A novel protective role of sacubitril/valsartan in cyclophosphamide induced lung injury in rats: impact of miRNA-150-3p on NF-κB/MAPK signaling trajectories

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. 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. CP may be also used in treatment of several autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus 2. CP causes serious adverse effects that can result in multiple organs damage. Among these adverse effects are cardiotoxicity, hepatotoxicity, nephrotoxicity and lung toxicity 3,4. CP is primarily metabolized to the active metabolite 4-hydroxycyclophosphamide which is equilibrates with its tautomer; aldophosphamide. The freely diffusible proportion of aldophosphamide into cells is minor, which it is subject to decomposition into two phosphoramide

β-Elemene Attenuates Fibrosis after Esophageal Endoscopic Submucosal Dissection via Modulating the HIF-1α/HK2/p38-MAPK Signaling Axis

“…In this sense, we accordingly designed a series of gain- and loss-of function experiments, verifying that HIF-1α could modulate the fibrogenic activation of esophageal primary fibroblasts through HK2-mediated phosphorylation of the p38MAPK signaling pathway. This finding corroborates a recent report which correlated repressing the p38MAPK signaling pathway with abrogating lung fibrosis . Following the identification of the HIF-1α/HK2/p38MAPK axis, we further conducted a series of gain- and loss-of function experiments, so as to explore the effect of the β-elemene-mediated HIF-1α/HK2/p38MAPK axis on the proliferation and apoptosis of esophageal fibroblasts.…”

Protective effect of alogliptin against cyclophosphamide-induced lung toxicity in rats: Impact on PI3K/Akt/FoxO1 pathway and downstream inflammatory cascades

“…CP is associated with genotoxicity and numerous hazardous impacts on numerous organs due to its capability to stimulate oxidative burden with consequent cell death (El-Emam 2020). Among these toxicities are cardiotoxicity (Iqubal et al 2019), hepatotoxicity (Abdelfattah-Hassan et al 2019), nephrotoxicity (Sharma et al 2017), in addition to lung toxicity (El-kashef 2018;Abdel-Latif et al 2020).…”

Ellagic acid alleviates high glucose-induced podocyte and renal epithelial cell apoptosis and hyperglycemia-induced renal injury by regulating NF-κB/miR-150-3p/BCL2

“…The previous study exhibits that over-activation of NF-κB accelerates miR-150-3p expression to inhibit osteogenesis [26]. In addition, cyclophosphamide induces lung injury in rats by promoting NF-κBmediated up-regulation of miR-150-3p [25]. These ndings indicate that the NF-κB/miR-150-3p signaling axis may be associated with tissue injury.…”

“…EA has been highlighted as a NF-κB inhibitor to alleviate multiple pathological processes, including DN [9]. Moreover, NF-κB can modulate miR-150-3p expression in several diseases [25,26]. Herein, we hypothesized that EA-mediated NF-κB/miR-150-3p might be implicated in HG-induced RTEC and podocyte apoptosis.…”