Olive leaf extract (OLE) has potential health benefits and protects against cytotoxicity in different organs. However, nothing has yet been reported on its potential to prevent cyclophosphamide (CP)-induced nephrotoxicity. This study investigated the possible protective effect of OLE on CP-induced kidney injury in rats, focusing on oxidative stress, inflammation, apoptosis and Nrf2/ARE/HO-1 signaling. Rats received 100 or 200 mg/kg body weight OLE for 15 days and a single injection of 150 mg/kg CP at day 16. CP induced kidney injury evidenced by the significantly increased serum creatinine and urea, and histopathological alterations, including glomerular atrophy, interstitial hemorrhage, dilated urinary space and necrosis. CP-induced rats exhibited increased kidney lipid peroxidation, protein carbonyl, nitric oxide (NO) and pro-inflammatory cytokines, and up-regulated NF-κB, Bax, cytochrome c and caspase-3. OLE ameliorated kidney function markers and prevented CP-induced tissue damage. In addition, OLE significantly prevented oxidative stress, inflammation and apoptosis by enhancing the antioxidant defenses and Bcl-2 expression, and suppressing the pro-inflammatory and pro-apoptotic markers NF-κB, Bax, cytochrome c and caspase-3. OLE up-regulated Nrf2, HO-1 and NQO-1 expression in the kidney of CP-induced rats. In conclusion, OLE has a substantial protective role against CP-induced nephrotoxicity in rats by up-regulating the Nrf2/ARE/HO-1 signaling, enhancing the antioxidant activity and attenuating inflammation and apoptosis.

Significance: Parturition requires strong uterine contractions. A longstanding enigma has been how contractions strengthen despite also causing transient ischemia as they occlude uterine blood vessels. Here we demonstrate a hitherto undescribed mechanism whereby in an adaptation at labor, brief hypoxia in uterine muscle, stimulates the contractile activity. We have named this hypoxia-induced force increase, or HIFI. We identify the underlying mechanism, which involves adenosine and prostaglandin and a rise in intracellular calcium, and show it is present in animal and human uterus, but only close to delivery. We speculate that aberrations in this powerful mechanism could underlie contractions being triggered too early (preterm labor) or if HIFI is deficient, weak contractions, and thus poor and unsuccessful term labors.