Oral delivery of nanoparticle urolithin A normalizes cellular stress and improves survival in mouse model of cisplatin-induced AKI

Abstract

The popular anticancer drug cisplatin causes many adverse side effects, the most serious of which is acute kidney injury (AKI). Emerging evidence from laboratory and clinical studies suggests that the AKI pathogenesis involves oxidative stress pathways; therefore, regulating such pathways may offer protection. Urolithin A (UA), a gut metabolite of the dietary tannin ellagic acid, possesses antioxidant properties and has shown promise in mouse models of AKI. However, therapeutic potential of UA is constrained by poor bioavailability. We aimed to improve oral bioavailability of UA by formulating it into biodegradable nanoparticles that use a surface-conjugated ligand targeting the gut-expressed transferrin receptor. Nanoparticle encapsulation of UA led to a sevenfold enhancement in oral bioavailability compared with native UA. Treatment with nanoparticle UA also significantly attenuated the histopathological hallmarks of cisplatin-induced AKI and reduced mortality by 63% in the mouse model. Expression analyses indicated that nanoparticle UA therapy coincided with oxidative stress mitigation and downregulation of nuclear factor erythroid 2-related factor 2- and P53-inducible genes. Additionally, normalization of miRNA (miR-192-5p and miR-140-5p) implicated in AKI, poly(ADP-ribose) polymerase 1 levels, antiapoptotic signaling, intracellular NAD+, and mitochondrial oxidative phosphorylation were observed in the treatment group. Our findings suggest that nanoparticles greatly increase the oral bioavailability of UA, leading to improved survival rates in AKI mice, in part by reducing renal oxidative and apoptotic stress.

Emerging Role of MiR-192-5p in Human Diseases

“…In 2014, a study by Kanki and coworkers demonstrated that urinary miR-192-5p is especially upregulated in rats with cisplatin-induced injury to the proximal tubules, and maybe a potential noninvasive biomarker for assessing nephrotoxicity ( Kanki et al, 2014 ). Correspondingly, the levels of miR-192-5p resumed to nearly normal in cisplatin-induced murine acute kidney injury (AKI) following oral therapy with the nanoparticle urolithin A (UA), a gut metabolite of the dietary tannin, ellagic acid ( Zou D et al, 2019 ). Besides, one important study by Chen and coworkers demonstrated that the levels of miR-192-5p increase ectopically in vancomycin (VAN)-induced AKI and in the VAN-treated human renal tubular epithelial cell line, HK-2.…”

Immunomodulatory Role of Urolithin A on Metabolic Diseases

“…One suggestion is to research modes of delivery using nanoparticles encapsulating UroA. As of now, one study has focused on developing a biodegradable nanoparticle to package UroA to increase bioavailability; this has been tested only in mice, but it has shown promising results in protecting against acute kidney injury, improving survival rate, and mitigating oxidative stress [79]. In the case of pomegranate bioactive compounds, researchers found that pomegranate nanoprototypes are able to decrease proliferation of breast cancer cells by increasing bioavailability [80].…”

COVID-19: fighting the invisible enemy with microRNAs

“…Therefore, developing formulations that are suitable and can be applied to oral delivery of miRNAs is highly sought. Literature has identified that chitosan [80], mannose modified chitosan [81], bovine milk-derived exosomes [82], bovine lactoferrin [83], lipidic [84], and PLGA-based nanoformulations [85] are employed for effective oral delivery of miRNAs/therapeutics. Hence, developing oral nanoformulation(s) of miRNAs is achievable and is highly recommended for its successful implementation into the clinic.…”