Abstract
Cyclophosphamide (CP) is a chemotherapeutic agent that induces oxidative stress causing multiple organ damage. Sacubitril/valsartan, is a combined formulation of neprilysin inhibitor (sacubitril) and angiotensin II receptor blocker (valsartan), that induces the protective effect of brain natriuretic peptide. The aim of the current study is to investigate the prophylactic impacts of sacubitril/valsartan versus valsartan against CP-induced lung toxicity in rats. Rats were assigned randomly into 6 groups; control; received corn oil (2 ml/kg/day; p.o. for 6 days), sacubitril/valsartan (30 mg/kg; p.o. for 6 days), valsartan (15 mg/kg; p.o. for 6 days), CP (200 mg/kg; i.p. on day 5), sacubitril/valsartan + CP (30 mg/kg; p.o. for 6 days, 200 mg/kg; i.p. single dose on day 5, respectively), valsartan + CP (15 mg/kg; p.o. for 6 days, 200 mg/kg; i.p. single dose on day 5, respectively). Both sacubitril/valsartan and valsartan produced a significant decrease in the inflammation and fibrosis markers in the BALF, in comparison with the CP group. Both sacubitril/valsartan and valsartan produced an apparent decrease in the relative genes expression of miR-150-3p and NF-κB, as well as a significant decrease in the relative expression of P38 and ERK1/2 MAPKs and an increase in the relative gene expression of Nrf-2, compared to CP group. Intriguingly, sacubitril/valsartan , showed subtle superiority in almost all investigated parameters, compared to valsartan. In conclusion, sacubitril/valsartan effectively abrogated the CP induced lung inflammation and fibrosis, providing a potential promising protection that could be linked to their ability to inhibit miR-150-3p via inhibition of NF-κB and MAPK signaling pathways.
Highlights
Cyclophosphamide (CP) is a chemotherapy that is broadly prescribed for the treatment of different types of cancer such as lymphomas, leukemia and multiple myeloma[1]
Normal rats treated with sacubitril/valsartan or valsartan showed no significant difference in the relative gene expression or the protein concentration of Nrf-2 compared to control rats (Fig. 1A,B respectively)
Pretreatment with sacubitril/valsartan or valsartan followed by CP showed a marked increase in the relative gene expression of Nrf-2 together with an almost 40% increase in the protein concentration of Nrf-2 compared to CP treated rats (Fig. 1A,B respectively)
Summary
Cyclophosphamide (CP) is a chemotherapy that is broadly prescribed for the treatment of different types of cancer such as lymphomas, leukemia and multiple myeloma[1]. The positive regulation of Nrf[2] is ensued via its phosphorylation by PI3K, PKC, c-Jun, N-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK), while the bi-faceted regulation of Nrf[2] pathway by p38 MAPK is ensued both positively and negatively. Another noncanonical pathway of Nrf[2] activation involving autophagy is reported to be closely associated with the autophagy substrate p62. The dysregulation of autophagy results in excessive Nrf[2] activation that leads to pathological negative effects. Oxidative stress results in the activation of several MAPK regulators such as p38 and ERK1/2 resulting in further activation of NF-κB and the increase in the cell p roliferation[9]
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