PTGES2 and RNASET2 identified as novel potential biomarkers and therapeutic targets for basal cell carcinoma: insights from proteome-wide mendelian randomization, colocalization, and MR-PheWAS analyses.

Introduction: Basal cell carcinoma (BCC) is the most common skin cancer, lacking reliable biomarkers or therapeutic targets for effective treatment. Genome-wide association studies (GWAS) can aid in identifying drug targets, repurposing existing drugs, predicting clinical trial side effects, and reclassifying patients in clinical utility. Hence, the present study investigates the association between plasma proteins and skin cancer to identify effective biomarkers and therapeutic targets for BCC. Methods: Proteome-wide mendelian randomization was performed using inverse-variance-weight and Wald Ratio methods, leveraging 1 Mb cis protein quantitative trait loci (cis-pQTLs) in the UK Biobank Pharma Proteomics Project (UKB-PPP) and the deCODE Health Study, to determine the causal relationship between plasma proteins and skin cancer and its subtypes in the FinnGen R10 study and the SAIGE database of Lee lab. Significant association with skin cancer and its subtypes was defined as a false discovery rate (FDR) < 0.05. pQTL to GWAS colocalization analysis was executed using a Bayesian model to evaluate five exclusive hypotheses. Strong colocalization evidence was defined as a posterior probability for shared causal variants (PP.H4) of ≥0.85. Mendelian randomization-Phenome-wide association studies (MR-PheWAS) were used to evaluate potential biomarkers and therapeutic targets for skin cancer and its subtypes within a phenome-wide human disease category. Results: PTGES2, RNASET2, SF3B4, STX8, ENO2, and HS3ST3B1 (besides RNASET2, five other plasma proteins were previously unknown in expression quantitative trait loci (eQTL) and methylation quantitative trait loci (mQTL)) were significantly associated with BCC after FDR correction in the UKB-PPP and deCODE studies. Reverse MR showed no association between BCC and these proteins. PTGES2 and RNASET2 exhibited strong evidence of colocalization with BCC based on a posterior probability PP.H4 >0.92. Furthermore, MR-PheWAS analysis showed that BCC was the most significant phenotype associated with PTGES2 and RNASET2 among 2,408 phenotypes in the FinnGen R10 study. Therefore, PTGES2 and RNASET2 are highlighted as effective biomarkers and therapeutic targets for BCC within the phenome-wide human disease category. Conclusion: The study identifies PTGES2 and RNASET2 plasma proteins as novel, reliable biomarkers and therapeutic targets for BCC, suggesting more effective clinical application strategies for patients.

Research Progress in Nanoparticle Inhibitors for Crude Oil Asphaltene Deposition.

Currently, the alteration of external factors during crude oil extraction easily disrupts the thermodynamic equilibrium of asphaltene, resulting in the continuous flocculation and deposition of asphaltene molecules in crude oil. This accumulation within the pores of reservoir rocks obstructs the pore throat, hindering the efficient extraction of oil and gas, and consequently, affecting the recovery of oil and gas resources. Therefore, it is crucial to investigate the principles of asphaltene deposition inhibition and the synthesis of asphaltene inhibitors. In recent years, the development of nanotechnology has garnered significant attention due to its unique surface and volume effects. Nanoparticles possess a large specific surface area, high adsorption capacity, and excellent suspension and catalytic abilities, exhibiting unparalleled advantages compared with traditional organic asphaltene inhibitors, such as sodium dodecyl benzene sulfonate and salicylic acid. At present, there are three primary types of nanoparticle inhibitors: metal oxide nanoparticles, organic nanoparticles, and inorganic nonmetal nanoparticles. This paper reviews the recent advancements and application challenges of nanoparticle asphaltene deposition inhibition technology based on the mechanism of asphaltene deposition and nano-inhibitors. The aim was to provide insights for ongoing research in this field and to identify potential future research directions.

Upconversion dual-photosensitizer-expressing bacteria for near-infrared monochromatically excitable synergistic phototherapy.

Synergistic phototherapy stands for superior treatment prospects than a single phototherapeutic modality. However, the combined photosensitizers often suffer from incompatible excitation mode, limited irradiation penetration depth, and lack of specificity. We describe the development of upconversion dual-photosensitizer-expressing bacteria (UDPB) for near-infrared monochromatically excitable combination phototherapy. UDPB are prepared by integrating genetic engineering and surface modification, in which bacteria are encoded to simultaneously express photothermal melanin and phototoxic KillerRed protein and the surface primary amino groups are derived to free thiols for biorthogonal conjugation of upconversion nanoparticles. UDPB exhibit a near-infrared monochromatic irradiation-mediated dual-activation characteristic as the photothermal conversion of melanin can be initiated directly, while the photodynamic effect of KillerRed can be stimulated indirectly by upconverted visible light emission. UDPB also show living features to colonize hypoxic lesion sites and inhibit pathogens via bacterial community competition. In two murine models of solid tumor and skin wound infection, UDPB separately induce robust antitumor response and a rapid wound healing effect.

PD-1: A critical player and target for immune normalization.

Immune system imbalances contribute to the pathogenesis of several different diseases, and immunotherapy shows great therapeutic efficacy against tumours and infectious diseases with immune-mediated derivations. In recent years, molecules targeting the programmed cell death protein 1 (PD-1) immune checkpoint have attracted much attention, and related signalling pathways have been studied clearly. At present, several inhibitors and antibodies targeting PD-1 have been utilized as anti-tumour therapies. However, increasing evidence indicates that PD-1 blockade also has different degrees of adverse side effects, and these new explorations into the therapeutic safety of PD-1 inhibitors contribute to the emerging concept that immune normalization, rather than immune enhancement, is the ultimate goal of disease treatment. In this review, we summarize recent advancements in PD-1 research with regard to immune normalization and targeted therapy.

Enhancing anti-tumor efficacy and immune memory by combining 3p-GPC-3 siRNA treatment with PD-1 blockade in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is associated with a high mortality rate and presents a major challenge for human health. Activation of multiple oncogenes has been reported to be strongly associated with the progression of HCC. Moreover, the immunosuppressive tumor microenvironment (TME) and the host immune system are also implicated in the development of malignant HCC tumors. Glypican-3 (GPC-3), a proteoglycan involved in the regulation of cell proliferation and apoptosis, is aberrantly expressed in HCC. We synthesized a short 5'-triphosphate (3p) RNA targeting GPC-3, 3p-GPC-3 siRNA, and found that it effectively inhibited subcutaneous HCC growth by raising type I IFN levels in tumor cells and serum and promoting tumor cell apoptosis. Moreover, 3p-GPC-3 siRNA was able to enhance the activation of CD4+ T cells, CD8+ T cells, and natural killer (NK) cells while reducing the proportion of regulatory T cells (Tregs) in the TME. Most intriguingly, a blocking anti-PD-1 antibody improved the anti-tumor effect of 3p-GPC-3 siRNA, predominantly by activating the immune response, reversing immune exhaustion, and improving immune memory. Our study suggests that the combination of 3p-GPC-3 siRNA administration and PD-1 blockade may represent a promising therapeutic strategy for HCC.

Targeting T-cell metabolism to boost immune checkpoint inhibitor therapy.

Immune checkpoint inhibitors (ICIs) have shown promising therapeutic effects in the treatment of advanced solid cancers, but their overall response rate is still very low for certain tumor subtypes, limiting their clinical scope. Moreover, the high incidence of drug resistance (including primary and acquired) and adverse effects pose significant challenges to the utilization of these therapies in the clinic. ICIs enhance T cell activation and reverse T cell exhaustion, which is a complex and multifactorial process suggesting that the regulatory mechanisms of ICI therapy are highly heterogeneous. Recently, metabolic reprogramming has emerged as a novel means of reversing T-cell exhaustion in the tumor microenvironment; there is increasing evidence that T cell metabolic disruption limits the therapeutic effect of ICIs. This review focuses on the crosstalk between T-cell metabolic reprogramming and ICI therapeutic efficacy, and summarizes recent strategies to improve drug tolerance and enhance anti-tumor effects by targeting T-cell metabolism alongside ICI therapy. The identification of potential targets for altering T-cell metabolism can significantly contribute to the development of methods to predict therapeutic responsiveness in patients receiving ICI therapy, which are currently unknown but would be of great clinical significance.

Edaravone protects against liver fibrosis progression via decreasing the IL-1ß secretion of macrophages.

Edaravone (EDA), a strong novel free radical scavenger, have been demonstrated to exert neurovascular protective effects clinically. Furthermore, EDA can suppress the lung injury, pulmonary fibrosis and skin fibrosis, while the precise effects and mechanisms of EDA on liver injury and fibrosis remain unclear. The effects of EDA on the Thioacetamide (TAA)-induced liver fibrosis were evaluated by sirius red staining, α-SMA immunohistochemistry. The percentages of immune cell subsets were analyzed by flow cytometry. Immunofluorescence assay was performed to identify the fibrotic properties of hepatic stellate cells (HSCs). Western blot and qPCR were used to detect the levels of liver fibrosis-related molecules and IL-1ß. EDA displayed a hepatic protective role in TAA-induced chronic liver fibrosis via inhibiting monocyte/macrophages recruitment and IL-1ß production of macrophages. Mechanically, EDA inhibited of NF-κB signal pathway and reactive oxygen species (ROS) production in macrophages. Moreover, EDA treatment indirectly suppressed the activation of HSCs by decreasing the IL-1ß secretion of macrophages. Together, EDA protects against TAA-induced liver fibrosis via decreasing the IL-1ß production of macrophages, thereby providing a feasible solution for clinical treatment of liver fibrosis.

MCP-1 facilitates VEGF production by removing miR-374b-5p blocking of VEGF mRNA translation.

Monocyte chemotactic protein-1 (MCP-1) is known to be able to facilitate vascular endothelial growth factor (VEGF) gene expression, hence promoting vascular hyperpermeability and neovascularization. We show here that a microRNA molecule, miR-374b-5p can target the 3'-untranslated region of the VEGF mRNA, thus preventing VEGF production. Additionally, MCP-1 promotes the acetylation of transcription factor stat3 at Lys685, which facilitates the formation of an ac-stat3-DNA methyltransferase-histone methyltransferase complex (ac-stat3/DNMT1/EZH2) that binds to the promoter of the miR-374b-5p gene. This results in diminished miR-374b-5p expression and enhanced VEGF production. Moreover, treatment of appropriate animal models either with a miR-374b-5p mimicry or with inhibitors of either stat3 acetylation, DNMT1, or EZH2, leads to marked inhibition of MCP-1-promoted neovascularization and tumor growth. These findings indicate that MCP-1 facilitated inhibition of miR-374b-5p gene expression leads to the removal of a block of VEGF mRNA translation by miR-374b-5p. This mechanism could be of importance in the modulation of inflammatory conditions.

MERS-CoV nsp1 regulates autophagic flux via mTOR signalling and dysfunctional lysosomes.

Autophagy, a cellular surveillance mechanism, plays an important role in combating invading pathogens. However, viruses have evolved various strategies to disrupt autophagy and even hijack it for replication and release. Here, we demonstrated that Middle East respiratory syndrome coronavirus (MERS-CoV) non-structural protein 1(nsp1) induces autophagy but inhibits autophagic activity. MERS-CoV nsp1 expression increased ROS and reduced ATP levels in cells, which activated AMPK and inhibited the mTOR signalling pathway, resulting in autophagy induction. Meanwhile, as an endonuclease, MERS-CoV nsp1 downregulated the mRNA of lysosome-related genes that were enriched in nsp1-located granules, which diminished lysosomal biogenesis and acidification, and inhibited autophagic flux. Importantly, MERS-CoV nsp1-induced autophagy can lead to cell death in vitro and in vivo. These findings clarify the mechanism by which MERS-CoV nsp1-mediated autophagy regulation, providing new insights for the prevention and treatment of the coronavirus.

Sorafenib combined with STAT3 knockdown triggers ER stress-induced HCC apoptosis and cGAS-STING-mediated anti-tumor immunity.

Sorafenib is the first-line treatment for advanced hepatocellular carcinoma (HCC). However, it is difficult to alleviate this disease process using single-agent chemotherapy. Using combination therapies for advanced HCC has become a major trend. Given that STAT3 overexpression is involved in chemotherapy resistance and the immune escape of HCC cells, it has become a potential therapeutic target for HCC in recent years. GEO database analysis showed that STAT3 levels in tumor tissues from non-responders were significantly higher than those in responders to sorafenib. Our studies demonstrated that STAT3 knockdown promoted sorafenib-induced ER stress-induced apoptosis. Importantly, the DNA released by dead HCC cells stimulated the cGAS-STING signaling pathway in CD103+ DCs and promoted type I interferon production, thus, enhancing the anti-tumor function of CD8+ T and NK cells. In conclusion, our results revealed that the combination strategy of sorafenib and STAT3 knockdown might be a potential treatment strategy for HCC, directly and efficiently disturbing the tumor features of HCC cells while improving the tumor microenvironment via the cGAS-STING-Type I IFNs axis of DCs, inducing anti-HCC immune responses.

Targeted inhibition of STAT3 induces immunogenic cell death of hepatocellular carcinoma cells via glycolysis.

In hepatocellular carcinoma (HCC), the signal transducer and activator of transcription 3 (STAT3) is present in an overactive state that is closely related to tumour development and immune escape. STAT3 inhibition reshapes the tumour immune microenvironment, but the underlying mechanisms have not been fully clarified. We found that STAT3 inhibition could induce immunogenic cell death (ICD) of HCC cells via translocation of the "eat me" molecule calreticulin to the cell surface and a significant reduction in the expression of the "don't eat me" molecule leucocyte surface antigen CD47. STAT3 inhibition promoted dendritic cell (DC) activation and enhanced the recognition and phagocytosis of HCC cells by macrophages. Furthermore, STAT3 inhibition prevented the expression of key glycolytic enzymes, facilitating the induction of ICD in HCC. Interestingly, STAT3 directly regulated the transcription of CD47 and solute carrier family 2 member 1 (SLC2A1; also known as GLUT1). In subcutaneous and orthotopic transplantation mouse tumour models, the STAT3 inhibitor napabucasin prevented tumour growth and induced the expression of calreticulin and the protein disulfide isomerase family A member 3 (PDIA3; also known as ERp57) but suppressed that of CD47 and GLUT1. Meanwhile, the amount of tumour-infiltrated DCs and macrophages increased, along with the expression of costimulatory molecules. More CD4+ and CD8+ T cells accumulated in tumour tissues, and CD8+ T cells had lower expression of checkpoint molecules such as lymphocyte activation gene 3 protein (LAG-3) and programmed cell death protein 1 (PD-1). Significantly, the antitumour immune memory response was induced by treatment targeting STAT3. These findings provide a new mechanism for targeting STAT3-induced ICD in HCC, and confirms STAT3 as a potential target for the treatment of HCC via reshaping the tumour immune microenvironment.

TNFSF15 facilitates differentiation and polarization of macrophages toward M1 phenotype to inhibit tumor growth.

Macrophages of the M2 phenotype in malignant tumors significantly aid tumor progression and metastasis, as opposed to the M1 phenotype that exhibits anti-cancer characteristics. Raising the ratio of M1/M2 is thus a promising strategy to ameliorate the tumor immunomicroenvironment toward cancer inhibition. We report here that tumor necrosis factor superfamily-15 (TNFSF15), a cytokine with anti-angiogenic activities, is able to facilitate the differentiation and polarization of macrophages toward M1 phenotype. We found that tumors formed in mice by Lewis lung carcinoma (LLC) cells artificially overexpressing TNFSF15 exhibited retarded growth. The tumors displayed a greater percentage of M1 macrophages than those formed by mock-transfected LLC cells. Treatment of mouse macrophage RAW264.7 cells with recombinant TNFSF15 led to augmentation of the phagocytic and pro-apoptotic capacity of the macrophages against cancer cells. Mechanistically, TNFSF15 activated STAT1/3 in bone marrow cells and MAPK, Akt and STAT1/3 in naive macrophages. Additionally, TNFSF15 activated STAT1/3 but inactivated STAT6 in M2 macrophages. Modulations of these signals gave rise to a reposition of macrophage phenotypes toward M1. The ability of TNFSF15 to promote macrophage differentiation and polarization toward M1 suggests that this unique cytokine may have a utility in the reconstruction of the immunomicroenvironment in favor of tumor suppression.

CpG-C ODN M362 as an immunoadjuvant for HBV therapeutic vaccine reverses the systemic tolerance against HBV.

Chronic Hepatitis B virus (CHB) infection is a global public health problem. Oligodeoxynucleotides (ODNs) containing class C unmethylated cytosine-guanine dinucleotide (CpG-C) motifs may provide potential adjuvants for the immunotherapeutic strategy against CHB, since CpG-C ODNs stimulate both B cell and dendritic cell (DC) activation. However, the efficacy of CpG-C ODN as an anti-HBV vaccine adjuvant remains unclear. In this study, we demonstrated that CpG M362 (CpG-C ODN) as an adjuvant in anti-HBV vaccine (cHBV-vaccine) successfully and safely eliminated the virus in HBV-carrier mice. The cHBV-vaccine enhanced DC maturation both in vivo and in vitro, overcame immune tolerance, and recovered exhausted T cells in HBV-carrier mice. Furthermore, the cHBV-vaccine elicited robust hepatic HBV-specific CD8+ and CD4+ T cell responses, with increased cellular proliferation and IFN-γ secretion. Additionally, the cHBV-vaccine invoked a long-lasting follicular CXCR5+ CD8+ T cell response following HBV re-challenge. Taken together, CpG M362 in combination with rHBVvac cleared persistent HBV and achieved long-term virological control, making it a promising candidate for treating CHB.

Endoscope-Assisted Resection of a Vagal Neurofibroma Using a Posterior Styloid Approach.

It is very challenging to expose and remove tumors above the hard palate in the retrostyloid space using the typical cervical approach. Other approaches, such as the cervical-parotid approach, may result in prominent scars, facial paralysis, or masticatory dysfunction. Here, we report a case of a vagal neurofibroma between the internal carotid artery and internal jugular vein in the retrostyloid space. We used a 3D model to design a surgical approach that reduced the risk to the surrounding vessels and nerves. We performed an endoscope-assisted resection of the tumor using a posterior styloid approach. Following surgery, there were no obvious scars on the face or neck, facial paralysis, or dysphagia, but mild hoarseness.

miR-590-5p affects chondrocyte proliferation, apoptosis, and inflammation by targeting FGF18 in osteoarthritis.

OBJECTIVE: To investigate the potential miRNA targeting FGF18, and its role in regulating the proliferation, apoptosis and inflammation in human primary chondrocytes. METHODS: The normal human chondrocytes were induced by IL-1ß to mimic OA in vitro. qPCR and Western blotting were performed to evaluate the expression of FGF18. Target Scan analysis was performed to predict the miRNA targeting FGF18. Then, the expression of miR-590-5p was quantified by qPCR in IL-1ß-induced chondrocytes. After transfection of miR-590-5p mimics or inhibitors, CCK-8 assay was conducted to determine the cell viability and apoptosis-related proteins, and cartilage degeneration related biomarkers were assayed by qPCR and Western blotting. The levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8 were determined by ELISA. The targeting relationship between miR-590-5p and FGF18 was assayed by luciferase reporter assay in IL-1ß-induced chondrocytes. RESULTS: Target Scan analysis predicted that FGF18 is directly targeted by miR-590-5p. miR-590-5p was up-regulated, whereas FGF18 expression was inhibited in IL-1ß-induced chondrocytes. miR-590-5p mimics reduced the expression of FGF18 protein, inhibited the cell viability of chondrocytes, and promoted secretion of inflammatory factors in chondrocytes, while miR-590-5p inhibitors increased FGF18 levels in IL-1ß-treated chondrocytes. Furthermore, expression of inflammatory factors in chondrocytes was reduced by miR-590-5p inhibitors. The luciferase reporter assay showed that miR-590-5p could target FGF18. CONCLUSIONS: miR-590-5p promotes OA progression by targeting FGF18, which serves as a potential therapeutic target for OA.

Downregulation of Renal MRPs Transporters in Acute Lymphoblastic Leukemia Mediated by the IL-6/STAT3/PXR Signaling Pathway.

PURPOSE: Considering prior investigations on reductions of renal multidrug resistance-associated protein (MRP) 2 and 4 transporters in mice with acute lymphoblastic leukemia (ALL), we sought to characterize the underlying mechanisms responsible for IL-6/STAT3/PXR-mediated changes in the expression of MRP2 and MRP4 in ALL. SUBJECTS AND METHODS: ALL xenograft models were established and intravenously injected with methotrexate (MTX) of MRPs substrate in NOD/SCID mice. Protein expression of MRPs and associated mechanisms were detected by Western blotting and immunocytochemistry. Plasma concentrations of MTX were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). RESULTS: Plasma IL-6 levels in patients with newly diagnosed ALL were increased compared to children with pneumonia. Similarly, plasma IL-6 levels in ALL, ALL-tocilizumab (TCZ, an IL-6 receptor inhibitor) and ALL-S3I-201 (a selective inhibitor of STAT3) mice were increased compared to the control group. The MRP2, MRP4, and PXR expression in HK-2 cells treated with IL-6 were decreased, whereas the p-STAT3 expression was significantly increased compared to the control group results. These results are consistent with clearance of MRPs-mediated MTX in the ALL group. These effects were attenuated by blocking IL-6/STAT3/PXR signaling pathway. CONCLUSION: Inflammation-mediated changes in pharmacokinetics are thought to be executed through pathways IL-6-activated pathways, which can facilitate a better understanding of the potential for the use of IL-6 to predict the severity of adverse outcomes and the major implications on potential ALL treatments.

The Mechanisms of HBV-Induced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a common malignancy, and the hepatitis B virus (HBV) is its major pathogenic factor. Over the past decades, it has been confirmed that HBV infection could promote disease progression through a variety of mechanisms, ultimately leading to the malignant transformation of liver cells. Many factors have been identified in the pathogenesis of HBV-associated HCC (HBV-HCC), including HBV gene integration, genomic instability caused by mutation, and activation of cancer-promoting signaling pathways. As research in the progression of HBV-HCC progresses, the role of many new mechanisms, such as epigenetics, exosomes, autophagy, metabolic regulation, and immune suppression, is also being continuously explored. The occurrence of HBV-HCC is a complex process caused by interactions across multiple genes and multiple steps, where the synergistic effects of various cancer-promoting mechanisms accelerate the process of disease evolution from inflammation to tumorigenesis. In this review, we aim to provide a brief overview of the mechanisms involved in the occurrence and development of HBV-HCC, which may contribute to a better understanding of the role of HBV in the occurrence and development of HCC.

Matrix Metalloproteinase-9-Responsive Surface Charge-Reversible Nanocarrier to Enhance Endocytosis as Efficient Targeted Delivery System for Cancer Diagnosis and Therapy.

Nanoparticles, that can be enriched in the tumor microenvironment and deliver the payloads into cancer cells, are desirable carriers for theranostic agents in cancer diagnosis and treatment. However, efficient targeted delivery and enhanced endocytosis for probes and drugs in theranostics are still major challenges. Here, a nanoparticle, which is capable of charge reversal from negative to positive in response to matrix metalloproteinase 9 (MMP9) in tumor microenvironment is reported. This nanoparticle is based on a novel charge reversible amphiphilic molecule consisting of hydrophobic oleic acid, MMP9-cleavable peptide, and glutamate-rich segment (named as OMPE). The OMPE-modified cationic liposome forms an intelligent anionic nanohybrid (O-NP) with enhanced endocytosis through surface charge reversal in response to MMP9 in vitro. Successfully, O-NP nanohybrid performs preferential accumulation and enhances the endocytosis in MMP9-expressing xenografted tumors in mouse models, which improve the sensitivity of diagnosis agents and the antitumor effects of drugs in vivo by overcoming their low solubility and/or nonspecific enrichment. These results indicate that O-NP can be a promising delivery platform for cancer diagnosis and therapy.

A Supramolecular Strategy to Engineering a Non-photobleaching and Near-Infrared Absorbing Nano-J-Aggregate for Efficient Photothermal Therapy.

The design of organic photothermal agents (PTAs) for in vivo applications face a demanding set of performance requirements, especially intense NIR-absorptivity and sufficient photobleaching resistance. J-aggregation offers a facile way to tune the optical properties of dyes, thus providing a general design platform for organic PTAs with the desired performance. Herein, we present a supramolecular strategy to build a water-stable, nonphotobleaching, and NIR-absorbing nano-PTA (J-NP) from J-aggregation of halogenated BODIPY dyes (BDP) for efficient in vivo photothermal therapy. Multiple intermolecular halogen-bonding and π-π stacking interactions triggered the formation of BDP J-aggregate, which adsorbed amphiphilic polymer chains on the surface to provide PEGylated sheetlike nano-J-aggregate (J-NS). We serendipitously discovered that the architecture of J-NS was remodeled during a long-time ultrafiltration process, generating a discrete spherical nano-J-aggregate (J-NP) with controlled size. Compared with J-NS, the remodeled J-NP significantly improved cellular uptake efficiency. J-aggregation brought J-NP striking photothermal performance, such as strong NIR-absorptivity, high photothermal conversion efficiency up to 72.0%, and favorable nonphotobleaching ability. PEGylation and shape-remodeling imparted by the polymer coating enabled J-NP to hold biocompatibility and stability in vivo, thereby exhibiting efficient antitumor photothermal activities. This work not only presents a facile J-aggregation strategy for preparing PTAs with high photothermal performance but also establishes a supramolecular platform that enables the appealing optical functions derived from J-aggregation to be applied in vivo.

Promotion of epithelial-mesenchymal transformation by hepatocellular carcinoma-educated macrophages through Wnt2b/ß-catenin/c-Myc signaling and reprogramming glycolysis.

BACKGROUND: Tumour-associated macrophages (TAMs) in the tumour microenvironment (TME) can promote the progression of hepatocellular carcinoma (HCC). Some tumours can be suppressed by targeting Wnt2b in tumour cells. However, the role of Wnt2b in HCC is still unknown. In particular, the role of Wnt2b-mediated signal activation in macrophage polarization in the HCC microenvironment, and the regulatory effect between Wnt and glycolysis in TAMs has not been described. METHODS: The expression of Wnt2b in TAMs was detected by qPCR and immunofluorescence. Wnt2b/ß-catenin interference in HCC-TAMs was performed by lentivirus carrying targeted shRNA or TLR9 agonist. Markers related to macrophage polarization and the changes of key glycolytic enzymes expression were detected by flow cytometry and qPCR. ECAR was analysed by Seahorse analyser. MTT assay, wound healing assay, western blotting were used to evaluate the promoting effect of different HCC-TAMs on the proliferation, migration and EMT of HCC in vitro. Tumour cells and different HCC-TAMs were injected via subcutaneously into immunodeficient mice to assess the effects of CpG ODN, Wnt2b, or ß-catenin on HCC-TAMs in tumour growth in vivo. RESULTS: Polarization-promoting factors derived from HCC cells upregulated the expression of Wnt2b in macrophages, which promoted the polarization of TAMs to M2-like macrophages by activating Wnt2b/ß-catenin/c-Myc signalling. Furthermore, this process was associated with the activation of glycolysis in HCC-TAMs. These HCC-TAMs could promote the development of EMT, proliferation, and migration of HCC. In addition to silencing Wnt2b or ß-catenin expression, TLR9 agonist CpG ODN downregulated the level of glycolysis and inhibited the M2 polarization of HCC-TAMs, reversing the tumour-promoting effects of TAMs in vitro and vivo. CONCLUSIONS: As a potential target for HCC therapy, Wnt2b may play an important regulatory role for the functions of TAMs in the TME. Moreover, the TLR9 agonist CpG ODN might act as a Wnt2b signal inhibitor and can potentially be employed for HCC therapy by disturbing Wnt2b/ß-catenin/c-Myc and inhibiting glycolysis in HCC-TAMs.