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The anti-inflammatory, antiviral, and anti-cancer properties, as well as the mechanism of action of cyclo-[Pro-Pro-β3-HoPhe-Phe-] tetrapeptide (denoted as 4B8M), were recently described. The aim of this work was to synthesize and evaluate the immunosuppressive actions of the stereochemical variants of 4B8M by sequential substitution of L-amino acids by D-amino acids (a series of peptides denoted as P01–P07) using parent 4B8M as a reference compound. In addition, diverse available bioinformatics tools using machine learning and artificial intelligence were tested to find the bio-pharmacokinetic and polypharmacological attributes of analyzed stereomers. All peptides were non-toxic to human peripheral blood mononuclear cells (PBMCs) and only cyclo-[D-Pro-Pro-β3-HoPhe-Phe-] peptide (P03) was capable of inhibiting mitogen-induced PBMC proliferation. The peptides inhibited the lipopolysaccharide (LPS)-induced production of tumor necrosis factor-alpha (TNF-α) to various degrees, with P04 (cyclo-[Pro-Pro-D-β3-HoPhe-Phe-]) and P03 being the most potent. For further in vivo studies, P03 was selected because it had the combined properties of inhibiting cell proliferation and TNF-α production. P03 demonstrated a comparable ability to 4B8M in the inhibition of auricle edema and lymph node cell number and in the normalization of a distorted blood cell composition in contact sensitivity to the oxazolone mouse model. In the mouse model of carrageenan-induced inflammation of the air pouch, P03 exhibited a similar inhibition of the cell number in the air pouches as 4B8M, but its inhibitory effects on the percentage of neutrophils and eosinophils in the air pouches and blood, as well as on mastocyte degranulation in the air pouches, were stronger in comparison to 4B8M. Lastly, in a mouse model of dextran sulfate-induced colitis, similar effects to 4B8M regarding thymocyte number restoration and normalization of the blood cell pictures by P03 were observed. In summary, depending on either experimental findings or in silico predictions, P03 demonstrated comparable, or even better, anti-inflammatory and bio-pharmacokinetic properties to 4B8M and may be considered as a potential therapeutic. The possibility of P00 and P03 identification by circular dichroism measurements was tested by quantum-chemical calculations. [ABSTRACT FROM AUTHOR]

The anti-inflammatory, antiviral, and anti-cancer properties, as well as the mechanism of action of cyclo-[Pro-Pro-β3-HoPhe-Phe-] tetrapeptide (denoted as 4B8M), were recently described. The aim of this work was to synthesize and evaluate the immunosuppressive actions of the stereochemical variants of 4B8M by sequential substitution of L-amino acids by D-amino acids (a series of peptides denoted as P01–P07) using parent 4B8M as a reference compound. In addition, diverse available bioinformatics tools using machine learning and artificial intelligence were tested to find the bio-pharmacokinetic and polypharmacological attributes of analyzed stereomers. All peptides were non-toxic to human peripheral blood mononuclear cells (PBMCs) and only cyclo-[D-Pro-Pro-β3-HoPhe-Phe-] peptide (P03) was capable of inhibiting mitogen-induced PBMC proliferation. The peptides inhibited the lipopolysaccharide (LPS)-induced production of tumor necrosis factor-alpha (TNF-α) to various degrees, with P04 (cyclo-[Pro-Pro-D-β3-HoPhe-Phe-]) and P03 being the most potent. For further in vivo studies, P03 was selected because it had the combined properties of inhibiting cell proliferation and TNF-α production. P03 demonstrated a comparable ability to 4B8M in the inhibition of auricle edema and lymph node cell number and in the normalization of a distorted blood cell composition in contact sensitivity to the oxazolone mouse model. In the mouse model of carrageenan-induced inflammation of the air pouch, P03 exhibited a similar inhibition of the cell number in the air pouches as 4B8M, but its inhibitory effects on the percentage of neutrophils and eosinophils in the air pouches and blood, as well as on mastocyte degranulation in the air pouches, were stronger in comparison to 4B8M. Lastly, in a mouse model of dextran sulfate-induced colitis, similar effects to 4B8M regarding thymocyte number restoration and normalization of the blood cell pictures by P03 were observed. In summary, depending on either experimental findings or in silico predictions, P03 demonstrated comparable, or even better, anti-inflammatory and bio-pharmacokinetic properties to 4B8M and may be considered as a potential therapeutic. The possibility of P00 and P03 identification by circular dichroism measurements was tested by quantum-chemical calculations.

Scope: Polyphenols exhibit their antioxidant activity downstream the activation of the nuclear factor erythroid 2-related factor 2 pathway (Nrf2), but the connection between lipid metabolism and the Nrf2 pathway is still unknown. Flavonoid-rich concentrated extract from Prunus mahaleb (mahaleb concentrated fruit extract; MCFE) may act on oxido-reductive homeostasis and hepatic lipid metabolism via Nrf2., Methods & Results: MCFE ability to enhance the activity of Nrf2-mediated antioxidant/detoxifying enzymes is investigated in liver and colon of BALB/c mice. After a 4-week supplementation, macroscopic, histological, and biochemical signs of colitis are examined in mouse colon pulsed with 5% (w/v) dextran sodium sulfate (DSS). Untreated or DSS-supplemented mice are used as negative or positive control. MCFE effect on liver lipid metabolism and its possible link with the Nrf2 pathway is investigated. MCFE intake increases antioxidant defenses in mice colon and its pretreatment blunts pathological signs of colitis, as compared to positive control. In the liver, the increase in antioxidant defenses is associated with enhanced oxidative metabolism and with higher levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and of hemeoxygenase-1 (HO-1), in comparison with negative controls., Conclusion: Cytoprotective and hypolipidemic effect produced by MCFE intake results, at least in part, by the activation of the Nrf2 pathway., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)