Berry consumption mitigates the hypertensive effects of a high-fat, high-sucrose diet via attenuation of renal and aortic AT1R expression resulting in improved endothelium-derived NO bioavailability.

Dysregulation of the renin-angiotensin system (RAS) is a contributor to high-fat diet-related blood pressure (BP) increases. Deleterious effects of dysregulated RAS result in an overproduction of reactive oxygen species and a decrease in endothelial nitric oxide (NO) bioavailability due to increased NADPH oxidase (NOX) expression. Dietary polyphenols have been shown to mitigate the imbalance in the redox state and protect against endothelial dysfunction induced by a high-fat diet. Thus, we aim to determine whether polyphenol-rich blackberry and raspberry, alone and in combination, attenuate the detrimental effects of a high-fat, high-sucrose (HFHS) diet on the vascular endothelium and kidneys of mice. We show that a HFHS diet increased the expression of renal and aortic angiotensin type 1 receptor (AT1R). Further, NOX1 and NOX4 expression were increased in the kidney contributing to fibrotic damage. In human aortic endothelial cells (HAECs), palmitic acid increased the expression of NOX4, potentially driving oxidative damage in the aorta, as evidenced by increased nitrotyrosine expression. Berries reduced the expression of renal and aortic AT1R, leading to a subsequent decrease in renal NOX expression and reduced aortic oxidative stress evidenced by reduced nitrotyrosine expression. Blackberry and raspberry in combination increased the expression of NRF2 and its downstream proteins in HAECs, thereby reducing the oxidative burden to the endothelium. In combination, blackberry and raspberry also increased serum levels of NO metabolites. These findings indicate that blackberry and raspberry unique polyphenols may act synergistically to favorably modulate the abovementioned pathways and attenuate HFHS diet-induced increases in BP.

Raspberry and blackberry act in a synergistic manner to improve cardiac redox proteins and reduce NF-κB and SAPK/JNK in mice fed a high-fat, high-sucrose diet.

BACKGROUND AND AIMS: Increased cardiac inflammation and oxidative stress are common features in obesity, and toll-like receptor (TLR)4 signaling is a key inflammatory pathway in this deleterious process. This study aimed to investigate whether berries could attenuate the detrimental effects of a high-fat, high-sucrose (HFHS) diet on the myocardium at the molecular level. METHODS AND RESULTS: Eight-week-old male C57BL/6 mice consumed a low-fat, low-sucrose (LFLS) diet alone or supplemented with 10% blackberry (BL), 10% raspberry (RB) or 10% blackberry + raspberry (BL + RB) for four weeks. Animals were then switched to a HFHS diet for 24 weeks with or without berry supplementation or maintained on a LFLS control diet without berry supplementation. Left ventricles of the heart were isolated for protein and mRNA analysis. Berry consumption, particularly BL + RB reduced NADPH-oxidase (NOX)1 and NOX2 and increased catalase (CAT) and superoxide dismutase (SOD)2, expression while BL and RB supplementation alone was less efficacious. Downstream TLR4 signaling was attenuated mostly by both RB and BL + RB supplementation, while NF-κB pathway was attenuated by BL + RB supplementation. Stress-activated protein kinase (SAPK)/Jun amino-terminal kinase (JNK) was also attenuated by BL + RB supplementation, and reduced TNF-α transcription and protein expression was observed only with BL + RB supplementation. CONCLUSION: The synergistic effects of BL + RB may reduce obesity-induced cardiac inflammation and oxidative stress to a greater extent than BL or RB alone.

Temporal Patterns of Novel Circulating Biomarkers in IL-2-mediated Vascular Injury in the Rat.

Recombinant interleukin-2 (rIL-2) administration in oncology indications is hampered by vascular toxicity, which presents as a vascular leak syndrome. We used this aspect of the toxicity of rIL-2 to evaluate candidate biomarkers of drug-induced vascular injury (DIVI) in rats given 0.36 mg/kg rIL-2 daily. Groups of rats were given either 2 or 5 doses of rIL-2 or 5 doses of rIL-2 followed by a 7-day recovery. The histomorphologic lexicon and grading scheme developed by the Vascular Injury Working Group of the Predictive Safety Testing Consortium of the Critical Path Institute were utilized to enable semiquantitative integration with circulating biomarker levels. The administration of rIL-2 was associated with time-dependent endothelial cell hyperplasia and hypertrophy and perivascular inflammation that correlated with increases in circulating angiopoietin-2, lipocalin-2, monocyte chemotactic protein-1, tissue inhibitor of metalloproteinase-1, vascular endothelial growth factor A, E-selectin, and chemokine (C-X-C motif) ligand-1, and the microRNAs miR-21, miR-132, and miR-155. The dose groups were differentially identified by panels comprising novel candidate biomarkers and traditional hematologic parameters. These results identify biomarkers of the early stages of DIVI prior to the onset of vascular smooth muscle necrosis.