The CD24-Siglec G axis protects mice against cuprizone-induced oligodendrocyte loss: targeting danger signal for neuroprotection

Oligodendrocytes play a critical role in neuroprotection by both remyelination-dependent and remyelination-independent mechanisms and confer protection in both inflammatory and degenerative diseases that involve the central nervous system,including multiple sclerosis,Alzheimer’s disease and potentially Parkinson’s disease.1,2,3,4 Although accumulating data have supported a major role for inflammation in the susceptibility of oligodendrocytes to cuprizone,the molecular pathways that regulate oligodendrocyte survival have not been well established.Here,we report that the targeted mutation of either Cd24 or Siglecg,which forms an axis that selectively regulates the innate inflammatory response to danger-associated molecular patterns(DAMPs),protects mice against cuprizone-induced oligodendrocyte loss.Moreover,the systemic administration of CD24Fc,which is known to stimulate Siglec G signaling and suppress the inflammatory response in vivo,protects oligodendrocytes against chronic exposure to cuprizone.Our data suggest that the host response to cellular injury actively participates in oligodendrocyte loss and provides a new approach to maintain oligodendrocytes under pathological conditions.

New insights into molecules and pathways of cancer metabolism and therapeutic implications

Cancer cells are abnormal cells that can reproduce and regenerate rapidly.They are characterized by unlimited proliferation,transformation and migration,and can destroy normal cells.To meet the needs for cell proliferation and migration,tumor cells acquire molecular materials and energy through unusual metabolic pathways as their metabolism is more vigorous than that of normal cells.Multiple carcinogenic signaling pathways eventually converge to regulate three major metabolic pathways in tumor cells,including glucose,lipid,and amino acid metabolism.The distinct metabolic signatures of cancer cells reflect that metabolic changes are indispensable for the genesis and development of tumor cells.In this review,we report the unique metabolic alterations in tumor cells which occur through various signaling axes,and present various modalities available for cancer diagnosis and clinical therapy.We further provide suggestions for the development of anti-tumor therapeutic drugs.

En masse discovery of anti-cancer human monoclonal antibodies by de novo assembly of immunoglobulin sequences from transcriptomes and genome sequences of cancer tissues

TO THE EDITOR:Characterization of the tumor-infiltrating B cell immunoglobulin(Ig)repertoire is critical to understanding B cell immunity in tumors and developing monoclonal antibody therapy.However,the generation of specific antibodies for cancer therapy1,2 is a major endeavor,involving a lengthy process of antigen identification,immunization,hybridoma production and,in most cases,antibody humanization.As a radical departure from the conventional approach,we hereby describe a rapid and potentially en masse identification of cancer-specific antibodies directly from human cancer tissues by de novo assembly from transcriptome and genome sequences.Our integrated computational framework was developed and successfully tested for antibody discovery by mining 1945 solid tumor RNA-sequencing-based samples for abundant Ig CDR3 sequences among the TCGA database of glioblastoma multiforme(GBM),lower grade glioma(LGG),lung adenocarcinoma(LUAD),lung squamous carcinoma(LUSC),pancreatic adenocarcinoma(PAAD),and skin cutaneous melanoma(SKCM).

重组nkx2.5腺病毒抑制过氧化氢诱导的H9c2细胞凋亡

为研究心脏发育关键基因nkx2.5的功能及应用价值,构建Ad-Nkx2.5重组腺病毒,并检测nkx2.5过表达拮抗氧化应激损伤的效应及机制。采用AdEasy腺病毒表达系统构建Ad-Nkx2.5重组腺病毒,建立H2O2诱导H9c2心肌细胞凋亡模型,分别用Ad-Nkx2.5重组病毒或对照病毒感染细胞,采用Hoechst33342染色观察细胞形态变化、MTT法检测细胞存活率,免疫印迹检测caspase-3活化、细胞色素C的胞浆含量。并通过Real-timePCR检测凋亡相关基因bcl-2和bax表达。结果发现,nkx2.5过表达促进H9c2细胞存活,抑制H2O2诱导的caspase-3活化及线粒体细胞色素C的释放。Nkx2.5过表达上调bcl-2表达,显著下调H2O2诱导的bax表达。并发现H2O2对Nkx2.5核定位无明显影响。结果显示重组腺病毒介导的Nkx2.5过表达可通过调控凋亡相关基因表达,抑制线粒体凋亡途径,保护心肌细胞抗氧化损伤。

抗病毒免疫和自身免疫中的浆细胞样树突状细胞

浆细胞样树突状细胞(pDCs)是一类重要的免疫细胞,在病毒感染应答中产生大量的Ⅰ型干扰素.pDCs通过特异性表达TLR7和TLR9识别病毒核酸,成为专职的Ⅰ型干扰素产生细胞.pDCs产生的Ⅰ型干扰素可以直接抑制病毒复制,同时使pDCs成为连接先天性免疫和获得性免疫的桥梁.由Toll样受体识别自身核酸导致的pDCs的异常活化,以及由此持续产生Ⅰ型干扰素的现象普遍发生在一些自身免疫性疾病中.在病毒感染性和自身免疫性疾病的治疗过程中,pDCs可以作为调控免疫系统的重要靶点发挥作用.

Siglec genes confer resistance to systemic lupus erythematosus in humans and mice

A recent meta-analysis revealed the contribution of the SIGLEC6 locus to the risk of developing systemic lupus erythematosus(SLE).However,no specific Siglec(sialic acid-binding immunoglobulin-like lectin)genes(Siglecs)have been implicated in the pathogenesis of SLE.Here,we performed in silico analysis of the function of three major protective alleles in the locus and found that these alleles were expression quantitative trait loci that enhanced expression of the adjacent SIGLEC12 gene.These data suggest that SIGLEC12 may protect against the development of SLE in Asian populations.Consistent with human genetic data,we identified two missense mutations in lupus-prone B6.NZMSle1/Sle2/Sle3(Sle1–3)mice in Siglece,which is the murine Siglec with the greatest homology to human SIGLEC12.Since the mutations resulted in reduced binding of Siglec E to splenic cells,we evaluated whether Siglece−/−mice had SLE phenotypes.We found that Siglece−/−mice showed increased autoantibody production,glomerular immune complex deposition and severe renal pathology reminiscent of human SLE nephropathy.Our data demonstrate that the Siglec genes confer resistance to SLE in mice and humans.

Trap1a is an X-linked and cell-intrinsic regulator of thymocyte development

The X-linked Trap1a gene encodes the tumor rejection antigen P1A,which is expressed in fetal tissues and multiple lineages of tumor cells.The function of this gene remains unknown.Using chimeric mice with wild-type(WT)and Trap1a^(−/y)bone marrow,we show that Trap1a^(−/y)donor cells are capable of generating most lineages of hematopoietic cells,with the notable exception of T cells.Deletion of Trap1a selectively arrests T-cell development at double-negative stage 1(DN1,with a CD4^(−)CD8^(−)CD25^(−)CD44^(+)phenotype).Because Trap1a is expressed in Lin^(−)Sca-1^(+)c-Kit^(+)and common lymphoid progenitors but not in immature thymocytes(DN1-DN4),Trap1a mutations affect the differentiation potential of progenitor cells without directly acting on T cells.Despite a similarity in the blockade of DN1 to DN2 transition,the Trap1a^(−/y)DN1 cells have normal expression of c-Kit,in contrast to what was reported in the Notch1^(−/−)DN1.Complementary DNA profiling of Trap1a^(−/y)and WT embryonic stem cells shows that Trap1a does not regulate the Notch pathway.Our data reveal that Trap1a is an X-linked regulator that affects the differentiation potential of progenitor cells into T cells through a Notch-independent mechanism and identify an important function for the Trap1a gene.

PLGA nanodepots co-encapsulating prostratin and anti-CD25 enhance primary natural killer cell antiviral and antitumor function

Natural killer(NK)cells are attractive effector cells of the innate immune system against human immunodeficiency virus(HIV)and cancer.However,NK cell therapies are limited by the fact that target cells evade NK cells,for example,in latent reservoirs(in HIV)or through upregulation of inhibitory signals(in cancer).To address this limitation,we describe a biodegradable nanoparticlebased“priming”approach to enhance the cytotoxic efficacy of peripheral blood mononuclear cell-derived NK cells.We present poly(lactic-co-glycolic acid)(PLGA)nanodepots(NDs)that co-encapsulate prostratin,a latency-reversing agent,and anti-CD25(aCD25),a cell surface binding antibody,to enhance primary NK cell function against HIV and cancer.We utilize a nanoemulsion synthesis scheme to encapsulate both prostratin and aCD25 within the PLGA NDs(termed Pro-aCD25-NDs).Physicochemical characterization studies of the NDs demonstrated that our synthesis scheme resulted in stable and monodisperse Pro-aCD25-NDs.The NDs successfully released both active prostratin and anti-CD25,and with controllable release kinetics.When Pro-aCD25-NDs were administered in an in vitro model of latent HIV and acute T cell leukemia using J-Lat 10.6 cells,the NDs were observed to prime J-Lat cells resulting in significantly increased NK cell-mediated cytotoxicity compared to free prostratin plus anti-CD25,and other controls.These findings demonstrate the feasibility of using our Pro-aCD25-NDs to prime target cells for enhancing the cytotoxicity of NK cells as antiviral or antitumor agents.

Targeting HECTD3-IKKα axis inhibits inflammation-related metastasis

Metastasis is the leading cause of cancer-related death.The interactions between circulating tumor cells and endothelial adhesion molecules in distant organs is a key step during extravasation in hematogenous metastasis.Surgery is a common intervention for most primary solid tumors.However,surgical trauma-related systemic inflammation facilitates distant tumor metastasis by increasing the spread and adhesion of tumor cells to vascular endothelial cells(ECs).Currently,there are no effective interventions to prevent distant metastasis.Here,we show that HECTD3 deficiency in ECs significantly reduces tumor metastasis in multiple mouse models.HECTD3 depletion downregulates expression of adhesion molecules,such as VCAM-1,ICAM-1 and E-selectin,in mouse primary ECs and HUVECs stimulated by inflammatory factors and inhibits adhesion of tumor cells to ECs both in vitro and in vivo.We demonstrate that HECTD3 promotes stabilization,nuclear localization and kinase activity of IKKa by ubiquitinating IKKa with K27-and K63-linked polyubiquitin chains at K296,increasing phosphorylation of histone H3 to promote NF-kB target gene transcription.Knockout of HECTD3 in endothelium significantly inhibits tumor cells lung colonization,while conditional knockin promotes that.IKKa kinase inhibitors prevented LPS-induced pulmonary metastasis.These findings reveal the promotional role of the HECTD3-IKKa axis in tumor hematogenous metastasis and providea potential strategy for tumormetastasis prevention.

How sugar instigates macrophages to be evils in tumor

In a recent issue of the journal Cancer Cell,Shi et al.reported that glucose metabolism remodels pro-tumoral functions of tumor-associated macrophages(TAMs)to support cancer metastasis and chemoresistance.Mechanistically,the consumption of glucose fuels hexosamine biosynthetic pathway(HBP)and enhances O-GlcNAcylation of Cathepsin B in macrophages,which upon secretion disrupts the tumor microenvironment(TME)[1].

Strategic consideration on treatment of multiple myeloma

Multiple myeloma （MM） remains an incurable neoplastic disease, although high-dose chemotherapy supported by autologous stem cells, and the latest integration of several novel agents, including thalidomide, bortezomib and lenalidomide, into each step of therapeutics have substantially improved the outcome of patients with MM.1-5 Herein, we gave our own considerations on some promising directions in the near future, aiming at further improving the survival and the quality of life of MM patients, and even achieving our final goal of the cure of MM, including highlighting stratified and individualized therapies, pursuing novel targets and strategies, unraveling the biological characteristics of myeloma initiation cells and strengthening post-transplant immunotherapies.