In the human body, docosahexaenoic acid (DHA) contained in fish oil is converted to trace amounts of specialized pro-resolving mediators (SPMs) as the principal bioactive metabolites for their pharmacological effects. Protectin Dx (PDX), an SPM, is an important medicinal compound with biological activities such as modulation of endogenous antioxidant systems, inflammation pro-resolving action, and inhibition of influenza virus replication. Although it can be biotechnologically synthesized from DHA, it has not yet been produced quantitatively. Here, we found that 15S-lipoxygenase from Burkholderia thailandensis (BT 15SLOX) converted 10S-hydroxydocosahexaenoic acid (10S-HDHA) to PDX using enzymatic reactions, which was confirmed by LC-MS/MS and NMR analyses. Thus, whole-cell reactions of Escherichia coli cells expressing BT 15SLOX were performed in flasks to produce PDX from lipase-treated DHA-enriched fish oil along with E. coli cells expressing Mus musculus (mouse) 8S-lipoxygenase (MO 8SLOX) that converted DHA to 10S-HDHA. First, 1 mM DHA (DHA-enriched fish oil hydrolysate, DFOH) was obtained from 455 mg/L DHA-enriched fish oil by lipase for 1 h. Second, E. coli cells expressing MO 8SLOX converted 1 mM DHA in DFOH to 0.43 mM 10S-HDHA for 6 h. Finally, E. coli cells expressing BT 15SLOX converted 0.43 mM 10S-HDHA in MO 8SLOX-treated DFOH to 0.30 mM (108 mg/L) PDX for 5 h. Consequently, DHA-enriched fish oil at 455 mg/L was converted to 108 mg/L PDX after a total of 12 h (conversion yield: 24% (w/w); productivity: 4.5 mg/L/h). This study is the first report on the quantitative production of PDX via biotechnological approaches.

Sepsis is a life-threatening syndrome driven by dysregulated immune activation and multi-organ dysfunction, with limited effective therapies. Oxylipins are endogenous lipid mediators that promote the resolution of inflammation and tissue repair, yet their therapeutic potential in systemic inflammatory diseases remains incompletely understood. In this study, we evaluated the effects of two oxylipins, 10-epi-Protectin DX (10-epi-PDX) and Resolvin D5_{n-3 DPA} (RvD5_{n-3 DPA}), in a lipopolysaccharide (LPS)-induced murine endotoxemia model. Given that this model recapitulates key features of systemic inflammation and multi-organ injury relevant to sepsis-associated conditions, oxylipin effects were assessed across major organs implicated in systemic inflammatory pathology. Administration of either oxylipin significantly reduced systemic tissue injury and inflammatory damage in the lungs, kidneys, and liver. These protective effects were accompanied by suppression of inflammatory responses and marked improvements in histopathological outcomes. These findings indicate that 10-epi-PDX and RvD5_{n-3 DPA} possess organ-protective, anti-inflammatory properties in endotoxemia and support further investigation of their potential as therapeutic candidates for limiting systemic inflammatory injury.

Obesity-associated metabolic dysfunction is driven by chronic inflammation and disrupted lipid metabolism, however the potential of lipid-derived regulatory mediators in counteracting these processes remains poorly understood. 10-epimer-protectin DX (10-epi-PDX), a novel epimeric derivative of protectin DX, has recently emerged as a promising modulator of metabolic and inflammatory pathways. In this study, we investigated the therapeutic efficacy and underlying mechanisms of 10-epi-PDX in a mouse model of diet-induced obesity. Administration of 10-epi-PDX significantly ameliorated obesity-related metabolic abnormalities, including excessive weight gain, hepatic steatosis, and adipose tissue inflammation. Furthermore, treatment with 10-epi-PDX markedly enhanced glucose tolerance and insulin sensitivity compared to vehicle-treated obese controls. Hepatic RNA sequencing revealed that 10-epi-PDX reprogrammed obesity-altered lipid metabolism by restoring the expression of key genes involved in lipid droplet formation, lipid transport, and steroid biosynthesis. These transcriptomic alterations closely paralleled the observed improvements in metabolic phenotypes. Collectively, this study provides the first evidence that 10-epi-PDX mitigates obesity-induced metabolic impairment through the coordinated regulation of inflammation and hepatic lipid metabolic pathways. These findings identify 10-epi-PDX as a novel lipid-derived regulator and highlight its potential as a therapeutic and nutraceutical candidate for obesity and its associated metabolic complications.