Perigestational high folic acid: impact on offspring's peripheral metabolic response.

Offspring of dams exposed to excess folic acid during the perigestational period have been shown by us to be predisposed to metabolic dysfunction revealed by hyperglycemia, glucose intolerance, increased insulin and decreased adiponectin in late adulthood. This work aims to characterize adipocyte phenotype and expression profile of genes in the regulation of lipid and glucose metabolism in visceral adipose tissue and in skeletal muscle. From mating until weaning, a recommended dose of folic acid for pregnancy (C, 2 mg of folic acid per kg of diet) or a high folic acid dose (HFA, 40 mg of folic acid per kg of diet) was administered to Sprague-Dawley females. At 10 months of age progeny were divided into groups fed the standard chow (C/STD and HFA/STD) and groups fed the standard chow plus drinking water with 10% fructose (C/FRU and HFA/FRU), as an additional metabolic challenge. Adipocyte morphology and quantification of key genes involved in lipid and glucose metabolism were studied in visceral adipose tissue and skeletal muscle of 13 months old offspring. HFA exposure led to an enlargement of visceral adipose cells most likely mediated by an upregulation of lipoprotein lipase, and it tended to downregulate Glut4 in visceral adipose tissue and skeletal muscle. Fructose exposure in a background of perigestational excess folic acid, but not in controls, induced an upregulation of lipogenesis pathway genes and it decreased jejunal expression of the proton-coupled folate transporter (Pcft1). In addition, fructose exposure led to a downregulation of jejunal Sglt1 in control animals. Our data suggest that high folic acid exposure during the perigestational period caused morphologic and genic alterations related to insulin resistant states indicating that this intervention may act as an effective programmer of long-term metabolic dysfunction.

Isoxanthohumol modulates angiogenesis and inflammation via vascular endothelial growth factor receptor, tumor necrosis factor alpha and nuclear factor kappa B pathways.

Angiogenesis and inflammation are becoming distinguished players in the pathogenesis of many heterogeneous diseases, such as diabetes, cardiovascular disease, and cancer. Therefore, it is crucial to study new compounds that are able to modulate these events. Isoxanthohumol (IXN) is a polyphenol with antioxidant, anti-inflammatory, and antiangiogenic properties. The aim of this study was to evaluate the effects of IXN on blood vessel proliferation and maturation and describe underlying molecular mechanisms in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). Angiogenic profile of IXN was analyzed by retinal angiogenesis at different time points. IXN modulation of angiogenic and inflammatory signaling pathways was evaluated by Western blotting on EC and VSMC cultures. IXN inhibited by 20% sprouting angiogenesis and decreased vascular coverage by mural cells up to 39%. IXN of 10 µM also decreased inflammatory signals, namely tumor necrosis factor alpha (TNF-α) (26 and 40%) and factor nuclear kappa B (24 and 42%) in human aortic smooth muscle cells (HASMCs) and human umbilical vein endothelial cells (HUVECs). Angiogenic regulators, including vascular endothelial growth factor receptor 2 (HUVEC, 55%), angiopoietins 1 (HUVEC, 39%; HASMC, 35%), angiopoietin 2 (HUVEC, 38%), and Tie2 (HUVEC, 56%) were also inhibited by 10 µM of IXN treatments. Akt activation was reduced by 47% in HUVEC-treated cells and Erk activation was also reduced by 52 and 69% upon IXN treatment of HUVEC and HASMC. IXN seems to regulate in vivo vascular proliferation and stabilization and the EC-VSMC-inflammatory crosstalk, leaving this molecule as an interesting nutritional player for angiogenesis and inflammation-related diseases.

Xanthohumol-supplemented beer modulates angiogenesis and inflammation in a skin wound healing model. Involvement of local adipocytes.

Angiogenesis and inflammation are two intermingled processes that play a role in wound healing. Nevertheless, whenever exacerbated, these processes result in nonhealing wounds. Xanthohumol (XN), a beer-derived polyphenol, inhibits these processes in many physiopathological situations. This study aimed at examining whether XN ingestion affects wound healing. Wistar rats drinking water, 5% ethanol, stout beer (SB) or stout beer supplemented with 10 mg/L XN (Suppl SB) for 4 weeks, were subjected to a 1.5 cm full skin-thickness longitudinal incision, and further maintained under the same beverage conditions for another week. No differences in beverage consumption or body weight were found throughout the study but food intake decreased in every group relative to controls. Consumption of Suppl SB resulted in decreased serum VEGF levels (18.42%), N-acetylglucosaminidase activity (27.77%), IL1ß concentration (9.07%), and NO released (77.06%), accompanied by a reduced redox state as observed by increased GSH/GSSG ratio (to 198.80%). Also, the number of blood vessels within the wound granulation tissue seems to reduce in animals drinking Suppl SB (23.08%). Interestingly, SB and primarily Suppl SB showed a tendency to increase adipocyte number (to 194.26% and 156.68%, respectively) and reduce adipocyte size (4.60% and 24.64%, respectively) within the granuloma. Liver function and metabolism did not change among the animal groups as analyzed by plasma biochemical parameters, indicating no beverage toxicity. This study shows that XN intake in its natural beer context reduced inflammation, oxidative stress, and angiogenesis, ameliorating the wound healing process, suggesting that this polyphenol may exert beneficial effect as a nutritional supplement.