**4. Preeclampsia**

Preeclampsia, a pregnancy-specific syndrome characterized by hypertension, proteinuria and edema, causes fetal and maternal morbidity and mortality with high incidence in devel‐ oping countries [55]. Symptoms of preeclampsia are currently combated by sodium restric‐ tion, rest and medication for blood pressure control to avoid complications for the mother and prolong the pregnancy for fetal maturation [56-58]. However, this attempt is rather un‐ specific with possible side effects for the developing fetus [59, 60]. Currently, the only thera‐ py of preeclamsia involves placenta removal resulting in pre-term birth [61]. Therefore, novel drug development for pregnancy-specific conditions remains a challenge [59].

The pathology of preeclampsia involves systemic inflammation, oxidative stress, alterations in the levels of angiogenic factors, and vascular reactivity leading to hypertension of the mother and metabolic alterations in the fetus [61, 62]. A number of evidence suggests that clinical manifestations are caused by endothelial malfunction including insufficient produc‐ tion of NO [63, 64]. Levels of eNOS, the enzyme responsible for NO synthesis in the endo‐ thelium from L-arginine, are decreased in human umbilical vein endothelial cells from pregnant women suffering from preeclampsia [62] together with impaired AS expression [65]. The low availability of L-arginine uncouples eNOS activity, decreases NO production and increases eNOS-dependent superoxide generation [62, 66], consequently resulting in re‐ duced vasodilatation or in inflammatory processes observed in preeclampsia [66, 67]. There‐ fore, it is expected that the sustained concentration of L-arginine in endothelial cells is likely to play a critical role not only in the control of systemic blood pressure, but also in inhibition of inflammatory processes [68].

**Figure 1.** *Bj***-PRO-10c-induced effects on endothelial cell from healthy and pregnant women suffering from preeclampsia**. In endothelial cells from normotensive pregnant women (NORMAL), NO production is adequate to maintain normal gestation. In cells from patients with the disease (PREECLAMPSIA) both decreased NO production

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duced expression of eNOS and AS and uncoupled eNOS. When endothelial cells from pregnant women suffering from preeclampsia are exposed to *Bj*-PRO-10c (PREECLAMPSIA + *Bj*-PRO-10c), production of NO and superoxide return to normal ranges, since *Bj*-PRO-10c initiates a signaling cascade including increases of cytosolic calcium concentration ac‐

Citrullinemia, a disorder causing serious episodes of neurological symptoms associated with hyperammonemia involving disorientation, abnormal behaviors (aggression, irritabili‐ ty, and hyperactivity), seizures, coma, and potentially death from brain edema [70], occurs in two variants: CTLN1 (MIM#215700) or classical neonatal onset, and CTLN2 (MIM#603471) or adult-onset [71-74]. Classical citrullinemia in children is associated with a mutation in the AS gene [75]. However, in CTLN2 the enzyme reveals normal kinetic prop‐ erties and is quantitatively deficient only in the liver of adult-onset citrullinemia patients [71-74]. The most successful therapy of CTLN2 has been liver transplantation [76, 77] be‐ cause this treatment prevents hyperammonemic crises and corrects consequent metabolic

It has been reported that administration of L-arginine to CTLN2 patients is effective in de‐ creasing blood ammonia concentration [78, 79]. For ammonia detoxification, arginine needs to enter the liver via the portal vein where is metabolized by mitochondrial arginase to pro‐ vide ornithine for citrulline and aspartate synthesis and for the priming of the urea cycle [80]. However, care must be taken when administering L-arginine, as fatal cases caused by L-arginine hydrochloride overdose have been reported [81]. In general, the dose of L-argi‐ nine supplementation used in the treatment of hyperammoaemia is in the high range be‐ tween 100 and 700 mg/kg body weight per day [82-85]. In animal models the effects of hyperargininaemia can be observed, reflecting toxic effects of high L-arginine concentration

) production are observed together with enhanced activity of the enzyme arginase, re‐

and increased superoxide (O2

**5. Citrullinemia**

disturbances [70].

tivating eNOS and augmenting AS activity.


Recently, we have reported that a *Bj*-PRO containing ten amino acid residues (*Bj*-PRO-10c), activating AS, is able to correct dysfunction of human umbilical vein endothelial cells from pregnant women suffering from preeclampsia [65] (Figure 1).

*Bj*-PRO-10c, besides augmenting the activity of AS both *in vitro* and *in vivo* [14] increases sig‐ nificantly eNOS expression of human umbilical vein endothelial cells obtained from preg‐ nant women suffering from preeclampsia [65]. It was observed that the increase in NO levels induced by *Bj*-PRO-10c diminished the oxidative stress of the endothelial cells of pree‐ clamptic women, shown as a 50% reduction in superoxide levels [65] (Figure 1).

Most importantly, *Bj*-PRO-10c promoted NO production only in endothelial cells from pa‐ tients suffering from the disorder and not in normotensive pregnant women. In agreement, *Bj*-PRO-10c is a molecule endowed with antihypertensive activity that reduced blood pres‐ sure in hypertensive but not in normotensive rats [69]. These observations led to suggest that *Bj*-PRO-10c promotes its anti-hypertensive effect in mothers with preeclampsia without any effect on the blood pressure of the fetus, a problem with drugs currently used for mini‐ mizing health problems arising from preeclampsia. Taken together, *Bj*-PRO-10c becomes a potential tool for the development of an efficient drug for preeclampsia treatment.

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**Figure 1.** *Bj***-PRO-10c-induced effects on endothelial cell from healthy and pregnant women suffering from preeclampsia**. In endothelial cells from normotensive pregnant women (NORMAL), NO production is adequate to maintain normal gestation. In cells from patients with the disease (PREECLAMPSIA) both decreased NO production and increased superoxide (O2 - ) production are observed together with enhanced activity of the enzyme arginase, re‐ duced expression of eNOS and AS and uncoupled eNOS. When endothelial cells from pregnant women suffering from preeclampsia are exposed to *Bj*-PRO-10c (PREECLAMPSIA + *Bj*-PRO-10c), production of NO and superoxide return to normal ranges, since *Bj*-PRO-10c initiates a signaling cascade including increases of cytosolic calcium concentration ac‐ tivating eNOS and augmenting AS activity.
