An Evaluation of Zebrafish, an Emerging Model Analyzing the Effects of Toxicants on Cognitive and Neuromuscular Function.

An emerging alternative to conventional animal models in toxicology research is the zebrafish. Their accelerated development, regenerative capacity, transparent physical appearance, ability to be genetically manipulated, and ease of housing and care make them feasible and efficient experimental models. Nonetheless, their most esteemed asset is their 70% (+) genetic similarity with the human genome, which allows the model to be used in a variety of clinically relevant studies. With these attributes, we propose the zebrafish is an excellent model for analyzing cognitive and neuromuscular responses when exposed to toxicants. Neurocognition can be readily analyzed using visual discrimination, memory and learning, and social behavior testing. Neuromuscular function can be analyzed using techniques such as the startle response, assessment of activity level, and evaluation of critical swimming speed. Furthermore, selectively mutated zebrafish is another novel application of this species in behavioral and pharmacological studies, which can be exploited in toxicological studies. There is a critical need in biomedical research to discover ethical and cost-effective methods to develop new products, including drugs. Through mutagenesis, zebrafish models have become key in meeting this need by advancing the field in numerous areas of biomedical research.

Synergistic effects of exercise and catalase overexpression on gut microbiome.

Exercise influences metabolic parameters in part by modulating redox stress and as recently suggested, by affecting the gut microbiome. However, whether excess endogenous antioxidant potentiates or interferes with the beneficial effects of exercise on the gut microbiome is not known. A comparison of the gut microbiome of C57Bl6 (C57/WT) mice to the 'stress-less' catalase overexpressing mice models ([Tg(CAT)± ] and Bob-Cat), that were either exercised or remained sedentary, showed differences in both alpha and beta diversity. The significant variation was explained by genotypes along with exercise, suggesting a synergistic relationship between exercise and genotypic traits. Linear discriminant analysis effect size (LEfSe) analysis also revealed differential taxa within the exercised/genotype cohorts in contrast to those within sedentary/genotype cohorts. Functional pathway predictions from PICRUSt2 showed enrichment for the metabolism of short-chain fatty acids, butanoate and propanoate pathways in exercised groups. Spearman correlations between enriched taxa and metabolic parameters showed correlations with body or fat weight in some of the cohorts. However, there were significant correlations of differential taxa among all cohorts against parameters that predict energy metabolism, such as respiratory exchange ratio and energy expenditure. Overall, our study showed that there was a synergistic beneficial influence of antioxidant overexpression and exercise on the gut microbiome.

Catalase overexpression modulates metabolic parameters in a new 'stress-less' leptin-deficient mouse model.

Oxidative stress plays a key role in obesity by modifying the function of important biological molecules, thus altering obesogenic pathways such as glucose and lipid signaling. Catalase, is an important endogenous antioxidant enzyme that catabolizes hydrogen peroxide produced by the dismutation of superoxide. Recent studies have shown knockdown of catalase exacerbates insulin resistance and leads to obesity. We hypothesized that overexpressing catalase in an obese mouse will modulate obesogenic pathways and protect against obesity. Therefore, we bred catalase transgenic ([Tg(CAT)+/-] mice with Ob/Ob mice to generate the hybrid "Bob-Cat" mice. This newly generated "stress-less" mouse model had decreased oxidative stress (oxidized carbonylated proteins). ECHO-MRI showed lower fat mass but higher lean mass in "Bob-Cat" mice. Comprehensive Lab Animal Monitoring System (CLAMS) showed light and dark cycle increase in energy expenditure in Bob-Cat mice compared to wild type controls. Circulating levels of leptin and resistin showed no change. Catalase mRNA expression was increased in key metabolic tissues (adipose, liver, intestinal mucosa, and brain) of the Bob-Cat mice. Catalase activity, mRNA and protein expression was increased in adipose tissue. Expression of the major adipokines leptin and adiponectin was increased while pro-inflammatory genes, MCP-1/JE and IL-1ß were lowered. Interestingly, sexual dimorphism was seen in body composition, energy expenditure, and metabolic parameters in the Bob-Cat mice. Overall, the characteristics of the newly generated "Bob-Cat" mice make it an ideal model for studying the effect of redox modulators (diet/exercise) in obesity.

Omega 3 rich diet modulates energy metabolism via GPR120-Nrf2 crosstalk in a novel antioxidant mouse model.

With obesity rates reaching epidemic proportions, more studies concentrated on reducing the risk and treating this epidemic are vital. Redox stress is an important metabolic regulator involved in the pathophysiology of cardiovascular disease, Type 2 diabetes, and obesity. Oxygen and nitrogen-derived free radicals alter glucose and lipid homeostasis in key metabolic tissues, leading to increases in risk of developing metabolic syndrome. Oxidants derived from dietary fat differ in their metabolic regulation, with numerous studies showing benefits from a high omega 3 rich diet compared to the frequently consumed "western diet" rich in saturated fat. Omega 3 (OM3) fatty acids improve lipid profile, lower inflammation, and ameliorate insulin resistance, possibly through maintaining redox homeostasis. This study is based on the hypothesis that altering endogenous antioxidant production and/or increasing OM3 rich diet consumption will improve energy metabolism and maintain insulin sensitivity. We tested the comparative metabolic effects of a diet rich in saturated fat (HFD) and an omega 3-enriched diet (OM3) in the newly developed 'stress-less' mice model that overexpresses the endogenous antioxidant catalase. Eight weeks of dietary intervention showed that mice overexpressing endogenous catalase compared to their wild-type controls when fed an OM3 enriched diet, in contrast to HFD, activated GPR120-Nrf2 cross-talk to maintain balanced energy metabolism, normal circadian rhythm, and insulin sensitivity. These findings suggest that redox regulation of GPR120/FFAR4 might be an important target in reducing risk of metabolic syndrome and associated diseases.

Copper-catalyzed synthesis of enantioenriched tetraarylethanes.

Herein we report the asymmetric synthesis of 1,2-dipyridyl-1,2-diarylethanes via an unusual Cu(I)-catalyzed dimerization reaction. Subjection of a variety of enantioenriched substituted 2-pyridyl alcohols to a one-pot protocol generates the desired products in good yields and diastereoselectivities and with ee's up to >99%.

Mitochondrial redox status as a target for cardiovascular disease.

Mitochondria are major players in cellular energetics, oxidative stress and programmed cell death. Mitochondrial dynamics regulate and integrate these functions. Mitochondrial dysfunction is involved in cardiac hypertrophy, hypertension and myocardial ischemia/reperfusion injury. Reactive oxygen species generation is modulated by the fusion-fission pathway as well as key proteins such as sirtuins that act as metabolic sensors of cellular energetics. Mitochondrial redox status has thus become a good target for therapy against cardiovascular diseases. Recently, there is an influx of studies garnered towards assessing the beneficial effects of mitochondrial targeted antioxidants, drugs modulating the fusion-fission proteins, sirtuins, and other mitochondrial processes as potential cardio-protecting agents.