d-Amino acids differentially trigger an inflammatory environment in vitro
Document Type
Article
Publication Date
2-1-2024
Abstract
Studies in vivo have demonstrated that the accumulation of D-amino acids (D-AAs) is associated with age-related diseases and increased immune activation. However, the underlying mechanism(s) of these observations are not well defined. The metabolism of D-AAs by D-amino oxidase (DAO) produces hydrogen peroxide (H2O2), a reactive oxygen species involved in several physiological processes including immune response, cell differentiation, and proliferation. Excessive levels of H2O2 contribute to oxidative stress and eventual cell death, a characteristic of age-related pathology. Here, we explored the molecular mechanisms of D-serine (D-Ser) and D-alanine (D-Ala) in human liver cancer cells, HepG2, with a focus on the production of H2O2 the downstream secretion of pro-inflammatory cytokine and chemokine, and subsequent cell death. In HepG2 cells, we demonstrated that D-Ser decreased H2O2 production and induced concentration-dependent depolarization of mitochondrial membrane potential (MMP). This was associated with the upregulation of activated NF-& kcy;B, pro-inflammatory cytokine, TNF-alpha, and chemokine, IL-8 secretion, and subsequent apoptosis. Conversely, D-Ala-treated cells induced H2O2 production, and were also accompanied by the upregulation of activated NF-& kcy;B, TNF-alpha, and IL-8, but did not cause significant apoptosis. The present study confirms the role of both D-Ser and D-Ala in inducing inflammatory responses, but each via unique activation pathways. This response was associated with apoptotic cell death only with D-Ser. Further research is required to gain a better understanding of the mechanisms underlying D-AA-induced inflammation and its downstream consequences, especially in the context of aging given the wide detection of these entities in systemic circulation.
Keywords
d-Amino acid oxidase, d-Serine, d-Alanine, Inflammation, TNF-alpha
Divisions
medicinedept,intern,pharchemistry
Funders
Fundamental Research Grant Scheme,Ministry of Higher Education, Government of Malaysia (FRGS/1/2019/SKK08/UM/02/7),International Centre for Genetic Engineering and Biotechnology (CRP/MYS17-05),Agilent Technologies, Inc (PV018-2017)
Publication Title
Amino Acids
Volume
56
Issue
1
Publisher
Springer Wien
Publisher Location
Prinz-Eugen-Strasse 8-10, A-1040 Vienna, AUSTRIA