Gossypol acetic acid regulates leukemia stem cells by degrading LRPPRC via inhibiting IL-6/JAK1/STAT3 signaling or resulting mitochondrial dysfunction

BACKGROUND Leukemia stem cells(LSCs)are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia(AML),as they are protected by the bone marrow microenvironment(BMM)against conventional therapies.Gossypol acetic acid(GAA),which is extracted from the seeds of cotton plants,exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2.AIM To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism.METHODS In this study,LSCs were magnetically sorted from AML cell lines and the CD34+CD38-population was obtained.The expression of leucine-rich pentatricopeptide repeat-containing protein(LRPPRC)and forkhead box M1(FOXM1)was evaluated in LSCs,and the effects of GAA on malignancies and mitochondrial RESULTS LRPPRC was found to be upregulated,and GAA inhibited cell proliferation by degrading LRPPRC.GAA induced LRPPRC degradation and inhibited the activation of interleukin 6(IL-6)/janus kinase(JAK)1/signal transducer and activator of transcription(STAT)3 signaling,enhancing chemosensitivity in LSCs against conventional chemotherapies,including L-Asparaginase,Dexamethasone,and cytarabine.GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC.Furthermore,GAA induced reactive oxygen species accumulation,disturbed mitochondrial homeostasis,and caused mitochondrial dysfunction.By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC,GAA resulted in the elimination of LSCs.Meanwhile,GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage.CONCLUSION Taken together,the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.

Shenqi Fuzheng Injection Ameliorates Radiation-induced Brain Injury

Shenqi Fuzheng injection(SFI)has been confirmed to be able to alleviate brain injury in mice.This study examined the brain-protective effect of SFI on patients after cranial radiation.Lung cancer patients with brain metastasis were randomly assigned to two groups.The SFI group received cranial radiation in combination with SFI.The control group received cranial radiation alone.The changes in cognitive function were evaluated pre- and post-radiation against the Mini-Mental State Exam(MMSE),Montreal Cognitive Assessement(MoCA),Zung Self-Rating Depression Scale(SDS)and Zung Self-Rating Anxiety Scale(SAS).The changes in inflammatory factors,such as TGF-β1,TNF-α and IL-10,were also detected before,during and after radiation(15Gy/5F).The results showed that 6 months after cranial radiation,the total scores on the MMSE and MoCA scales of the patients decreased,especially memory ability.The control group experienced a more evident decline,the memory ability being the greatest.TGF-β1 and TNF-α increased shortly after radiation and decreased one month later,and the change was more conspicuous in SFI group than in control group.IL-10 increased after radiation and stayed at a high level one month later in both groups,the level being higher in the SFI group than in the control group.Our study indicated that cognitive functions,especially memory ability,were impaired after cranial radiation.SFI could alleviate radiation-induced brain injury by regulating inflammatory factors.