MSC therapy in livestock models.

Mesenchymal stem cells (MSCs) have great value as therapeutic tools in a wide array of applications in regenerative medicine. The wide repertoire of cell functions regarding tissue regeneration, immunomodulation, and antimicrobial activity makes MSC-based therapy a strong candidate for treatment options in a variety of clinical conditions and should be studied to expand the current breadth of knowledge surrounding their physiological properties and therapeutic benefits. Livestock models are an appropriate resource for testing the efficacy of MSC therapies for their use in biomedical research and can be used to improve both human health and animal agriculture. Agricultural animal models such as pigs, cattle, sheep, and goats have grown in popularity for in vivo research relative to small animal models due to their overlapping similarities in structure and function that more closely mimic the human body. Cutaneous wound healing, bone regeneration, osteoarthritis, ischemic reperfusion injury, and mastitis recovery represent a few examples of the types of disease states that may be investigated in livestock using MSC-based therapy. Although the cost of agricultural animals is greater than small animal models, the information gained using livestock as a model holds great value for human applications, and in some cases, outcompetes the weight of information gained from rodent models. With emerging fields such as exosome-based therapy, proper in vivo models will be needed for testing efficacy and translational practice, i.e., livestock models should be strongly considered as candidates. The potential for capitalizing on areas that have crossover benefits for both agricultural economic gain and improved health of the animals while minimizing the gap between translational research and clinical practice are what make livestock great choices for experimental MSC models.

Astaxanthin inhibits inflammation and fibrosis in the liver and adipose tissue of mouse models of diet-induced obesity and nonalcoholic steatohepatitis.

The objective of this study was to determine if astaxanthin (ASTX), a xanthophyll carotenoid, can prevent obesity-associated metabolic abnormalities, inflammation and fibrosis in diet-induced obesity (DIO) and nonalcoholic steatohepatitis (NASH) mouse models. Male C57BL/6J mice were fed a low-fat (6% fat, w/w), a high-fat/high-sucrose control (HF/HS; 35% fat, 35% sucrose, w/w), or a HF/HS containing ASTX (AHF/HS; 0.03% ASTX, w/w) for 30 weeks. To induce NASH, another set of mice was fed a HF/HS diet containing 2% cholesterol (HF/HS/HC) a HF/HS/HC with 0.015% ASTX (AHF/HS/HC) for 18 weeks. Compared to LF, HF/HS significantly increased plasma total cholesterol, triglyceride and glucose, which were lowered by ASTX. ASTX decreased hepatic mRNA levels of markers of macrophages and fibrosis in both models. The effect of ASTX was more prominent in NASH than DIO mice. In epididymal fat, ASTX also decreased macrophage infiltration and M1 macrophage marker expression, and inhibited hypoxia-inducible factor 1-α and its downstream fibrogenic genes in both mouse models. ASTX significantly decreased tumor necrosis factor α mRNA in the splenocytes from DIO mice upon lipopolysaccharides stimulation compared with those from control mice fed an HF/HS diet. Additionally, ASTX significantly elevated the levels of genes that regulate fatty acid ß-oxidation and mitochondrial biogenesis in the skeletal muscle compared with control obese mice, whereas no differences were noted in adipose lipogenic genes. Our results indicate that ASTX inhibits inflammation and fibrosis in the liver and adipose tissue and enhances the skeletal muscle's capacity for mitochondrial fatty acid oxidation in obese mice.

Polyphenol-rich blackcurrant extract exerts hypocholesterolaemic and hypoglycaemic effects in mice fed a diet containing high fat and cholesterol.

Obesity is associated with an increased risk of metabolic abnormalities, such as hyperlipidaemia and hyperglycaemia. We investigated whether polyphenol-rich blackcurrant extract (BCE) can prevent high fat/high cholesterol (HF/HC) diet-induced metabolic disturbances in mice. Male C57BL/6J mice were fed a modified AIN-93M diet containing HF/HC (16% fat, 0·25% cholesterol, w/w) or the same diet supplemented with 0·1% BCE (w/w) for 12 weeks. There were no differences in total body weight and liver weight between groups. Plasma total cholesterol (TC) and glucose levels were significantly lower in BCE group than in controls, while plasma TAG levels were not significantly different. There was a decreasing trend in hepatic TAG levels, and histological evaluation of steatosis grade was markedly lower in the livers of mice fed BCE. Although the mRNA levels of major regulators of hepatic cholesterol metabolism, i.e. 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR) and LDL receptor (LDLR), were not significantly altered by BCE supplementation, protein expression of mature sterol-regulatory element-binding protein and LDLR was significantly increased with no change in HMGR protein. The expression of proprotein convertase subtilisin/kexin type 9 that facilitates LDLR protein degradation, as well as one of its transcriptional regulators, i.e. hepatocyte nuclear factor 4α, was significantly decreased in the livers of mice fed BCE. Taken together, BCE supplementation decreased plasma TC and glucose, and inhibited liver steatosis, suggesting that this berry may be consumed to prevent metabolic dysfunctions induced by diets high in fat and cholesterol.

Polyphenol-rich blackcurrant extract prevents inflammation in diet-induced obese mice.

Obesity is closely associated with chronic, low-grade inflammation. We investigated if polyphenol-rich blackcurrant extract (BCE) can prevent inflammation in vivo. Male C57BL/6J mice were fed a modified AIN-93M control diet containing high fat/high cholesterol (16% fat, 0.25% cholesterol by weight) or the control diet supplemented with 0.1% BCE (wt/wt) for 12 weeks. In BCE-fed mice, the percentage of body weight and adipocyte size of the epididymal fat were significantly lower than those of control mice. There were fewer crown-like structures (CLS) with concomitant decreases in F4/80, cluster of differentiation 68 and inhibitor of nuclear factor κB kinase ε (IKKε) mRNA in the epididymal adipose of BCE-fed mice. F4/80 and IKKε mRNA levels were positively correlated with CLS number. In the skeletal muscle of mice fed with BCE, mRNA expression of genes involved in energy expenditure and mitochondrial biogenesis, including PPARα, PPARδ, UCP-2, UCP-3 and mitochondrial transcription factor A, were significantly increased. When splenocytes from BCE-fed mice were stimulated by lipopolysaccharides, tumor necrosis factor α and interleukin-1ß mRNA were significantly lower than control splenocytes. Together, the results suggest that BCE supplementation decreases obesity-induced inflammation in adipose tissue and splenocytes, at least in part, by modulating energy metabolism in skeletal muscle.