Nrf2 dependent antiaging effect of milk‐derived bioactive peptide in old fibroblasts

• Published in: Journal of cellular biochemistry 2019-06, Vol.120 (6), p.9677-9691
• Main Authors: Kumar, Naveen, Reddi, Srinu, Devi, Savita, Mada, Sanusi Bello, Kapila, Rajeev, Kapila, Suman
• Format: Article
• Language: English
• Subjects: Aging; Aging (natural); Animals; Apoptosis; BAX protein; bioactive peptide; Biological activity; Cell adhesion & migration; Cell migration; Cellular Senescence - drug effects; Collagen; Cytokines; Deoxyribonucleic acid; DNA; Fibroblasts; Fibroblasts - metabolism; Galactosidase; Homeostasis; Inflammation; Kinases; Lipid peroxidation; Lipids; MAP Kinase Signaling System - drug effects; Milk - chemistry; Milk Proteins - chemistry; NF-E2-Related Factor 2 - metabolism; NF-κB protein; Nitric oxide; p38MAP kinase; Peptides; Peptides - chemistry; Peptides - pharmacology; Peroxidation; Phenotypes; Pretreatment; prolonged serial passage; Proteins; Rats; Reactive oxygen species; Senescence; senescence‐associated secretory phenotype; Skin; Tumor necrosis factor; β-Galactosidase
• ISSN: 0730-2312; 1097-4644; 1097-4644
• DOI: 10.1002/jcb.28246

Prolonged passaging of primary fibroblast cells totally shapes the natural biological phenomena and leads to the appearance of features related to senescence. As a result, it is a good natural tool to delineate the molecular mechanism of cellular aging. The present investigation revealed the antiaging effect of milk‐derived novel bioactive peptide (VLPVPQK). The peptide played an important role in downregulating apoptosis‐related markers in late passages of cultured fibroblast cells. The peptide treatment to aged fibroblasts caused enhancement in cell migration, DNA integrity, and decrease in the lipid peroxidation, reactive oxygen species, nitric oxide production as well as pro‐inflammatory cytokines, TNF‐α and IL‐6. Moreover, the peptide decreased the expression of apoptotic caspases, Bax, and senescence‐associated β‐galactosidase (SA‐β‐gal) proteins. The peptide pretreatment also enhanced the extracellular collagen protein and antiapoptotic, Bcl‐xL. In addition, the peptide treatment reversed the senescence‐related activity in fibroblasts by stimulating Nrf2 mediated antioxidative defense system and inhibiting the action of NFkB/p38MAPK signaling, similar to the commercially available inhibitor (SB203580) of p38MAPK. Thus, the peptide exhibits the antiaging effect in dermal fibroblast cells. Milk casein derived peptide, VLPVPQK reversed the senescence‐related dysfunctions by stimulating Nrf2 mediated antioxidative defense system and inhibiting the action of NFkB/p38MAPK signaling similar to the commercially available inhibitor (SB203580) of p38MAPK. Therefore, the peptide can serve as a valuable antiaging prodrug. Highlights 1. A novel bioactive peptide, VLPVPQK shows antiaging effect in prolonged serial passaged fibroblast cells. 2. The peptide causes activation and transmigration of Nrf2 for maintaining homeostasis. 3. The peptide rejuvenates the aged fibroblast cells by weakening the effects of the senescent associated secretory phenotype. 4. The peptide alleviates the NF‐kB/p38MAP kinase pathway in aged fibroblasts.