Renal tubule-targeted dexrazoxane suppresses ferroptosis in acute kidney injury by inhibiting ACMSD

Acute kidney injury(AKI)is a heterogeneous clinical complication with no existing definite or particular therapies.Therefore,molecular mechanisms and approaches for treating acute kidney injury are in urgent need.Herein,we demonstrated that dexrazoxane(DXZ),a U.S.Food and Drug Administration(FDA)-approved cardioprotective drug,can both functionally and histologically attenuate cisplatin or ischemia-reperfusion injury-induced AKI in vitro and in vivo via inhibiting ferroptosis specifically.This effect is characterized by decreasing lipid peroxidation,shown by the biomarker of oxidative stress 4-hydroxynonenal(HNE)and prostaglandinendoperoxide synthase 2(Ptgs2),while reversing the downregulation of glutathione peroxidase 4(GPX4)and ferritin 1(FTH-1).Mechanistically,the results revealed that DXZ targeted at the renal tubule significantly inhibits ferroptosis by suppressingα-amino-β-carboxymuconate-ε-semialdehyde decarboxylase(ACMSD).Furthermore,the conjugation of dexrazoxane and polysialic acid(DXZ-PSA)is specifically designed and utilized to enhance the therapeutic effect of DXZ by long-term effect in the kidney,especially retention and targeting in the renal tubules.This study provides a novel therapeutic approach and mechanistic insight for AKI by inhibiting ferroptosis through a new type drug DXZPSA with the enhanced renal distribution.

MicroRNAs participate in the cardioprotective activity of dexrazoxane against doxorubicin-induced cardiotoxicity

Background The co-administration of dexrazoxane （DEX） with each dose of doxoruhicin （Dox） is an efficient strategy to relieve Dox-induced cardiotoxicity, however, the mechanisms underlying the cardioprotective effect of DEX have not been well elucidated. MieroRNAs （miRNAs） are endogenous, small non-coding RNAs that negatively regulate gene expression in diverse biological and pathological processes. The aim of the present study was to investigate whether the certain cardiac miRNAs were involved in DOX-induced cardiotoxicity. Methods Male SD rats were randomized into five groups, including the 4-week （cumulative dose： 16 mg/kg） and the 8-week （cumulative dose： 32 mg/kg） Dox-treated groups, and the corresponding 4-week and 8-week Dox plus DEX-treated groups and the normal control group. Heart functions of the animals were detected by echocardiography. Quantitative real-time PCR was used to determine the expression of cardiac remodeling, apoptosis-related genes and mature micoRNAs of interest. Results The echocardiography detection showed that cardiac remodeling and impaired heart function were observed after 4-week and 8-week Dox treatment, and the cardiac remodeling and decreased ejection fraction （EF%） and fractional shortening （FS%） were efficiently rescued in the corresponding 4-week and 8-week Dox plus DEX-treated groups. The myocardial expression of Anp and CTGF mRNA was significantly upregulated by Dox treatment, but the upregulation of Anp and CTGF mHNA was blocked in the Dox plus DEX-treated groups. IGF-1 mRNA was significantly up-regulated in rat myocardium in Dox plus DEX-treated groups, with no significant changes of Bcl-2 and BAX mRNA expression. Mature miRNAs determination demonstrated that the myocardial miR-1 and -30e were significantly down-regulated and miR-21 and -208b were significantly up-regulated in Dox treatment groups, but the above miRNA dysregulation could be efficiently reversed after DEX treatment. Conclusions DEX could tune the microRNAs dysregulation in Dox-treated rat myocardium, miRNAs participated in the cardioprotective activity of DEX against Dox-induced cardiotoxicity.

Overview, prevention and management of chemotherapy extravasation

Chemotherapy extravasation remains an accidental complication of chemotherapy administration and may result in serious damage to patients. We review in this article the clinical aspects of chemotherapy extravasation and latest advances in definitions, classification, pre-vention, management and guidelines. We review the grading of extravasation and tissue damage according to various chemotherapeutic drugs and present an update on treatment and new antidotes including dexrazoxane for anthracyclines extravasation. We highlight the importance of education and training of the oncology team for prevention and prompt pharmacological and non-pharmacological management and stress the availability of new antidotes like dexrazoxane wherever anthracyclines are being infused.