Paradigm shift – Metabolic transformation of docosahexaenoic and eicosapentaenoic acids to bioactives exemplify the promise of fatty acid drug discovery

Abstract

Fatty acid drug discovery (FADD) is defined as the identification of novel, specialized bioactive mediators that are derived from fatty acids and have precise pharmacological/therapeutic potential. A number of reports indicate that dietary intake of omega-3 fatty acids and limited intake of omega-6 promotes overall health benefits. In 1929, Burr and Burr indicated the significant role of essential fatty acids for survival and functional health of many organs. In reference to specific dietary benefits of differential omega-3 fatty acids, docosahexaenoic and eicosapentaenoic acids (DHA and EPA) are transformed to monohydroxy, dihydroxy, trihydroxy, and other complex mediators during infection, injury, and exercise to resolve inflammation. The presented FADD approach describes the metabolic transformation of DHA and EPA in response to injury, infection, and exercise to govern uncontrolled inflammation. Metabolic transformation of DHA and EPA into a number of pro-resolving molecules exemplifies a novel, inexpensive approach compared to traditional, expensive drug discovery. DHA and EPA have been recommended for prevention of cardiovascular disease since 1970. Therefore, the FADD approach is relevant to cardiovascular disease and resolution of inflammation in many injury models. Future research demands identification of novel action targets, receptors for biomolecules, mechanism(s), and drug-interactions with resolvins in order to maintain homeostasis.

Race‐based and sex‐based differences in bioactive lipid mediators after myocardial infarction

“…Time-dependent cardiac repair in pathogen and risk-free rodents clearly suggests that the timing of the acute inflammatory phase coincides with the beginning of the resolving phase, to the same extent as MI patients biosynthesize resolution molecules within 2.5 h as the onset of initial inflammation post-MI. 20,33,36 Thus, beginning of acute inflammation-resolution programmes the termination of inflammatory response after cardiac injury of acute inflammation programmes the beginning of inflammatory resolution after cardiac injury. 43 A previous report indicates that SPMs levels in atheroma define the stable and unstable milieu, providing the rationale for precise and personalized therapy for atherosclerotic patients.…”

“…In response to immune activation events like MI, particularly, 12 LOX metabolizes fatty acids AA, DHA, and EPA to differential bioactive lipid metabolites. 20,33 We therefore tested racial and sex-associated differences in lipid signatures with respect to essential fatty acids AA, DHA, and EPA. First, we classified the distribution pattern of hydroxyeicosatetraenoic acids (HETEs), hydroxydocosahexaenoic acids (HDHAs), and hydroxyeicosapentaenoic acids (HEPEs).…”

Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells

“…DHA is converted into monohydroxy DHA (17-HDHA) by acetylated COX-2, CYP450, and 15-LOX [107,108] and then into RvD1 by 5-LOX [109,110]. RvD1 and its precursors have mostly been described at the periphery but have also been detected in the brain.…”

“…NPD1 acts through NFkB and then decreases pro-inflammatory gene expression [122,124,125]. At last, DHA can also be converted into 14-HDHA and then in Mar1-2 by 12/15-LOX [107,108,126]. Mar1 and its precursor 14-HDHA have recently been identified in the hippocampus of mice [70].…”

n-3 Polyunsaturated Fatty Acids and Their Derivates Reduce Neuroinflammation during Aging

“…Other SPMs are derived from DHA: di-hydroxy-DHA termed protectin D1 (PD1) or neuroprotectin D1 (NPD1) when produced in the CNS by 5-and 15-LOX [130][131][132][133], and maresin 1-2 (MaR1-2) by 12/15-LOX [114,115,134]. NPD1, MaR1, and its precursor 14-HDHA were measured in the hippocampus [135].…”