Cell surface engineering with functional polymers is an effective strategy to modulate cell activity. Here, a bio‐palladium catalyzed polymerization strategy was developed for in situ synthesis of conjugated polymers on living cell surfaces. Through Sonagashira polymerization, photoactive polyphenyleneethynylene (PPE) is synthesized on the cell surface via cell‐generated bio‐Pd catalyst. The in situ formed PPE is identified by excellent light‐harvest capacity and blue fluorescence on the surfaces of E. coli and C. pyrenoidosa. Besides imaging microbes for tracing the polymerization process, PPE also exhibits enhanced antibacterial activity against E. coli. It can also augment the ATP synthesis of C. pyrenoidosa through enlarging the light absorption and accelerating the cyclic electron transport of the algae. With this bio‐metal catalyzed polymerization method, functional polymers can be synthesized in situ on the living cell surface.
Dually targeted mitochondrial proteins usually possess an unconventional mitochondrial targeting sequence (MTS), which makes them difficult to predict by current bioinformatics approaches. Human apurinic/apyrimidinic endonuclease (APE1) plays a central role in the cellular response to oxidative stress. It is a dually targeted protein preferentially residing in the nucleus with conditional distribution in the mitochondria. However, the mitochondrial translocation mechanism of APE1 is not well characterized because it harbors an unconventional MTS that is difficult to predict by bioinformatics analysis. Two experimental approaches were combined in this study to identify the MTS of APE1. First, the interactions between the peptides from APE1 and the three purified translocase receptors of the outer mitochondrial membrane (Tom) were evaluated using a peptide array screen. Consequently, the intracellular distribution of green fluorescent protein-tagged, truncated, or mutated APE1 proteins was traced by tag detection. The results demonstrated that the only MTS of APE1 is harbored within residues 289 -318 in the C terminus, which is normally masked by the intact N-terminal structure. As a dually targeted mitochondrial protein, APE1 possesses a special distribution pattern of different subcellular targeting signals, the identification of which sheds light on future prediction of MTSs.Human APE1 (apurinic/apyrimidinic endonuclease) is an important multifunctional protein that plays a central role in the cellular response to oxidative stress. The two major activities of APE1 are DNA repair and redox regulation of transcriptional factors. On one hand, APE1 functions as a critical ratelimiting enzyme in DNA base excision repair and accounts for nearly all of the AP site incision activities in cell extracts (1). On the other hand, APE1 also exerts unique redox activity to regulate the DNA binding affinity of certain transcriptional factors by controlling the redox status of their DNA-binding domain (2). Inhibition of the redox function of APE1 blocks murine endothelial cell growth and angiogenesis and also blocks the growth of human tumor cell lines (3). The biological importance of APE1 is highlighted by the finding that APE1 knockout mice exhibit an embryonic lethal phenotype (4). Although APE1 has long been labeled as a nuclear protein, a growing body of evidence has shown that the subcellular distribution of APE1 can be cytoplasmic in some cell types with high metabolic or proliferative rates, with predominant localization in the mitochondria and the endoplasmic reticulum (5-7). Recent mitochondrial proteomic studies have further confirmed the existence of APE1 in the mitochondria (8). Considering the importance of the mitochondria in cellular response to oxidative stress, the roles of APE1 in the mitochondria have been extensively investigated.
Apurinic/apyrimidinic endonuclease1 (APE1), which has the dual functions of DNA repair and redox regulation, is considered to be a promising potential target in cancer treatment. Microarray and qRT-PCR were used to confirm the change of miRNA followed by analysis with comprehensive bioinformatics-based analysis. Both microarray and qRT-PCR demonstrated that 13 microRNAs (miRNAs) were significantly changed (>2-fold) in APE1 knockdown HOS cells; seven of them (hsa-miR-451, hsa-miR-1290, hsa-miR-765, hsa-miR-483-5p, hsa-miR-513a-5p, hsa-miR-129-5p and hsa-miR-31) were up-regulated and the other six (hsa-miR-29b, hsa-miR-197, has-let-7b, hsa-miR-324-5p, hsa-let-7i and hsa-miR-484) were down-regulated. Furthermore, pathway analysis showed that these miRNAs and their target genes affected by the expression of APE1 were involved in pathways relating to developmental processes, regulation of cellular processes, cell signaling (such as TGF-β, Wnt, MAPK and the p53 signaling pathway) and cancers. There are putative binding sites of NF-κB, p53, HIF-1α, AP-1, PEBP2, ATF, NF-Y, Pax-2,CREB and c-Myb in the promoters of several down regulated miRNAs, indicating that APE1 may regulate miRNAs via transcription factors. Our data suggest that our understanding of the biological functions of APE1 will inevitably expand due to the novel pathways that APE1 uses to regulate gene expression through miRNAs.
Resistance to radiotherapy is a key limitation for the treatment of human hepatocellular carcinoma (HCC). To overcome this problem, we investigated the correlation between radioresistance and the human apurinic/apyrimidinic endonuclease (APE1), a bifunctional protein, which plays an important role in DNA repair and redox regulation activity of transcription factors. In the present study, we examined the radiosensitivity profiles of three human HCC cell lines, HepG2, Hep3B, and MHCC97L, using the adenoviral vector Ad5/F35-mediated APE1 siRNA (Ad5/F35-siAPE1). The p53 mutant cell lines MHCC97L showed radioresistance, compared with HepG2 and Hep3B cells. APE1 was strongly expressed in MHCC97L cells and was induced by irradiation in a dose-dependent manner, and Ad5/F35-siAPE1 effectively inhibited irradiation-induced APE1 and p53 expression. Moreover, silencing of APE1 significantly potentiated the growth inhibition and apoptosis induction by irradiation in all tested human HCC cell lines. In addition, Ad5/F35-siAPE1 significantly enhanced inhibition of tumor growth and potentiated cell apoptosis by irradiation both in HepG2 and MHCC97L xenografts. In conclusion, down regulation of APE1 could enhance sensitivity of human HCC cells to radiotherapy in vitro and in vivo.
The synthesis of conjugated polymers with ionic substituents directly bound to their main chain repeat units is astrategy for generating strongly electron-accepting conjugated polyelectrolytes,a sd emonstrated through the synthesis of aseries of ionic azaquinodimethane (iAQM) compounds.The introduction of cationic substituents onto the quinoidal paraazaquinodimethane (AQM) core gives rise to as trongly electron-accepting building block, which can be employed in the synthesis of ionic small molecules and conjugated polyelectrolytes (CPEs). Electrochemical measurements alongside theoretical calculations indicate notably low-lying LUMO values for the iAQMs.T he optical band gaps measured for these compounds are highly tunable based on structure, ranging from 2.30 eV in small molecules down to 1.22 eV in polymers.The iAQM small molecules and CPEs showcase the band gap reduction effects of combining the donor-acceptor strategy with the bond-length alternation reduction strategy.As ad emonstration of their utility,t he iAQM CPEs so generated were used as active agents in photothermal therapy. Scheme 1. a) Illustration of two different types of CPEs. b) Structural diagram of the dicationic iAQM as abuilding block for CPEs. Nu = neutral nucleophiles such as pyridine, triphenylphosphine, etc.).Scheme2. The synthesis of avariety of iAQM small molecules via ditriflate intermediates.
PurposeTo define the role of the DNA repair protein apurinic/apyrimidinic endonuclease 1 (APE1) in predicting the prognosis and chemotherapeutic response of non-small cell lung cancer patients receiving platinum-containing chemotherapy.ResultsOur investigations found that serum APE1 level was significantly elevated in 229 of 412 NSCLC patients and correlated with its level in tissue (r2 = 0.639, p < 0.001). The elevated APE1 level in both tissue and serum of patients prior to chemotherapy was associated with worse progression-free survival (HR: 2.165, p < 0.001, HR: 1.421, p = 0.012), but not with overall survival. After 6 cycles of chemotherapy, a low APE1 serum level was associated with better overall survival (HR: 0.497, p = 0.010).Experimental DesignWe measured APE1 protein levels in biopsy tissue from 172 NSCLC patients and sera of 412 NSCLC patients receiving platinum-based chemotherapy by immunohistochemistry and a newly established sensitive and specific enzyme-linked immunosorbent assay, respectively. APE1 levels in sera of 523 healthy donors were also determined as control.ConclusionsOur studies indicate that APE1 is a biomarker for predicting prognosis and therapeutic efficacy in NSCLC. The chemotherapy-naïve serum APE1 level, which correlated with its tissue level inversely associated with progression-free survival of platinum-containing doublet chemotherapy, whereas post-treatment serum APE1 level was inversely associated with overall survival.
Constructing artificial hybrid biosystems, comprising of organisms and organic non‐biological functional material, will afford promising opportunities to achieve brand new or enhanced functions. In this work, a hybrid biosystem is designed and constructed by electrostatically recombining photoactive cationic poly(fluorene‐co‐phenylene) derivative (PFP) with a cyanobacterium (Synechococcus sp. PCC7942, Syne) for enhancing its photosynthesis and regulating exogenous redox state of protein. The light utility efficiency of Syne is significantly improved assisted by the excellent ultraviolet light‐harvesting ability of PFP, which accelerates electron‐transfer rate in non‐cyclic electron transport chain, and further augments the light‐dependent reaction in photosynthesis. As a result, O2, NADPH, and ATP production in the light‐dependent reaction are increased by 52.8%, 47.9%, and 27.2%, respectively. Moreover, the extracellular electron transfer property of Syne is able to realize electronic communication with external circumstances. Specifically, the electrons exported from Syne can reduce exogenous oxidized cytochrome c (Cyt c) and adsorbed PFP has the ability to regulate the reduction degree of Syne to Cyt c. This work reports an ideal design of a conjugated polymer‐based hybrid biosystem, providing a strategy to promote photosynthesis and regulate the redox state of protein.
Apurinic/apyrimidinic endonuclease 1 (APE1), which has the dual functions of both DNA repair and redox activity, has been reported to be highly expressed in non-small cell lung cancer (NSCLC), and this appears to be a characteristic related to chemotherapy resistance. In this study, we identified serum APE1 autoantibodies (APE1-AAbs) in NSCLC patients and healthy controls by immunoblotting and investigated the expression of APE1-AAbs by indirect ELISA from the serum of 292 NSCLC patients and 300 healthy controls. In addition, serum APE1-AAbs level alterations of 91 patients were monitored before and after chemotherapy. Our results showed that serum APE1-AAbs can be detected in both NSCLC patients and healthy controls. Serum APE1-AAbs were significantly higher than those of healthy controls and closely related to APE1 antigen levels both in tumor tissues and the peripheral blood. Moreover, the change in levels of serum APE1-AAbs in NSCLC is closely associated with the response to chemotherapy. These results suggest that APE1-AAbs is a potential tumor marker and predictor of therapeutic efficacy in NSCLC.
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