The potential protective effects of estradiol and 2-methoxyestradiol in ischemia reperfusion-induced kidney injury in ovariectomized female rats.

Investigating the impact of 17β estradiol (E2) and its endogenous non-hormonal metabolite 2-methoxyestradiol (2ME) on renal ischemia-reperfusion (RIR) induced kidney injury in ovariectomized (OVX) rats and the role of catechol-O-methyltransferase (COMT) in their effects. Eighty female rats were allocated into eight groups. Control group, Sham group, OVX group, OVX and RIR group, OVX + RIR + E2 group, OVX + RIR + 2ME group, OVX + RIR + E2 + Entacapone group and OVX + RIR + 2ME + Entacapone group, respectively. Twenty-four hours post RIR, creatinine (Cr) and blood urea nitrogen (BUN) were determined in serum, while malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), Glutathione (GSH), myeloperoxidase (MPO), as well as the expressions of COMT, hypoxia inducible factor-1α (HIF-1α) and tyrosine hydroxylase (TH) were assessed in the kidney tissues. Serum Cr, BUN, MPO, as well as HIF-1α and TH expressions were significantly higher with concomitant decrease in COMT expression, SOD and CAT activities and GSH content observed in OVX and RIR group compared to sham group. E2 and 2ME treatment significantly ameliorated all parameters measured in OVX and RIR rats. On the other hand, Entacapone significantly decreased the effect of E2, with no effect on 2ME treatment. E2 ameliorates RIR-induced kidney injury and this effect is mediated, at least in part, via its COMT-mediated conversion to 2ME. Thus, 2ME by the virtue of its pleiotropic pharmacological effects can be used as a safe and effective treatment of RIR injury.

Hassan E ，Allam S ，Mansour AM ，Shaheen A ，Salama SA ... -  《-》

2-Methoxyestradiol ameliorates doxorubicin-induced cardiotoxicity by regulating the expression of GLUT4 and CPT-1B in female rats.

The clinical usage of doxorubicin (DOX) is hampered due to cardiomyopathy. Studies reveal that estrogen (E2) modulates DOX-induced cardiotoxicity. Yet, the exact mechanism is unclear. The objective of the current study is to evaluate the influence of E2 and more specifically its metabolite 2-methoxyestradiol (2ME) on cardiac remodeling and the reprogramming of cardiac metabolism in rats subjected to DOX cardiotoxicity. Seventy-two female rats were divided into groups. Cardiotoxicity was induced by administering DOX (2.5 mg/kg three times weekly for 2 weeks). In some groups, the effect of endogenous E2 was abolished by ovariectomy (OVX) or by using the estrogen receptor (ER) blocker Fulvestrant (FULV). The effect of administering exogenous E2 or 2ME in the OVX group was studied. Furthermore, the influence of entacapone (COMT inhibitor) on induced cardiotoxicity was investigated. The evaluated cardiac parameters included ECG, histopathology, cardiac-related enzymes (creatine kinase isoenzyme-MB (CK-MB) and lactate dehydrogenase (LDH)), and lipid profile markers (total cholesterol (TC), triglyceride (TG), and high-density lipoprotein (HDL)). The expression levels of key metabolic enzymes (glucose transporter-4 (GLUT4) and carnitine palmitoyltransferase-1B (CPT-1B)) were assessed. Our results displayed that co-treatment of E2 and/or 2ME with DOX significantly reduced DOX-induced cardiomyopathy and enhanced the metabolism of the heart through the maintenance of GLUT4 and CPT-1B enzymes. On the other hand, co-treatment of DOX with OVX, entacapone, or FULV increased the toxic effect of DOX by further reducing these important metabolic enzymes. E2 and 2ME abrogate DOX-induced cardiomyopathy partly through modulation of GLUT 4 and CPT-1B enzymes.

Sobhy MH ，Ismail A ，Abdel-Hamid MS ，Wagih M ，Kamel M ... -  《-》

17β-Estradiol and vitamin E modulates oxidative stress-induced kidney toxicity in diabetic ovariectomized rat.

Ulas M ，Cay M 《-》

2-Methoxyestradiol ameliorates metabolic syndrome-induced hypertension and catechol-O-methyltransferase inhibited expression and activity in rats.

Metabolic syndrome (MetS) is a common disorder that is associated with hypertension and poses a significant cardiovascular risk. Deactivation of extra-neuronal norepinephrine is mediated by catechol-O-methyltransferase (COMT). Endogenous 2-methoxyestradiol (2ME) is a product of COMT activity. The current study investigated the impact of 2ME on MetS-induced hypertension and the possible alterations in COMT expression and activity in rats. Animals were randomly divided into 4 groups. Group 1 received drinking water and standard food pellets. Groups 2, 3 and 4 were subjected to experimental induction of MetS. Animals in groups 3 and 4 were given daily IP injection of 2ME (25 and 50 mg/kg, respectively). MetS animals showed significant increases in body weight gain and visceral fat, fasting blood glucose and serum insulin and insulin resistance. Meanwhile, MetS was associated with a significant hypertriglyceridemia. Further, MetS significantly increased systolic, diastolic and mean arterial blood pressure. These effects were associated with significant reduction in COMT expression in the liver, kidneys and aorta as well as reduced hepatic activity. 2ME inhibited the alterations in body weight gain, visceral fat accumulation, fasting blood glucose and serum insulin, insulin resistance and serum triglycerides. Elevations in blood pressure were significantly inhibited by 2ME. Also, it attenuated the decrease in liver, kidney and aorta COMT expression and hepatic COMT activity. MetS was associated with elevated epinephrine and norepinephrine levels. Only the higher dose of 2ME significantly mitigated the rise in epinephrine level. In conclusion, 2ME protects against MetS-induced hypertension and averts COMT inhibited expression and activity.

Azhar AS ，Zaher ZF ，Ashour OM ，Abdel-Naim AB ... -  《-》

The protective effects of prostaglandin E1 on lung injury following renal ischemia-reperfusion in rats.

For the purposes of the present study, the protective effect of prostaglandin E1 (PGE1) on lung injury following renal ischemia-reperfusion (RIR) was investigated. Adult male rats were divided into four groups, namely, (I) control rats given physiological saline; (II) rats given PGE1 (20 μg/kg, intravenously); (III) rats subjected to RIR; and (IV) rats subjected to RIR given PGE1 30 min prior to ischemia and just before reperfusion. The right nephrectomy was performed in the RIR model. The left renal pedicle was occluded for 60 min to induce ischemia and then the left kidney was subjected to reperfusion for 60 min. The lungs of rats were used for microscopic and biochemical analyses. Although rats subjected to RIR did not exhibit heavy degenerative alterations in the lung structure, they possessed pulmonary interstitial edema. Lung glutathione levels and catalase, superoxide dismutase, glutathione peroxidase, and tissue factor (TF) activities were decreased in rats subjected to RIR, while lung lipid peroxidation, myeloperoxidase (MPO), xanthine oxidase and serum lactate dehydrogenase (LDH) activities, and blood urea and serum creatinine levels were increased in these rats when compared with the control group. PGE1 treatments resulted in the regression of oxidative stress via induction of antioxidant system, the decreased MPO and LDH activities, the reduced urea and creatinine levels, and the induced TF activity in rats subjected to RIR, while edema still remained permanent. We conclude that PGE1 may be useful in preventing lung injury with the exception of edema that occurred as a result of RIR in rats.

Oztay F ，Kara-Kisla B ，Orhan N ，Yanardag R ，Bolkent S ... -  《-》