Docosahexaenoic acid-acylated curcumin diester alleviates cisplatin-induced acute kidney injury by regulating the effect of gut microbiota on the lipopolysaccharide- and trimethylamine-N-oxide-mediated PI3K/Akt/NF-κB signaling pathway in mice.

An increasing number of studies have reported the effects of curcumin (Cur) and docosahexaenoic acid (DHA) on alleviating acute kidney injury (AKI). In this work, we have performed a comparative investigation to determine the effect of dietary DHA-acylated Cur esters, ester derivatives of Cur, and recombination of curcumin and DHA on alleviating acute kidney injury in a mouse model induced by a single intraperitoneal injection with cisplatin (20 mg kg-1). The results showed that the DHA-acylated Cur diesters significantly decreased the abnormally increased blood urea nitrogen, creatinine, lipopolysaccharide (LPS) and trimethylamine-N-oxide (TMAO) in serum caused by AKI. Histopathological results confirmed that DHA-acylated Cur diesters clearly reduced the degree of renal tubular injury. The renal protective effect of the DHA-acylated Cur diester was better than that of the monoester and the recombination of Cur and DHA. Notably, we found that the DHA-acylated Cur diester treatment remarkably changed the relative abundance of microbiota related to LPS and TMAO/trimethylamine (TMA) metabolism. Moreover, dietary DHA-acylated Cur diesters clearly reduced the MDA content and elevated GSH levels in the kidney of AKI mice, as well as changed the fatty acid composition in the kidney. Further mechanism studies showed that DHA-acylated Cur diesters significantly inhibited inflammation, apoptosis and oxidative stress by preventing the LPS and TMAO-mediated PI3K/Akt/NF-κB signaling pathway. The above results indicate that DHA-acylated Cur diesters are a potentially novel candidate or targeted dietary pattern to prevent and treat drug-induced acute kidney injury.

EPA-Enriched Phospholipids Alleviate Renal Interstitial Fibrosis in Spontaneously Hypertensive Rats by Regulating TGF-ß Signaling Pathways.

Hypertensive nephropathy is a chronic kidney disease caused by hypertension. Eicosapentaenoic acid (EPA) has been reported to possess an antihypertensive effect, and our previous study suggested that EPA-enriched phospholipid (EPA-PL) had more significant bioactivities compared with traditional EPA. However, the effect of dietary EPA-PL on hypertensive nephropathy has not been studied. The current study was designed to examine the protection of EPA-PL against kidney damage in spontaneously hypertensive rats (SHRs). Treatment with EPA-PL for three weeks significantly reduced blood pressure through regulating the renin-angiotensin system in SHRs. Moreover, dietary EPA-PL distinctly alleviated kidney dysfunction in SHRs, evidenced by reduced plasma creatinine, blood urea nitrogen, and 24 h proteinuria. Histology results revealed that treatment of SHRs with EPA-PL alleviated renal injury and reduced tubulointerstitial fibrosis. Further mechanistic studies indicated that dietary EPA-PL remarkably inhibited the activation of TGF-ß and Smad 3, elevated the phosphorylation level of PI3K/AKT, suppressed the activation of NF-κB, reduced the expression of pro-inflammatory cytokines, including IL-1ß and IL-6, and repressed the oxidative stress and the mitochondria-mediated apoptotic signaling pathway in the kidney. These results indicate that EPA-PL has potential value in the prevention and alleviation of hypertensive nephropathy.

Short-term supplementation of DHA-enriched phospholipids attenuates the nephrotoxicity of cisplatin without compromising its antitumor activity in mice.

Cisplatin is one of the most effective chemotherapeutic agents used for the treatment of a wide variety of cancers. However, cisplatin has been associated with nephrotoxicity, which limits its application in clinical treatment. Various studies have indicated the protective effect of phospholipids against acute kidney injury. However, no study has focused on the different effects of phospholipids with different fatty acids on cisplatin-induced nephrotoxicity and on the combined effects of phospholipids and cisplatin in tumour-bearing mice. In the present study, the potential renoprotective effects of phospholipids with different fatty acids against cisplatin-induced nephrotoxicity were investigated by determining the serum biochemical index, renal histopathological changes, protein expression level and oxidative stress. The results showed that docosahexaenoic acid-enriched phospholipids (DHA-PL) and eicosapentaenoic acid-enriched phospholipids (EPA-PL) could alleviate cisplatin-induced nephrotoxicity by regulating the caspase signaling pathway, the SIRT1/PGC1α pathway, and the MAPK (mitogen-activated protein kinase) signaling pathway and by inhibiting oxidative stress. In particular, DHA-PL exhibited a better inhibitory effect on oxidative stress and apoptosis compared to EPA-PL. Furthermore, DHA-PL exhibited an additional effect with cisplatin on the survival of ascitic tumor-bearing mice. These findings suggested that DHA-PL are one kind of promising supplement for the alleviation of cisplatin-induced nephrotoxicity without compromising its antitumor activity.

Docosahexaenoic Acid-Acylated Astaxanthin Esters Exhibit Superior Renal Protective Effect to Recombination of Astaxanthin with DHA via Alleviating Oxidative Stress Coupled with Apoptosis in Vancomycin-Treated Mice with Nephrotoxicity.

Prevention of acute kidney injury caused by drugs is still a clinical problem to be solved urgently. Astaxanthin (AST) and docosahexaenoic acid (DHA) are important marine-derived active ingredients, and they are reported to exhibit renal protective activity. It is noteworthy that the existing forms of AST in nature are mainly fatty acid-acylated AST monoesters and diesters, as well as unesterified AST, in which DHA is an esterified fatty acid. However, no reports focus on the different bioactivities of unesterified AST, monoesters and diesters, as well as the recombination of DHA and unesterified AST on nephrotoxicity. In the present study, vancomycin-treated mice were used to evaluate the effects of DHA-acylated AST monoesters, DHA-acylated AST diesters, unesterified AST, and the recombination of AST and DHA in alleviating nephrotoxicity by determining serum biochemical index, histopathological changes, and the enzyme activity related to oxidative stress. Results found that the intervention of DHA-acylated AST diesters significantly ameliorated kidney dysfunction by decreasing the levels of urea nitrogen and creatinine, alleviating pathological damage and oxidative stress compared to AST monoester, unesterified AST, and the recombination of AST and DHA. Further studies revealed that dietary DHA-acylated AST esters could inhibit the activation of the caspase cascade and MAPKs signaling pathway, and reduce the levels of pro-inflammatory cytokines. These findings indicated that the administration of DHA-acylated AST esters could alleviate vancomycin-induced nephrotoxicity, which represented a potentially novel candidate or therapeutic adjuvant for alleviating acute kidney injury.