Cynaroside regulates the AMPK/SIRT3/Nrf2 pathway to inhibit doxorubicin-induced cardiomyocyte pyroptosis

Doxorubicin(DOX)is a commonly administered chemotherapy drug for treating hematological malignancies and solid tumors;however,its clinical application is limited by significant cardiotoxicity.Cynaroside(Cyn)is a flavonoid glycoside distributed in honeysuckle,with confirmed potential biological functions in regulating inflammation,pyroptosis,and oxidative stress.Herein,the effects of Cyn were evaluated in a DOX-induced cardiotoxicity(DIC)mouse model,which was established by intraperitoneal injections of DOX(5 mg/kg)once a week for three weeks.The mice in the treatment group received dexrazoxane,MCC950,and Cyn every two days.Blood biochemistry,histopathology,immunohistochemistry,reverse transcription-quantitative polymerase chain reaction(RT-qPCR),and western blotting were conducted to investigate the cardioprotective effects and potential mechanisms of Cyn treatment.The results demonstrated the significant benefits of Cyn treatment in mitigating DIC;it could effectively alleviate oxidative stress to a certain extent,maintain the equilibrium of cell apoptosis,and enhance the cardiac function of mice.These effects were realized via regulating the transcription levels of pyroptosis-related genes,such as nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3),caspase-1,and gasdermin D(GSDMD).Mechanistically,for DOX-induced myocardial injury,Cyn could significantly modulate the expression of pivotal genes,including adenosine monophosphate-activated protein kinase(AMPK),peroxisome proliferator-activated receptorγcoactivator-1α(PGC-1α),sirtuin 3(SIRT3),and nuclear factor erythroid 2-related factor 2(Nrf2).We attribute it to the mediation of AMPK/SIRT3/Nrf2 pathway,which plays a central role in preventing DOX-induced cardiomyocyte injury.In conclusion,the present study confirms the therapeutic potential of Cyn in DIC by regulating the AMPK/SIRT3/Nrf2 pathway.

Real-world outcomes of niraparib treatment in patients with ovarian cancer:amulticenter non-interventional study in China

Dear Editor,Ovarian cancer remains the deadliest among all gynecological cancers.Although most patients at advanced stage respond to initial treatment,the majority experience recurrence[1].It was estimated that 55,342 new cases and 37,519 deaths from ovarian cancer occurred in China annually[2].Contemporarily,the treatment landscape has changed rapidly since the role of poly(adenosine diphosphate-ribose)polymerase inhibitors(PARPi)in ovarian cancer treatmentwas explored.Based on data from the PRIMA/ENGOT-OV26/GOG-3012[3]and ENGOTOV16/NOVA trials[4],niraparib has been approved globally as maintenance therapy for newly diagnosed and platinum-sensitive recurrent ovarian cancer.The indication of niraparib for salvage treatment was based on the results of the QUADRA(NCT02354586)trial[5].Although niraparib has been tested in prospective randomized clinical trials(RCTs),no multicenter study on its real-world application in China had been conducted.Considering the differences in population,accessibility and affordability of drugs,the results of the real-world settings may differ from those of RCTs.Therefore,we conducted this multicenter,non-interventional study at 8 hospitals.