocarrier probe (64Cu-NOTA-D500) administered by oral, enema, and intraperitoneal routes to evaluate the delivery route dependence of biodistribution across healthy and diseased tissues in a murine model of dextran sodium sulfate (DSS)-induced colitis. High inter-subject variability of probe uptake in intestinal tissue was reduced by normalization to uptake in liver or total intestines. Differences in normalized uptake between healthy and DSS colitis animal intestines were highest for oral and IP routes. Differences in absolute liver uptake reflected a possible secondary diagnostic metric of IBD pathology. These results should inform the preclinical development of inflammation-targeted contrast agents for IBD and related gut disorders to improve diagnostic accuracy.

Dietary tomato inhibits angiogenesis in TRAMP prostate cancer but is not protective with a Western-style diet in this pilot study.

Prostate cancer (PCa) remains the second most diagnosed cancer worldwide. Higher body weight is associated with chronic inflammation, increased angiogenesis, and treatment-resistant tumor phenotypes. Dietary tomato reduces PCa risk, which may be due to tomato inhibition of angiogenesis and disruption of androgen signaling. This pilot study investigated the interplay between tomato powder (TP), incorporated into control (CON) and obesogenic (OB) diets, and PCa tumor growth and blood perfusion over time in a transgenic model of PCa (TRAMP). Ultrasound microvessel imaging (UMI) results showed good agreement with gold-standard immunohistochemistry quantification of endothelial cell density, indicating that this technique can be applied to non-invasively monitor tumor blood perfusion in vivo. Greater body weight was positively associated with tumor growth. We also found that TP significantly inhibited prostate tumor angiogenesis but that this inhibition differentially affected measured outcomes depending on CON or OB diets. TP led to reduced tumor growth, intratumoral inflammation, and intratumoral androgen-regulated gene expression (srd5a1, srd5a2) when incorporated with the CON diet but greater tumor growth and intratumoral gene expression when incorporated with the OB diet. Results from this study show that protective benefits from dietary tomato are lost, or may become deleterious, when combined with a Western-style diet.

Nanocarriers targeting adipose macrophages increase glucocorticoid anti-inflammatory potency to ameliorate metabolic dysfunction.

Obesity is associated with systemic inflammation due to macrophage accumulation in adipose tissue (AT). AT macrophages are, therefore, a target for therapeutics to modulate inflammation and prevent comorbidities. Because inflammatory processes have pleiotropic effects throughout the body and are intertwined with metabolic axes, systemic anti-inflammatory therapies are often harmful. We report that targeting AT macrophages using dextran nanocarriers radically alters the pharmacology of anti-inflammatory glucocorticoids, uncoupling the metabolic axis in obese mice. Following a single treatment, expression of inflammatory mediators and markers of inflammatory macrophages decreased with a nearly 20-fold higher potency compared with free drug. As a result, long-term treatment resulted in potent fat mobilization, AT reduction, weight loss, improved glucose tolerance, and altered AT gene expression profiles that led to elevated liver stress. Two weeks after treatment ceased, gene expression of inflammatory mediators in AT remained lower than obese controls, while gene expression related to metabolic function improved. These data demonstrate that nanocarriers show potential for amelioration of obesity-related AT inflammation and metabolic dysfunction, highlighting an important opportunity for nanomedicine to impact chronic metabolic disorders with complex and poorly understood etiology.

Dietary Tomato or Lycopene Do Not Reduce Castration-Resistant Prostate Cancer Progression in a Murine Model.

BACKGROUND: Dietary tomato products or lycopene protect against prostate carcinogenesis, but their impact on the emergence of castration-resistant prostate cancer (CRPC) is unknown. OBJECTIVE: We hypothesized that tomato or lycopene products would reduce the emergence of CRPC. METHODS: Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were castrated at 12-13 wk and the emergence of CRPC was monitored by ultrasound in each study. In Study 1, TRAMP mice (n = 80) were weaned onto an AIN-93G-based control diet (Con-L, n = 28), a 10% tomato powder diet (TP-L, 10% lyophilized w/w, n = 26), or a control diet followed by a tomato powder diet after castration (TP-Int1, n = 26). In Study 2, TRAMP mice (n = 85) were randomized onto a control diet with placebo beadlets (Con-Int, n = 29), a tomato diet with placebo beadlets (TP-Int2, n = 29), or a control diet with lycopene beadlets (Lyc-Int, n = 27) following castration (aged 12 wk). Tumor incidence and growth were monitored by ultrasound beginning at an age of 10 wk. Mice were euthanized 4 wk after tumor detection or aged 30 wk if no tumor was detected. Tissue weights were compared by ANOVA followed by Dunnett's test. Tumor volumes were compared using generalized linear mixed model regression. RESULTS: Ultrasound estimates for the in vivo tumor volume were strongly correlated with tumor weight at necropsy (R2 = 0.75 and 0.94, P <0.001 for both Studies 1 and 2, respectively). Dietary treatments after castration did not significantly impact cancer incidence, time to tumor detection, or final tumor weight. CONCLUSIONS: In contrast to studies of de novo carcinogenesis in multiple preclinical models, tomato components had no significant impact on the emergence of CRPC in the TRAMP model. It is possible that specific mutant subclones of prostate cancer may continue to show some antiproliferative response to tomato components, but further studies are needed to confirm this.

Low fat but not soy protein isolate was an effective intervention to reduce nonalcoholic fatty liver disease progression in C57BL/6J mice: monitored by a novel quantitative ultrasound (QUS) method.

Untreated nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) lead to irreversible liver damage. We hypothesized that a low-fat diet (LFD) or a high-fat diet (HFD) with soy protein isolate (SPI) would be an effective intervention to halt or reverse NAFLD progression. To test these hypotheses, we conducted 2 studies. In the first study, we fed an HFD to 7-week-old C57BL/6J mice to induce NAFLD compared to an LFD (control). Hepatic steatosis was monitored by quantitative ultrasound (QUS) scans (in vivo and ex vivo). Animals were euthanized after 0, 2, 4, and 6 weeks of feeding. In the second study, 7-week-old mice were randomized onto an LFD or HFD with SPI intervention after 4 weeks of feeding HFD. Animals from each group were scanned with QUS and euthanized after 4, 9, and 12 weeks of feeding. Animals fed the HFD developed NAFLD (100%) and NASH (80%) characterized by increased liver weight, lipid accumulation, and histological scores for inflammation by 4 weeks in the first study. In the second study, the LFD ameliorated this NAFLD phenotype after 5 weeks of feeding; however, the SPI intervention failed to significantly attenuate NAFLD. QUS parameters were significantly increased with the HFDs (P < .05) and steatosis grade (P < .05) and were positively correlated with hepatic lipid concentrations. In conclusion, dietary modification may be effective at reversing NAFLD and NASH at early stages. Furthermore, QUS may become a valuable tool to track hepatic steatosis. Additional studies are needed to further evaluate the effectiveness of these interventions.

Can Lycopene Impact the Androgen Axis in Prostate Cancer?: A Systematic Review of Cell Culture and Animal Studies.

First-line therapy for advanced or metastatic prostate cancer (PCa) involves the removal of tumor-promoting androgens by androgen deprivation therapy (ADT), resulting in transient tumor regression. Recurrent disease is attributed to tumor adaptation to survive, despite lower circulating androgen concentrations, making the blockage of downstream androgen signaling a chemotherapeutic goal for PCa. Dietary intake of tomato and its predominant carotenoid, lycopene, reduce the risk for PCa, and preclinical studies have shown promising results that tomato and lycopene can inhibit androgen signaling in normal prostate tissue. The goal of this systematic review was to evaluate whether mechanistic evidence exists to support the hypothesis that tomato or lycopene interact with the androgen axis in PCa. Eighteen studies (n = 5 in vivo; n = 13 in vitro) were included in the final review. A formal meta-analysis was not feasible due to variability of the data; however, the overall estimated directions of effect for the compared studies were visually represented by albatross plots. All studies demonstrated either null or, more commonly, inhibitory effects of tomato or lycopene treatment on androgen-related outcomes. Strong mechanistic evidence was unable to be ascertained, but tomato and lycopene treatment appears to down-regulate androgen metabolism and signaling in PCa.

Processed and raw tomato consumption and risk of prostate cancer: a systematic review and dose-response meta-analysis.

BACKGROUND: Prostate cancer (PCa) is the second most frequently diagnosed cancer among men worldwide. Many epidemiological studies have found an inverse association between increased tomato consumption and PCa risk. This study aims to determine the associations between consumption of various types of tomato products and PCa risk and to investigate potential dose-response relationships. METHODS: We conducted a systematic review and dose-response meta-analysis of dietary tomato in relation to PCa. Eligible studies were published before April 10, 2017 and were identified from PubMed, Web of Science, and the Cochrane Library. We estimated pooled risk ratios (RRs) and 95% confidence intervals (CI) using random and fixed effects models. Linear and nonlinear dose-response relationships were also evaluated for PCa risk. RESULTS: Thirty studies related to tomato consumption and PCa risk were included in the meta-analysis, which summarized data from 24,222 cases and 260,461 participants. Higher total tomato consumption was associated with a reduced risk of PCa (RR = 0.81, 95% CI: 0.71-0.92, p = 0.001). Specifically, tomato foods (RR = 0.84, 95% CI: 0.72-0.98, p = 0.030) and cooked tomatoes and sauces (RR = 0.84, 95% CI: 0.73-0.98, p = 0.029) were associated with a reduced risk of PCa. However, no associations were found for raw tomatoes (RR = 0.96, 95% CI: 0.84-1.09, p = 0.487). There was a significant dose-response association observed for total tomato consumption (p = 0.040), cooked tomatoes and sauces (p < 0.001), and raw tomatoes (p = 0.037), but there was not a significant association with tomato foods (plinear = 0.511, pnonlinear = 0.289). CONCLUSIONS: Our data demonstrate that increased tomato consumption is inversely associated with PCa risk. These findings were accompanied with dose-response relationships for total tomato consumption and for cooked tomatoes and sauces. Further studies are required to determine the underlying mechanisms of these associations.

Soy Consumption and the Risk of Prostate Cancer: An Updated Systematic Review and Meta-Analysis.

Prostate cancer (PCa) is the second most commonly diagnosed cancer in men, accounting for 15% of all cancers in men worldwide. Asian populations consume soy foods as part of a regular diet, which may contribute to the lower PCa incidence observed in these countries. This meta-analysis provides a comprehensive updated analysis that builds on previously published meta-analyses, demonstrating that soy foods and their isoflavones (genistein and daidzein) are associated with a lower risk of prostate carcinogenesis. Thirty articles were included for analysis of the potential impacts of soy food intake, isoflavone intake, and circulating isoflavone levels, on both primary and advanced PCa. Total soy food (p < 0.001), genistein (p = 0.008), daidzein (p = 0.018), and unfermented soy food (p < 0.001) intakes were significantly associated with a reduced risk of PCa. Fermented soy food intake, total isoflavone intake, and circulating isoflavones were not associated with PCa risk. Neither soy food intake nor circulating isoflavones were associated with advanced PCa risk, although very few studies currently exist to examine potential associations. Combined, this evidence from observational studies shows a statistically significant association between soy consumption and decreased PCa risk. Further studies are required to support soy consumption as a prophylactic dietary approach to reduce PCa carcinogenesis.

Role of retinoids in the prevention and treatment of colorectal cancer.

Vitamin A and its derivatives, retinoids, have been widely studied for their use as cancer chemotherapeutic agents. With respect to colorectal cancer (CRC), several critical mutations dysregulate pathways implicated in progression and metastasis, resulting in aberrant Wnt/ß-catenin signaling, gain-of-function mutations in K-ras and phosphatidylinositol-3-kinase/Akt, cyclooxygenase-2 over-expression, reduction of peroxisome proliferator-activated receptor γ activation, and loss of p53 function. Dysregulation leads to increased cellular proliferation and invasion and decreased cell-cell interaction and differentiation. Retinoids affect these pathways by various mechanisms, many involving retinoic acid receptors (RAR). RAR bind to all-trans-retinoic acid (ATRA) to induce the transcription of genes responsible for cellular differentiation. Although most research concerning the chemotherapeutic efficacy of retinoids focuses on the ability of ATRA to decrease cancer cell proliferation, increase differentiation, or promote apoptosis; as CRC progresses, RAR expression is often lost, rendering treatment of CRCs with ATRA ineffective. Our laboratory focuses on the ability of dietary vitamin A to decrease CRC cell proliferation and invasion via RAR-independent pathways. This review discusses our research and others concerning the ability of retinoids to ameliorate the defective signaling pathways listed above and decrease tumor cell proliferation and invasion through both RAR-dependent and RAR-independent mechanisms.