Aminoglycosides (AGs) such as gentamicin (gen) are considered as the optimum therapy for many infections and diseases. Unfortunately, AGs treatment has been linked to acute kidney injury that is also referred to as nephrotoxicity. In the current study, we sought to explore the protective roles of peppermint (pep) and licorice (Lic) extracts as well as their mixture on gen-induced nephrotoxicity. Forty male and female Wistar albino rats were divided into 5 experimental groups: C-was administered with 2 ml of normal saline as a single daily dose intraperitoneally (i.p.) for 14 d. C+ was administered with once-daily i.p. injections of 100 mg/kg BW gen for 8 d. T1 group was administered once-daily i.p. of gen (100mg/kg BW) for 8 d. and Lic ethanolic extract (EE) (100mg/kg BW) every 12 hr for 14 d. T2 was administered once-daily i.p. of gen for 8 d. and pep EE (100mg/kg BW) every 12 hr for 14 d. T3 was administered once-daily i.p. of gen for 8 d. in addition to lic and pep EE mixture (100mg/kg BW) every 12 hr for 14 d. At the end of the study, all rats were anesthetized and trunk blood collected to study renal injury parameters. Those include serum enzymes such as AST, ALT, and ALP; kidney damage markers including urea, creatinine, and total protein; serum electrolytes including Cl, K, and Na levels as well as other renal function markers such as Glutathione peroxidase (GSH) and superoxide dismutase (SOD). All the parameters that indicated the nephrotoxicity occurrence in the C+ group in response to gen were found to be highly improved in most of the studied aspects in T1, T2, and T3. We found that Lic and pep extracts improve renal injury, kidney damage, and renal function markers opposed to gentamicin treatment. In conclusion, our study suggests prescribing those remedies to AGs receiving patients.

Asparaginase (ASNase) is widely used to treat acute lymphoblastic leukemia (ALL) in children but it causes metabolic complications related to liver toxicity. ASNase results in synthesis of some factors such as ATF4. The eIF2-ATF4 pathway is essential for cell survival during amino acid starvation conditions. Activation of the AAR in liver requires the eIF2 kinase called general control nonderepressible 2 kinase (GCN2). To what extent activation of the GCN2-eIF2-AAR is mediated by ATF4 is unknown. Our objective and hypothesis are addressed in our aim to describe the liver response to ASNase in mice deleted for Atf4. RNA sequencing alongside complementary biochemical approaches were performed in the livers of mice treated with eight daily injections of ASNase or saline excipient. Differences in gene expression were evaluated. We also explored the relationship between the different treatment groups and strains. This research provides insight into the importance of genetic background of patients in choosing ASNase as a treatment.

Asparaginase (ASNase) treatment results in synthesis of some factors such as ATF4. The eIF2-ATF4 pathway is essential for cell survival during amino acid starvation conditions. Activation of the AAR in liver requires the eIF2 kinase called general control nonderepressible 2 kinase (GCN2). To what extent activation of the GCN2-eIF2-AAR is mediated by ATF4 is unknown. Our objective and hypothesis are addressed in our aim to describe the liver response to ASNase in mice deleted for Atf4. RNA sequencing alongside complementary biochemical approaches were performed in the livers of mice treated with eight daily injections of ASNase or saline excipient. Cellular pathways examined in detail included the AAR. We discovered that global hepatic gene expression patterns in Atf4 knockout mice overlapped with Gcn2 knockout mice. Shared hepatic pathways or processes altered during ASNase included mTOR signaling, and xenobiotic metabolism. On the other hand, loss of Atf4 during ASNase uniquely altered gene expression signatures reflecting signaling via eIF2 and ER stress. This research provides insight into the importance of genetic background of patients in choosing ASNase as a treatment.