Synergistic Effect of Hyperthermia and Neferine on Reverse Multidrug Resistance in Adriamycin-resistant SGC7901/ADM Gastric Cancer Cells

Multidrug resistance（MDR） plays a major obstacle to successful gastric cancer chemotherapy.The purpose of this study was to investigate the MDR reversal effect and mechanisms of hyperthermia in combination with neferine（Nef） in adriamycin（ADM） resistant human SGC7901/ADM gastric cancer cells.The MDR cells were heated at 42℃ and 45℃ for 30 min alone or combined with 10 μg/mL Nef.The cytotoxic effect of ADM was evaluated by MTT assay.Cellular plasma membrane lipid fluidity was detected by fluorescence polarization technique.Intracellular accumulation of ADM was monitored with high performance liquid chromatography.Mdr-1 mRNA,P-glycoprotein（P-gp）,γH2AX expression and γH2AX foci formation were determined by real-time PCR,Western blot and immunocytochemical staining respectively.It was found that different heating methods induced different cytotoxic effects.Water submerged hyperthermia had the strongest cytotoxicity of ADM and Nef combined with hyperthermia had a synergistic cytotoxicity of ADM in the MDR cells.The water submerged hyperthermia increased the cell membrane fluidity.Both water submerged hyperthermia and Nef increased the intracellular accumulation of ADM.The water submerged hyperthermia and Nef down-regulated the expression of mdr-1 mRNA and P-gp.The water submerged hyperthermia could damage DNA and increase the γH2AX expression of SGC7901/ADM cells.The higher temperature was,the worse effect was.Our results show that combined treatment of hyperthermia with Nef can synergistically reverse MDR in human SGC7901/ADM gastric cancer cells.

The non-canonical poly(A)polymerase FAM46C promotes erythropoiesis

The post-transcriptional regulation of mRNA is a crucial component of gene expression.The disruption of this process has detrimental effects on the normal development and gives rise to various diseases.Searching for novel post-transcriptional regulators and exploring their roles are essential for understanding development and disease.Through a multimodal analysis of red blood cell trait genome-wide association studies(GWAS)and transcriptomes of erythropoiesis,we identify FAM46C,a non-canonical RNA poly(A)polymerase,as a necessary factor for proper red blood cell development.FAM46C is highly expressed in the late stages of the erythroid lineage,and its developmental upregulation is controlled by an erythroidspecific enhancer.We demonstrate that FAM46C stabilizes mRNA and regulates erythroid differentiation in a polymerase activity-dependent manner.Furthermore,we identify transcripts of lysosome and mitochondria components as highly confident in vivo targets of FAM46C,which aligns with the need of maturing red blood cells for substantial clearance of organelles and maintenance of cellular redox homeostasis.In conclusion,our study unveils a unique role of FAM46C in positively regulating lysosome and mitochondria components,thereby promoting erythropoiesis.

CXCR4 and CXCR5 orchestrate dynamic germinal center reactions and may contribute to the pathogenesis of systemic lupus erythematosus

In a previous publication in Cellular and Molecular Immunology,Zhao et al.1 showed data from patients with treatment-naïve systemic lupus erythematosus(SLE),demonstrating the clinical significance and possible mechanisms of the aberrant expression of the chemokine receptor CXCR4 on lupus B cells.In this commentary,we will discuss the roles of CXCL12-CXCR4 and CXCL13-CXCR5 pairs and related signaling pathways in guiding dynamic germinal center(GC)reactions and B cell selection and describe how their dysregulation may contribute to the pathogenesis of SLE.

SIRT6 is an epigenetic repressor of thoracic aortic aneurysms via inhibiting inflammation and senescence

Thoracic aortic aneurysms(TAAs)develop asymptomatically and are characterized by dilatation of the aorta.This is considered a life-threating vascular disease due to the risk of aortic rupture and without effective treatments.The current understanding of the pathogenesis of TAA is still limited,especially for sporadic TAAs without known genetic mutation.Sirtuin 6(SIRT6)expression was significantly decreased in the tunica media of sporadic human TAA tissues.Genetic knockout of Sirt6 in mouse vascular smooth muscle cells accelerated TAA formation and rupture,reduced survival,and increased vascular inflammation and senescence after angiotensin II infusion.Transcriptome analysis identified interleukin(IL)-1βas a pivotal target of SIRT6,and increased IL-1βlevels correlated with vascular inflammation and senescence in human and mouse TAA samples.Chromatin immunoprecipitation revealed that SIRT6 bound to the Il1b promoter to repress expression partly by reducing the H3K9 and H3K56 acetylation.Genetic knockout of Il1b or pharmacological inhibition of IL-1βsignaling with the receptor antagonist anakinra rescued Sirt6 deficiency mediated aggravation of vascular inflammation,senescence,TAA formation and survival in mice.The findings reveal that SIRT6 protects against TAA by epigenetically inhibiting vascular inflammation and senescence,providing insight into potential epigenetic strategies for TAA treatment.

KHSRP combines transcriptional and posttranscriptional mechanisms to regulate monocytic differentiation

RNA-binding proteins(RBPs)are widely involved in the transcriptional and posttranscriptional regulation of multiple biological processes.The transcriptional regulatory ability of RBPs was indicated by the identification of chromatin-enriched RBPs(Che-RBPs).One of these proteins,KH-type splicing regulatory protein(KHSRP),is a multifunctional RBP that has been implicated in mRNA decay,alternative splicing,and miRNA biogenesis and plays an essential role in myeloid differentiation by facilitating the maturation of miR-129.In this study,we revealed that KHSRP regulates monocytic differentiation by regulating gene transcription and RNA splicing.KHSRP-occupied specific genomic sites in promoter and enhancer regions to regulate the expression of several hematopoietic genes through transcriptional activation and bound to pre-mRNA intronic regions to modulate alternative splicing during monocytic differentiation.Of note,KHSRP had co-regulatory effects at both the transcriptional and posttranscriptional levels on MOGOH and ADARB1.Taken together,our analyses revealed the dual DNA-and RNA-binding activities of KHSRP and have provided a paradigm to guide the analysis of other functional Che-RBPs in different biological systems.

RNA and hematopoiesis

Hematopoietic stem cells(HSCs)can differentiate into all mature functional blood cells via hematopoiesis,but can also self-renew to replenish the progenitor cell pool.Both hema-topoiesis and HSC renewal are strictly orchestrated processes to guard against dysregulation that could lead to life-threat-ening blood malignancies,such as leukemia.RNA regulatory networks have essential roles in ensuring normal hematopoi-esis.Now,state-of-the-art,high-throughput sequencing tech-nologies,including RNA-seq,CLIP-seq,ChIP-seq,ChIRP-seq,MeRIP-seq,are allowing us to gain comprehensive insights into the contribution of RNA regulatory networks to hema-topoiesis and how they might be perturbed to promote malignancies.