Recent advance in the structural analysis of HIV-1 envelope protein

Human immunodeficiency virus type 1 （HIV-1）, a causative agent of AIDS, is affecting today more than 35 millions of people worldwide. The advance of anti-HIV chemotherapy has made AIDS a chronic non-fatal disease in resourceful countries. Longawaited anti-HIV-1 vaccine is still not with us yet; however, great progress in structural analyses of the envelope protein of HIV-1 in recent years starts to shed light on rational intervention targeted at the envelope protein, as will be reviewed in this article.

TNFR2 expression on non-bone marrow-derived cells is crucial for lipopolysaccharide-induced septic shock and downregulation of soluble TNFR2 level in serum

Persistently high serum levels of soluble tumor-necrosis factor(TNF)receptor 2(sTNFR2)have been observed in septic shock and many inflammatory diseases.However,its origin and regulation during these pathological processes are still largely unknown.In this study,murine bone marrow(BM)chimeras selectively expressing TNFR2 on either BM-derived or non-BM-derived cells were generated and challenged with lipopolysaccharide(LPS).The results show that TNFR2 expression on non-BM-derived cells is crucial for both the sensitivity of mice to LPS and the downregulation of sTNFR2 in serum.Most importantly,sTNFR2 was released from both BM-and non-BM-derived cells.Non-BM TNFR1 expression influenced the sensitivity of mice to LPS challenge but not the level of serum sTNFR2.These results provide the first in vivo evidence for the origin and regulation of sTNFR2 in serum and could aid in the development of novel anti-TNF strategies against septic shock.

Paradoxical Roles of IL-4 in Tumor Immunity

Interleukin(IL)-4 is a crucial cytokine in tumor immunology.In the initial murine experiments,IL-4 exhibited potent anti-tumor ability.Tumors genetically modified to produce IL-4 were rejected,while parental tumors grew progressively.Mice rejected IL-4-producing tumors got long-lasting anti-tumor immunity.The comparative study showed that IL-4 induced the most effective immune response among several cytokines in both prophylactic and therapeutic models.All of these indicate IL-4 has strong potential as a tumor therapy agent.However,contrary evidence indeed exists,and is becoming more and more abundant which shows IL-4 is a tumor-promoting molecule.IL-4 amounts are usually elevated in human cancer patients.IL-4 knockout mice are more resistant to tumor challenge than IL-4 competent mice.Furthermore,tumor cells of various histological origins often express increased levels of IL-4 receptor in comparison to their normal counterparts.By carefully examining presently available data,we found the effects of IL-4 in tumor immunity are closely related to its sources,expressing time and dose,as well as the molecular and cellular environments.In this mini-review,we concentrate on illustrating the paradoxical roles and underlying mechanisms of IL-4 in tumor immunity and try to understand how one molecule has opposite effects.

Impaired tumor angiogenesis and VEGF- induced pathway in endothelial CD146 knockout mice

CD146 is a newly identified endothelial biomarker that has been implicated in angiogenesis. Though in vitro angio- genic function of CD146 has been extensively reported, in vivo evidence is still lacking. To address this issue, we generated endothelial-specific CD146 knockout （CD146 EC-Ko） mice using the Tg（Tek-cre） system. Surprisingly, these mice did not exhibit any apparent morphological defects in the development of normal retinal vasculature. To evaluate the role of CD146 in pathological angiogenesis, a xenograft tumor model was used. We found that both tumor volume and vascular density were significantly lower in CD146Ec-KO mice when compared to WT littermates. Additionally, the ability for sprouting, migration and tube formation in response to VEGF treatment was impaired in endothelial cells （ECs）of CD146Ec-Ko mice. Mechanistic studies further confirmed that VEGF- induced VEGFR-2 phosphorylation and AKT/p38 MAPKs/ NF-KB activation were inhibited in these CD146-null ECs, which might present the underlying cause for the observed inhibition of tumor angiogenesis in CD146Ec-Ko mice. These results suggest that CD146 plays a redundant role in physiological angiogenic processes, but becomes essential during pathological angiogenesis as observed in tumorigenesis.

Nanozymes： an emerging field bridging nanotechnology and biology

Enzymes are biological catalysts that can convert substrates into products in biochemical reactions.In 1926,the first enzyme,urease,was determined to be a protein by James B.Sumner who won the Nobel Prize in 1946.Since then,enzymes have been considered to be proteins,which allows them to achieve their high catalytic activity with high specific activity under mild conditions.However,in general,the enzyme activity of proteins is lost after exposure to extremes of p H and high temperature,and proteins are also susceptible to digestion by proteases in the environment,which dramatically hinders their practical applications in

Conserved arginine residue in the membrane-spanning domain of HIV-1 gp41 is required for efficient membrane fusion

Despite the high mutation rate of HIV-1,the amino acid sequences of the membrane-spanning domain(MSD)of HIV-1 gp41 are well conserved.Arginine residues are rarely found in single membrane-spanning domains,yet an arginine residue,R696(the numbering is based on that of HXB2),is highly conserved in HIV-1 gp41.To examine the role of R696,it was mutated to K,A,I,L,D,E,N,and Q.Most of these substitutions did not affect the expression,processing or surface distribution of the envelope protein(Env).However,a syncytia formation assay showed that the substitution of R696 with amino acid residues other than K,a naturally observed mutation in the gp41 MSD,decreased fusion activity.Substitution with hydrophobic amino acid residues(A,I,and L)resulted in a modest decrease,while substitution with D or E,potentially negatively-charged residues,almost abolished the syncytia formation.All the fusion-defective mutants showed slower kinetics with the cell-based dual split protein(DSP)assay that scores the degree of membrane fusion based on pore formation between fusing cells.Interestingly,the D and E substitutions did show some fusion activity in the DSP assays,suggesting that proteins containing D or E substitutions retained some fusion pore-forming capability.However,nascent pores failed to develop,due probably to impaired activity in the pore enlargement process.Our data show the importance of this conserved arginine residue for efficient membrane fusion.

Myeloid-derived suppressor cells promote B-cell production of IgA in a TNFR2-dependent manner

Myeloid-derived suppressor cells(MDSCs)are well known for their capacity to suppress antitumor T-cell responses,but their effects on B-cell function and antibody production remain unclear.Here,we found that MDSCs that accumulated around the germinal center in the spleen of tumor-bearing mice co-located with B cells.In the presence of MDSCs,the antibody reaction to a surrogate antigen was significantly enhanced in mice,especially the immunoglobulin(Ig)A subtype.Co-culture with MDSCs promoted both proliferation and differentiation of B cells into IgA-producing plasma cells in vitro.Interestingly,the cross talk between MDSCs and B cells required cell-cell contact.MDSCs from tumor necrosis factor receptor(TNFR)2^(−/−)mice,but not from TNFR1^(−/−)mice,failed to promote B-cell responses.Further investigation suggested that interleukin-10 and transforming growth factor-β1 were crucial for the MDSC-mediated promotion of IgA responses.These results demonstrate a novel mechanism of MDSC-mediated immune regulation during tumor growth.

A shedding soluble form of interleukin-17 receptor D exacerbates collagen-induced arthritis through facilitating TNF-α-dependent receptor clustering

Rheumatoid arthritis(RA)is exacerbated by TNF-alpha signaling.However,it remains unclear whether TNF-α-activated TNFR1 and TNFR2 are regulated by extracellular factors.Here,we showed that soluble glycosylated interleukin-17 receptor D(sIL-17RD),which was produced by proteolytic cleavage,enhanced TNF-α-induced RA.We revealed that IL-17RD shedding was induced by the proteolytic enzyme TACE and enhanced by TNF-αexpression in macrophages.Intriguingly,sIL-17RD was elevated in the sera of arthritic mice and rats.Recombinant sIL-17RD significantly enhanced the TNF-α-induced proinflammatory response by promoting TNF-α-TNFR-sIL-17RD complex formation and receptor clustering,leading to the accelerated development of collagen-induced arthritis.Our observations revealed that ectodomain shedding of IL-17RD occurred in RA to boost the TNF-α-induced inflammatory response.Targeting sIL-17RD may provide a new strategy for the therapy of RA.

TNFR-1 on tumor cells contributes to the sensitivity of fi brosarcoma to chemotherapy

Impaired tumor necrosis factor receptor-1(TNFR-1)signaling has been found in some malignant tumors with poor prognosis.However,the exact role of TNFR-1 signaling in fi brosarcoma remains unclear.Here,we explored the question by comparing the growth of TNFR-1 deficient(Tnfr1-)and TNFR-1 competent(Tnfr1+)fibrosarcoma FB61 cells(FB61-m and FB61-R1)in mice.TNFR-1 expression on fibrosarcoma cells delayed their growth in vivo but not in vitro.Moreover,reduced FB61-R1 tumor growth was also obtained in T NFR-1 knockout mice.The mechanism relies mainly on the TNFR-1-mediated down-regulation of vascular endothelial growth factor(VEGF)production by tumor cells.Importantly,treatment of FB61-m tumors with melphalan resulted in a short delay of tumor growth,followed by a quick r emission.However,when FB61-R1 tumors were treated with melphalan,tumor growth was similarly delayed at fi rst and then completely rejected.Our results reveal evidence for TNFR-1 on tumor cells as a prerequisite in chemotherapy for fi brosarcoma,and provide novel insight into the therapeutic approach against some types of tumors using TNFR-1 angonist.

FXYD6： a novel therapeutic target toward hepatocellular carcinoma

FXYD6, FXYD domain containing ion transport regulator 6, has been reported to affect the activity of Na＋/K＋-ATP- ase and be associated with mental diseases. Here, we demonstrate that FXYD6 is up-regulated in hepatocellular carcinoma （HCC） and enhances the migration and prolif- eration of HCC cells. Up-regulation of FXYD6 not only positively correlates with the increase of Na＋IK＋-ATPase but also coordinates with the activation of its downstream Src-ERK signaling pathway. More importantly, blocking FXYD6 by its functional antibody significantly inhibits the growth potential of the xenografted HCC tumors in mice, indicating that FXYD6 represents a potential therapeutic target toward HCC. Altogether, our results establish a critical role of FXYD6 in HCC progression and suggest that the therapy targeting FXYD6 can benefit the clinical treatment toward HCC patients.

Questions about horse the blood brain barrier receptor 1 spleen ferritin crossing via mouse transferrin

Ferritin, an iron storage protein naturally occurring in the body, has emerged as a promising nanocarrier thanks to its unique architecture, excellent biocompatibility, and ability to self-assemble/disassemble （Fan et al., 2013）. More specifically, the finding that human H-ferritin intrinsically targets tumor cells via binding to its receptor transferrin receptor 1 （TfR1） （Li et al., 2010; Fan et al., 2012; Liang et al., 2014; Zhao et al., 2016） inspired research into using ferritins for tumor target therapy.