Phenylketonuria and type 1 diabetes: a clinical and nutritional challenge in a young adult-a case report.

Cardiovascular diseases (CVDs) remain a leading cause of global morbidity and mortality. Hypertension, a major risk factor for CVDs, is characterized by persistently elevated blood pressure exceeding 140/90 mmHg. Although the etiology of hypertension is not entirely elucidated, the renin-angiotensin system (RAS) is recognized as a central regulator of blood pressure []. In the RAS, angiotensin-converting enzyme (ACE) converts angiotensin I to the vasoconstrictor angiotensin II (Ang II), while ACE2 counterbalances this effect by converting Ang II to the vasodilator Angiotensin (1–7) (Ang (1–7)) [,]. Inhibition of ACE is the classical strategy in lowering blood pressure, and in recent years, many food-derived ACE inhibitory (ACEi) bioactive peptides have been discovered []. For example, the peptide IRW, derived from egg white protein, shows strong ACEi activity and effectively lowers blood pressure in SHRs, though not directly by inhibiting ACE [,]. Subsequent studies reveal a distinct mechanism by which IRW lowers blood pressure via upregulation of ACE2 []. This discovery makes IRW the first food-derived peptide that reduce blood pressure through increasing ACE2 activity, in contrast to most peptides primarily through ACE inhibition []. Like many bioactive food compounds, peptides are susceptible to degradation and metabolism during absorption and circulation []. IRW has a bioavailability of 11.7 %, suggesting that most of it is likely not absorbed or is degraded. The time to reach the maximum concentration of IRW was about 17 min, with a significant blood pressure lowering activity being observed much later at around 1.5 h in the gavage group []. The lag between reaching the maximum concentration of IRW and the time it takes to reduce blood pressure suggests that metabolites of IRW, rather than the intact peptide, are responsible for the blood pressure lowering activity. To investigate the changes in metabolites following treatment and to study the broader metabolomic profile, metabolomics is commonly conducted []. An acute time course metabolomics study revealed kynurenine as partially responsible for the acute antihypertensive effects of IRW in SHRs, though its long-term treatment remains unknown []. Parallel research into the mechanism of IRW-mediated ACE2 upregulation, through network-based analysis, identified hepatocyte nuclear factor 1 α (HNF1α) as a potential transcriptional regulator of ACE2 []. The same study also confirmed that the IRW-activated phosphatidylinositiol-3,4,5-triphisphate (PIP3)/phosphoinositide 3-kinase (PI3K)/ protein kinase B (Akt) pathway targeting HNF1α, contributing to ACE2 transcriptional activation in vascular smooth muscle cells (VSMCs). Notably, levels of PIP3, PI3K, -Akt, and HNF1α had similar increases to that of ACE2, suggesting coordinated regulation of ACE2 []. While these findings provide important insights, IRW-mediated ACE2 expression may differ due to IRW’s degradation and metabolism. Moreover, although it is understood that most IRW does not reach target organs in its intact form [], the metabolomic profile of IRW and its bioactive derivatives after long-term treatment remains largely unexplored.