Search Results (4)

Background: This study investigates how sorafenib induces toxicity in glomerular cells and examines the protective role of 8,9-epoxyeicosatrienoic acid (8,9-EET) analogs in reducing this kidney damage. Methods: Human renal mesangial cells (HRMCs) and podocytes were treated with no treatment, sorafenib alone, or sorafenib combined with 8,9-EET analogs. Cell viability and apoptosis were measured in both cell types. Results: Sorafenib (1–10 µM) lowered cell viability and increased caspase 3/7 activity in a dose-dependent way in HRMCs and podocytes. Five of twenty 8,9-EET analogs significantly enhanced cell survival and decreased apoptosis. RNA sequencing showed that sorafenib altered 1244 genes, including those involved in cell cycle and the Raf/MEK/ERK pathway. The 8,9-EET analog MDB-52a raised ANGPTL4 levels, linked to metabolism and vascular health, and reduced ACTA2, which could activate protective pathways. Nephroseq data correlated these gene changes with glomerulosclerosis. Conclusions: MDB-52 appears to counteract gene disruptions and protect against sorafenib-induced kidney damage. Overall, 8,9-EET analogs targeting glomerular cells could be potential therapeutic agents to lessen sorafenib-related nephrotoxicity. Full article

Wollemi pine, Wollemia nobilis W. G. Jones, K. D. Hill & J. M. Allan (Araucariaceae) was discovered in a remote canyon 150 km north-west of Sydney, Australia. As fewer than 100 adult trees of this plant survive in the wild, efforts to conserve this species have included seed storage. Fresh and stored seeds were analysed for yield and composition of the seed oil. The seed kernels, from both fresh and stored seed, were rich in oil with contents of 42% and 48%, respectively. The fatty acid profile of Wollemi pine seed oil was determined by GC-MS analyses of fatty acid methyl ester derivatives. Oleic acid makes up 32% of the fatty acid profile, while the major polyunsaturated fatty acid is linoleic acid (25%). Most of the detectable omega-3 fatty acid content of the oil is α-linolenic acid (3%). The seed oil has a high content of C20 to C24 fatty acids (25%) consisting of long-chain saturated fatty acids (19%). The polyunsaturated C20 omega-6 fatty acid content consists of eicosadienoic acid, dihomo-γ-linolenic acid, and arachidonic acid (total 4%). ¹H NMR analyses of the intact oil showed that the lipids were largely in the form of triglycerides with a degree of unsaturation of 1.5 double bond equivalents per fatty acid residue. In artificially aged or stored seeds, minor additional ¹H NMR spectral signals were attributed to an omega-3 epoxylipid, tentatively identified as cis-15,16-epoxy-9Z,12Z-octadecadienoic acid or ester derivative. Other minor signals were characteristic of a hydroxy or a hydroperoxy E,Z diene containing fatty acid. These products are typically formed by metabolic lipid oxidation of fatty acids. The content of the omega-3 epoxylipid, determined by the ¹H NMR method, varied with storage conditions and duration from less than 0.1% to a maximum of 3.3%. Full article

Epoxide metabolites from n-3 and n-6 polyunsaturated fatty acids arouse interest thanks to their physiological and pharmacological activities. Their chemical synthesis has significant drawbacks, and enzymes emerge as an alternative with potentially higher selectivity and greener nature. Conversion of eleven eicosanoid, docosanoid, and other n-3/n-6 fatty acids into mono-epoxides by fungal unspecific peroxygenases (UPOs) is investigated, with emphasis on the Agrocybe aegerita (AaeUPO) and Collariella virescens (rCviUPO) enzymes. GC-MS revealed the strict regioselectivity of the n-3 and n-6 reactions with AaeUPO and rCviUPO, respectively, yielding 91%-quantitative conversion into mono-epoxides at the last double bond. Then, six of these mono-epoxides were obtained at mg-scale, purified and further structurally characterized by ¹H, ¹³C and HMBC NMR. Moreover, chiral HPLC showed that the n-3 epoxides were also formed (by AaeUPO) with total S/R enantioselectivity (ee > 99%) while the n-6 epoxides (from rCviUPO reactions) were formed in nearly racemic mixtures. The high regio- and enantioselectivity of several of these reactions unveils the synthetic utility of fungal peroxygenases in fatty acid epoxidation. Full article

Age-associated changes leading to a decline in cardiac structure and function contribute to the increased susceptibility and incidence of cardiovascular diseases (CVD) in elderly individuals. Indeed, age is considered a risk factor for heart failure and serves as an important predictor for poor prognosis in elderly individuals. Effects stemming from chronic, low-grade inflammation, inflammaging, are considered important determinants in cardiac health; however, our understanding of the mechanisms involved remains unresolved. A steady decline in mitochondrial function is recognized as an important biological consequence found in the aging heart which contributes to the development of heart failure. Dysfunctional mitochondria contribute to increased cellular stress and an innate immune response by activating the NLRP-3 inflammasomes, which have a role in inflammaging and age-related CVD pathogenesis. Emerging evidence suggests a protective role for CYP450 epoxygenase metabolites of N-3 and N-6 polyunsaturated fatty acids (PUFA), epoxylipids, which modulate various aspects of the immune system and protect mitochondria. In this article, we provide insight into the potential roles N-3 and N-6 PUFA have modulating mitochondria, inflammaging and heart failure. Full article