Effects of Hesperidin Consumption on the Cardiovascular System in Pre- and Stage 1 Hypertensive Subjects: Targeted and Non-Targeted Metabolomic Approaches (CITRUS Study).

SCOPE: The aim of the present work is to determine new biomarkers of the biological effects of hesperidin in orange juice (OJ) applying a non-targeted metabolomics approach validated by targeted metabolomics analyses of compliance biomarkers. METHODS AND RESULTS: Plasma/serum and urine targeted (HPLC-MS/MS) and untargeted (1 H-NMR) metabolomics signatures are explored in a subsample with pre- and stage-1 hypertension subjects of the CITRUS study (N = 159). Volunteers received 500 mL day-1 of control drink, OJ, or hesperidin-enriched OJ (EOJ) for 12-weeks. A 6-h postprandrial study is performed at baseline. Targeted analyses reveals plasma and urine hesperetin 7-O-ß-d-glucuronide as the only metabolite differing between OJ and EOJ groups after 12-weeks consumption, and in urine is correlated with a decreased systolic blood pressure level. The non-targeted approach shows that after single dose and 12-weeks consumption of OJ and EOJ change several metabolites related with an anti-inflammatory and antioxidant actions, lower blood pressure levels and uremic toxins. CONCLUSIONS: Hesperetin 7-O-ß-d-glucuronide can be a candidate marker for distinguishing between the consumption of different hesperidin doses at 12-weeks consumption as well as a potential agent mediating blood pressure reduction. Moreover, changes in different endogenous metabolites can explain the mechanisms of action and the biological effects of hesperidin consumption.

Effects of hesperidin consumption on cardiovascular risk biomarkers: a systematic review of animal studies and human randomized clinical trials.

CONTEXT: The cardioprotective effects of the flavonoid hesperidin, which is present in citrus products, are controversial and unclear. This systematic review was conducted in accordance with the PRISMA 2015 guidelines. OBJECTIVE: To evaluate the current evidence from animal and human clinical studies and thus determine whether the consumption of hesperidin exerts beneficial effects on cardiovascular risk factors. DATA SOURCES: PICOS (Population, Intervention, Comparison, Outcome, and Study Design) criteria defined the research question. Searches of the PubMed and Cochrane Plus databases were conducted and studies that met the inclusion criteria and were published in English in the last 15 years were included. DATA EXTRACTION: The first author, year of publication, study design, characteristics of animals and humans, intervention groups, dose of hesperidin, route of administration, duration of the intervention, cardiovascular risk biomarkers assessed, and results observed were extracted from the included articles. RESULTS: A total of 12 animal studies and 11 randomized clinical trials met the inclusion criteria. In the animal studies, the glucose, total and LDL cholesterol, and triglyceride levels decreased with chronic flavonoid consumption. In the human studies, endothelial function improved with flavonoid consumption, whereas no conclusive results were observed for the other biomarkers. CONCLUSIONS: Animal studies have revealed that hesperidin and hesperetin consumption reduces glucose levels and various lipid profile parameters. However, a definitive conclusion cannot be drawn from the existing human clinical trials. Further research is needed to confirm whether the findings observed in animal models can also be observed in humans. SYSTEMATIC REVIEW REGISTRATION: Prospero registration number CRD42018088942.