Gold nanoparticles (AuNPs) with simultaneous plasmonic and biocatalytic properties provide a promising approach to developing versatile bioassays. However, the combination of AuNPs' intrinsic enzyme-mimicking properties with their surface-enhanced Raman scattering (SERS) activities has yet to be explored. Here we designed a peroxidase-mimicking nanozyme by in situ growing AuNPs into a highly porous and thermally stable metal-organic framework called MIL-101. The obtained AuNPs@MIL-101 nanozymes acted as peroxidase mimics to oxidize Raman-inactive reporter leucomalachite green into the active malachite green (MG) with hydrogen peroxide and simultaneously as the SERS substrates to enhance the Raman signals of the as-produced MG. We then assembled glucose oxidase (GOx) and lactate oxidase (LOx) onto AuNPs@MIL-101 to form AuNPs@MIL-101@GOx and AuNPs@MIL-101@LOx integrative nanozymes for in vitro detection of glucose and lactate via SERS. Moreover, the integrative nanozymes were further explored for monitoring the change of glucose and lactate in living brains, which are associated with ischemic stroke. The integrative nanozymes were then used to evaluate the therapeutic efficacy of potential drugs (such as astaxanthin for alleviating cerebral ischemic injuries) in living rats. They were also employed to determine glucose and lactate metabolism in tumors. This study not only demonstrated the great promise of combining AuNPs' multiple functionalities for versatile bioassays but also provided an interesting approach to designing nanozymes for biomedical and catalytic applications.

Background: Circular RNAs (circRNAs) are a novel class of endogenous noncoding RNAs formed by a covalently closed loop, and increasing evidence has revealed that circRNAs play crucial functions in regulating gene expression. CircSLC8A1 is a circRNA generated from the SLC8A1 gene. Currently, the role and underlying molecular mechanisms of circSLC8A1 in bladder cancer remain unknown. Methods: The differentially expressed circRNAs were identified from RNA-sequencing data, and circSLC8A1 was determined as a new candidate circRNA. qRT-PCR was used to detect the expression of circRNAs, miRNAs and mRNAs in human tissues and cells. RNA pull-down assay and luciferase reporter assay were used to investigate the interactions between the specific circRNA, miRNA and mRNA. The effects of circSLC8A1 on bladder cancer cells were explored by transfecting with plasmids in vitro and in vivo. The expression of PTEN was detected by Western blot. The biological roles were measured by wound healing assay, transwell assay, and CCK-8 assay. Results: In the present study, we found that circSLC8A1 was down-regulated in bladder cancer tissues and cell lines, and circSLC8A1 expression was associated with the pathological stage and histological grade of bladder cancer. Over-expression of circSLC8A1 inhibited cell migration, invasion and proliferation both in vitro and in vivo. Mechanistically, circSLC8A1 could directly interact with miR-130b/miR-494, and subsequently act as a miRNA sponge to regulate the expression of the miR-130b/miR-494 target gene PTEN and downstream signaling pathway, which suppressed the progression of bladder cancer. Conclusions: CircSLC8A1 acts as a tumor suppressor by a novel circSLC8A1/miR-130b, miR-494/PTEN axis, which may provide a potential biomarker and therapeutic target for the management of bladder cancer. Background Bladder cancer is the most common malignancy of the urinary system and is one of the most prevalent malignancies worldwide [1]. In China, the mortality and morbidity of bladder cancer ranked first among all the tumors of urinary system [2]. Bladder cancer can be classified into two types according to the depth of tumor invasion: non-muscle invasive tumor (70~80%) and muscle-invasive tumor (20~30%) [3].For the patients with muscle-invasive bladder cancer, the occurrence of metastasis is more frequent, and the prognosis is poorer [4]. Even in those muscle-invasive bladder cancer patients who receive optimal treatment with surgery and chemotherapy, the 5-year overall survival rate is only 60% due to distant metastasis [5]. Therefore, it is of great clinical significance to clarify the molecular mechanisms that drive the progression of bladder cancer, which will help to develop more effective anticancer therapies. Circular RNA (circRNA) is a novel class of endogenous noncoding RNA molecules generally characterized

Photodynamic therapy (PDT) is an emerging effective treatment for cancer. However, the great promise of PDT for bladder cancer therapy has not yet been realized because of tumor hypoxia. To address this challenge, we fabricated O2-generating HSA-MnO2-Ce6 NPs (HSA for human serum albumin, Ce6 for chlorin e6, and NPs for nanoparticles) to overcome tumor hypoxia and thus enhance the photodynamic effect for bladder cancer therapy.Methods: The HSA-MnO2-Ce6 NPs were prepared. We investigated the O2 generation of NPs in vitro and in vivo. The orthotopic bladder cancer model in C57BL/6 mice was established for in vivo study, and dual-modal imaging of NPs were demonstrated. Therapeutic efficacy of NPs for bladder cancer was evaluated.Results: HSA-MnO2-Ce6 NPs had an excellent performance in generating O2 in vitro upon reaction with H2O2 at endogenous levels. Moreover, 1O2 generation was increased two-fold by using HSA-MnO2-Ce6 NPs instead of HSA-Ce6 NPs in the presence of H2O2 under 660 nm laser irradiation. In vitro cell viability assays showed that HSA-MnO2-Ce6 NPs themselves were non-toxic but greatly enhanced PDT effects on bladder cancer cells under laser irradiation. In vivo near-infrared (NIR) fluorescence and magnetic resonance (MR) imaging suggested the excellent bladder tumor-targeting property of HSA-MnO2-Ce6 NPs. O2 content in orthotopic bladder cancer was increased 3.5-fold after injection of HSA-MnO2-Ce6 NPs as compared with pre-injection. Given the excellent tumor-targeting ability and negligible toxicity, HSA-MnO2-Ce6 NPs were then used to treat orthotopic bladder cancer by PDT. The PDT with HSA-MnO2-Ce6 NPs showed remarkably improved therapeutic efficacy and significantly prolonged lifetime of mice as compared with controls.Conclusion: This study not only demonstrated the great potential of HSA-MnO2-Ce6 NPs for bladder cancer photodynamic ablation but also provided a new therapeutic strategy to overcoming tumor hypoxia.

Here, an integrated cascade nanozyme with a formulation of Pt@PCN222-Mn is developed to eliminate excessive reactive oxygen species (ROS). This nanozyme mimics superoxide dismutase by incorporation of a Mn–[5,10,15,20-tetrakis(4-carboxyphenyl)porphyrinato]–based metal-organic framework compound capable of transforming oxygen radicals to hydrogen peroxide. The second mimicked functionality is that of catalase by incorporation of Pt nanoparticles, which catalyze hydrogen peroxide disproportionation to water and oxygen. Both in vitro and in vivo experimental measurements reveal the synergistic ROS-scavenging capacity of such an integrated cascade nanozyme. Two forms of inflammatory bowel disease (IBD; i.e., ulcerative colitis and Crohn’s disease) can be effectively relieved by treatment with the cascade nanozyme. This study not only provides a new method for constructing enzyme-like cascade systems but also illustrates their efficient therapeutic promise in the treatment of in vivo IBDs.

Metal-organic framework (MOF) nanosheets are a class of two-dimensional (2D) porous and crystalline materials that hold promise for catalysis and biodetection. Although 2D MOF nanosheets have been utilized for in vitro assays, ways of engineering them into diagnostic tools for live animals are much less explored. In this work, a series of MOF nanosheets are successfully engineered into a highly sensitive and selective diagnostic platform for in vivo monitoring of heparin (Hep) activity. The iron-porphyrin derivative is selected as a ligand to synthesize a series of archetypical MOF nanosheets with intrinsic heme-like catalytic sites, mimicking peroxidase. Hep-specific AG73 peptides as recognition motifs are physically adsorbed onto MOF nanosheets, blocking active sites from nonspecific substrate-catalyst interaction. Because of the highly specific interaction between Hep and AG73, the activity of AG73-MOF nanosheets is restored upon the binding of Hep, but not Hep analogues and other endogenous biomolecules. Furthermore, by taking advantages of biocompatibility and diagnostic property enabled by AG73-MOF nanosheets, the elimination process of Hep in live rats is quantitatively monitored by coupling with microdialysis technology. This work expands the biomedical applications of 2D MOF nanomaterials and provides access to a promising in vivo diagnostic platform.

The PDL1: PD1 costimulatory pathway plays an important role in the inhibition of alloimmune responses as well as in the induction and maintenance of peripheral tolerance. It has recently been demonstrated that PDL1 can also bind B7.1 to inhibit T cell responses in vitro. Using the bm12 into B6 heart transplant model, we investigated the functional significance of this interaction in alloimmune responses in vivo. PD1 blockade unlike PDL1 blockade failed to accelerate bm12 allograft rejection suggesting a role for an additional binding partner for PDL1 other than PD1 in transplant rejection. PDL1 blockade was able to accelerate allograft rejection in B7.2-deficient recipients but not B7.1-deficient recipients, indicating that PDL1 interaction with B7.1 was important in inhibiting rejection. Administration of the novel 2H11 anti-PDL1 mAb, which only blocks PDL1: B7.1 interaction, aggravated chronic injury of bm12 allografts in B6 recipients. Aggravated chronic injury was associated with an increased frequency of alloreactive IFN-γ-, IL-4-, and IL-6-producing splenocytes and a decreased percentage of regulatory T cells in the recipients. Using an in vitro cell culture assay, blockade of the interaction of PDL1 on dendritic cells with B7.1 on T cells increased IFN-γ production from alloreactive CD4+ T cells, whereas blockade of dendritic cell B7.1 interaction with T cell PDL1 did not. These data indicate that PDL1 interaction with B7.1 plays an important role in the inhibition of alloimmune responses in vivo and suggests a dominant direction for PDL1 and B7.1 interaction.

Our purpose was to explore whether 68 Ga-PSMA PET/CT alone (PET/CT) or in combination with multiparametric MRI (PET/MRI) can improve the detection of clinically significant prostate cancer (PCa). Methods: We retrospectively enrolled 54 patients who underwent both MRI and PET/CT before radical prostatectomy. Regions of interest on MR images, PET/CT images, and pathologic images were marked. A lesion was defined as a region of interest marked on images obtained with any of the 3 modalities. All lesions were characterized using the prostate imaging reporting and data system (PI-RADS), the molecular imaging PSMA expression score, and the pathologic results and analyzed. Diagnostic performance was analyzed by receiver-operating-characteristic analysis. Specific improvement for lesions with different PI-RADS scores was analyzed using the net reclassification index (NRI). Results: In total, 90 lesions from 54 patients were analyzed, among which 66 lesions represented clinically significant PCa. Receiver-operating-characteristic analysis showed PET/MRI to perform better than MRI in detecting clinically significant PCa (change in area under the curve, 0.06; 95% confidence interval, 0.01-0.12; P , 0.05). With the calculated cutoff, PET/MRI performed significantly better than MRI (NRI, 21.9%; P , 0.01), with an improvement in sensitivity (89% vs. 76%, P , 0.01) at no sacrifice of specificity (96% vs. 88%, P . 0.05). Improvement in diagnosing clinically significant PCa occurred for lesions classified as PI-RADS 3 (NRI, 66.7%; P , 0.01). Conclusion: PET/MRI improves the detection of clinically significant PCa for PI-RADS 3 lesions.

High tumor recurrence is frequently observed in patients with urinary bladder cancers (UBCs), with the need for biomarkers of prognosis and drug response. Chemoresistance and subsequent recurrence of cancers are driven by a subpopulation of tumor initiating cells, namely cancer stem-like cells (CSCs). However, the underlying molecular mechanism in chemotherapy-induced CSCs enrichment remains largely unclear. In this study, we found that during gemcitabine treatment lncRNA-Low Expression in Tumor (lncRNA-LET) was downregulated in chemoresistant UBC, accompanied with the enrichment of CSC population. Knockdown of lncRNA-LET increased UBC cell stemness, whereas forced expression of lncRNA-LET delayed gemcitabine-induced tumor recurrence. Furthermore, lncRNA-LET was directly repressed by gemcitabine treatment-induced overactivation of TGFβ/SMAD signaling through SMAD binding element (SBE) in the lncRNA-LET promoter. Consequently, reduced lncRNA-LET increased the NF90 protein stability, which in turn repressed biogenesis of miR-145 and subsequently resulted in accumulation of CSCs evidenced by the elevated levels of stemness markers HMGA2 and KLF4. Treatment of gemcitabine resistant xenografts with LY2157299, a clinically relevant specific inhibitor of TGFβRI, sensitized them to gemcitabine and significantly reduced tumorigenecity in vivo. Notably, overexpression of TGFβ1, combined with decreased levels of lncRNA-LET and miR-145 predicted poor prognosis in UBC patients. Collectively, we proved that the dysregulated lncRNA-LET/NF90/miR-145 axis by gemcitabine-induced TGFβ1 promotes UBC chemoresistance through enhancing cancer cell stemness. The combined changes in TGFβ1/lncRNA-LET/miR-145 provide novel molecular prognostic markers in UBC outcome. Therefore, targeting this axis could be a promising therapeutic approach in treating UBC patients.