Resveratrol Antagonized Ionizing Radition-induced Myelosuppression In Mice Via JAK2/STAT3 Pathway

Background:Radiotherapy with ionizing radiation（IR）is a common auxiliary treatment for gastrointestinal cancers,but it can lead to myelosuppression,a side effect that severely affect the anticancer effects of radiotherapy.Therefore,how to alleviate the myelosuppression caused by radiotherapy has become an urgent problem to be solved,which is the key to ensure the efficacy of radiotherapy.Elevated levels of Reactive oxygen species（ROS）play a key role in radiotherapy-induced myelosuppression,and certain antioxidants antagonize IR-induced myelosuppression.Resveratrol（RSV）is a kind of non-toxic strong antioxidant with certain anti-radiation function.The JAK2/STAT3signaling has a protective effect on the hematopoietic system,and activated JAK2/STAT3 signaling leads to radiation resistance in cells.Objective:In this study,we will explore the antagonism of RSV against IR-induced myelosuppression and whether the bone marrow JAK2/STAT3 signaling pathway mediates the antagonistic effect of RSV.Methods:（1）Mice received 6Gy 137^Cs X-ray total body irradiation（TBI）for once to replicate the damage model of myelosuppression caused by IR radiotherapy;（2）The number of peripheral blood image-related indicators were detected by automated hematology analyzer;（3）Use a blood cell counter under an optical microscope to determine the number of Bone marrow mononuclear cells（BMNCs）;（4）Western blot was used to detect the expression level of JAK2/STAT3 signaling pathway related proteins（P-JAK2,JAK2,P-STAT3,and STAT3）.Results:（1）RSV antagonized TBI-induced peripheral blood cell injury in miceRSV（50,100 mg/kg,i.g.）pretreatment significantly reversed the TBI（6Gy）-induced the decrease in the number of WBC,RBC,PLT,HGB and LYM,as well as the increased of NE number.These data indicated that RSV antagonized TBI-induced peripheral blood cell injury in mice.（2）RSV antagonized TBI-induced BMNCs injury in miceRSV（50,100 mg/kg,i.g.）pretreatment significantly reversed TBI（6Gy）-induced the reduction of BMNCs,suggesting that RSV antagonized the injury of BMNCs induced by TBI in mice.（3）RSV antagonized TBI-induced the down-regulation of JAK2/STAT3signaling in bone marrow of miceRSV（50,100 mg/kg,i.g.）pretreatment significantly reversed TBI（6Gy）-induced the decrease in the ratio of P-JAK2/JAK2 and P-STAT3/STAT3 in bone marrow cells of mice,suggesting that RSV antagonized the down-regulation of JAK2/STAT3 signal in bone marrow of mice induced by TBI.（4）AG490 reversed antagonistic effect of RSV on TBI-induced peripheral blood cell injury in miceAG490（10mg/kg,i.p.）significantly reversed RSV（100mg/kg,i.g.）-exerted the increase on the number of WBC,RBC,PLT,HGB and LYM,as well as the decrease on NE number in the peripheral blood of TBI（6Gy）-exposed mice.These data indicated that AG490 effectively reversed the antagonistic effect of RSV on TBI-induced peripheral blood cell injury in mice.（5）AG490 reversed antagonistic effect of RSV on TBI-induced BMNCs injury in miceAG490（10mg/kg,i.p.）significantly reversed the increase of RSV on BMNCs in TBI（6Gy）-exposed mice,indicating that AG490 effectively reversed the antagonistic effect of RSV on TBI-induced BMNCs injuy mice.Conclusion:Resveratrol antagonized IR-induced myelosuppression in mice via JAK2/STAT3 signaling pathway.