Promoter variations in DBR2-like affect artemisinin production in different chemotypes of Artemisia annua

Artemisia annua is the only known plant source of the potent antimalarial artemisinin,which occurs as the low-and high-artemisinin producing(LAP and HAP)chemotypes.Nevertheless,the different mechanisms of artemisinin producing between these two chemotypes were still not fully understood.Here,we performed a comprehensive analysis of genome resequencing,metabolome,and transcriptome data to systematically compare the difference in the LAP chemotype JL and HAP chemotype HAN.Metabolites analysis revealed that 72.18%of sesquiterpenes was highly accumulated in HAN compared to JL.Integrated omics analysis found a DBR2-Like(DBR2L)gene may be involved in artemisinin biosynthesis.DBR2L was highly homologous with DBR2,belonged to ORR3 family,and had the DBR2 activity of catalyzing artemisinic aldehyde to dihydroartemisinic aldehyde.Genome resequencing and promoter cloning revealed that complicated variations existed in DBR2L promoters among different varieties of A.annua and were clustered into three variation types.The promoter activity of diverse variant types showed obvious differences.Furthermore,the core region(-625 to 0)of the DBR2L promoter was identified and candidate transcription factors involved in DBR2L regulation were screened.Thus,the result indicates that DBR2L is another key enzyme involved in artemisinin biosynthesis.The promoter variation in DBR2L affects its expression level,and thereby may result in the different yield of artemisinin in varieties of A.annua.It provides a novel insight into the mechanism of artemisinin-producing difference in LAP and HAP chemotypes of A.annua,and will assist in a high yield of artemisinin in A.annua.

lncRNA HITT Inhibits Lactate Production by Repressing PKM2 Oligomerization to Reduce Tumor Growth and Macrophage Polarization

Lactic acid acidifies the tumor microenvironment and promotes multiple critical oncogenic processes,including immune evasion.Pyruvate kinase M2(PKM2)is a dominant form of pyruvate kinase(PK)expressed in cancers that plays essential roles in metabolic reprograming and lactate production,rendering it as an attractive therapeutic target of cancer.However,the mechanism underlying PKM2 regulation remains unclear.Here,we show that long noncoding RNA(lncRNA)HIF-1αinhibitor at transcription level(HITT)inhibits lactate production in a PKM2-dependent manner.Mechanistically,it physically interacts with PKM2 mapped to a region that has been involved in both dimer(less-active)and tetramer(more-active)formation,inhibiting PKM2 oligomerization and leading to dramatic reduction of PK activity.Under glucose starvation,HITT was reduced as a result of miR-106 induction,which subsequently facilitates PKM2 oligomerization and increases vulnerability to apoptosis under glucose starvation stress.In addition,the interaction also reduces lactate secretion from cancer cells,which subsequently polarizes macrophages toward an M2-like anti-inflammatory phenotype and thus possibly contributes to immune escape in vivo.This study highlights an important role of an lncRNA in regulating PKM2 activity and also reveals a metabolic regulatory effect of PKM2 on macrophage polarization.

Single stage complete resection of giant dumbbell lumbar ganglioneuroma: a case report and review of the literature

Background;Ganglioneuroma is a rare benign tumor,which is usually located in the posterior mediastinum and retroperitoneum.Occasionally,it involves the paraspinal region with intraspinal extension and becomes dumbbell shaped.Dumbbell ganglioneuromas rarely affect the lumbar spine,and only nine cases of dumbbell lumbar ganglioneuromas have been reported previously.Case presentation;We are reporting an extremely rare case of a giant dumbbell tumor in the lumbar spine.We performed a one stage total resection of the tumor with posterior approach and long-segment fixation and fusion.This approach is different from previous methods.Histopathological examination of the surgical specimen confirmed the diagnosis of ganglioneuroma.Thirty months follow up showed a satisfactory outcome.Conclusions:Single-stage posterior tumor resection with fixation and fusion is effective and an appropriate choice for the treatments of lumbar dumbbell ganglioneuromas.