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Nature Communications Jun 2024Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic...
Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic cells (DC) and other myeloid cells with antigen presenting and cancer cell killing capacities is an attractive but not fully exploited approach. Here, we show that PIKFYVE is a shared gene target of clinically relevant protein kinase inhibitors and high expression of this gene in DCs is associated with poor patient response to immune checkpoint blockade (ICB) therapy. Genetic and pharmacological studies demonstrate that PIKfyve ablation enhances the function of CD11c cells (predominantly dendritic cells) via selectively altering the non-canonical NF-κB pathway. Both loss of Pikfyve in CD11c cells and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively regulates the function of CD11c cells, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.
Topics: Animals; Humans; Dendritic Cells; Mice; Phosphatidylinositol 3-Kinases; CD11c Antigen; Morpholines; Cell Line, Tumor; Immunotherapy; Neoplasms; Mice, Inbred C57BL; Female; Immune Checkpoint Inhibitors; NF-kappa B; T-Lymphocytes; Protein Kinase Inhibitors; Hydrazones; Pyrimidines
PubMed: 38942798
DOI: 10.1038/s41467-024-48931-9 -
International Journal of Pharmaceutics Jun 2024We have recently witnessed that considerable progresses have been made in the rapid detection and appropriate treatments of COVID-19, but still this virus remains one of...
We have recently witnessed that considerable progresses have been made in the rapid detection and appropriate treatments of COVID-19, but still this virus remains one of the main targets of world research. Based on the knowledge of the complex mechanism of viral infection we designed peptide-dendrimer inhibitors of SARS-CoV-2with the aim to block cell infection through interfering with the host-pathogen interactions. We used two different strategies: i) the first one aims at hindering the virus anchorage to the human cell; ii) the second -strategy points to interfere with the mechanism of virus-cell membrane fusion. We propose the use of different nanosized carriers, formed by several carbosilane dendritic wedges to deliver two different peptides designed to inhibit host interaction or virus entry. The antiviral activity of the peptide-dendrimers, as well as of free peptides and free dendrimers was evaluated through the use of SARS-CoV-2 pseudotyped lentivirus. The results obtained show that peptides designed to block host-pathogen interaction represent a valuable strategy for viral inhibition.
PubMed: 38942185
DOI: 10.1016/j.ijpharm.2024.124389 -
Journal of Controlled Release :... Jun 2024Tumor-associated macrophages (TAMs) constitute 50-80% of stromal cells in most solid tumors with high mortality and poor prognosis. Tumor-infiltrating dendritic cells...
Tumor-associated macrophages (TAMs) constitute 50-80% of stromal cells in most solid tumors with high mortality and poor prognosis. Tumor-infiltrating dendritic cells (TIDCs) and TAMs are key components mediating immune responses within the tumor microenvironment (TME). Considering their refractory properties, simultaneous remodeling of TAMs and TIDCs is a potential strategy of boosting tumor immunity and restoring immunosurveillance. In this study, mannose-decorated poly(lactic-co-glycolic acid) nanoparticles loading with R848 (Man-pD-PLGA-NP@R848) were prepared to dually target TAMs and TIDCs for efficient tumor immunotherapy. The three-dimensional (3D) cell culture model can simulate tumor growth as influenced by the TME and its 3D structural arrangement. Consequently, cancer spheroids enriched with tumor-associated macrophages (TAMs) were fabricated to assess the therapeutic effectiveness of Man-pD-PLGA-NP@R848. In the TME, Man-pD-PLGA-NP@R848 targeted both TAMs and TIDCs in a mannose receptor-mediated manner. Subsequently, Man-pD-PLGA-NP@R848 released R848 to activate Toll-like receptors 7 and 8, following dual-reprograming of TIDCs and TAMs. Man-pD-PLGA-NP@R848 could uniquely reprogram TAMs into antitumoral phenotypes, decrease angiogenesis, reprogram the immunosuppressive TME from "cold tumor" into "hot tumor", with high CD4+ and CD8+ T cell infiltration, and consequently hinder tumor development in B16F10 tumor-bearing mice. Therefore, dual-reprograming of TIDCs and TAMs with the Man-pD-PLGA-NP@R848 is a promising cancer immunotherapy strategy.
PubMed: 38942083
DOI: 10.1016/j.jconrel.2024.06.062 -
Klinische Monatsblatter Fur... Jun 2024
PubMed: 38942034
DOI: 10.1055/a-2350-1122 -
Klinische Monatsblatter Fur... Jun 2024Corneal nerves and dendritic cells are increasingly being visualised to serve as clinical parameters in the diagnosis of ocular surface diseases using intravital... (Review)
Review
Corneal nerves and dendritic cells are increasingly being visualised to serve as clinical parameters in the diagnosis of ocular surface diseases using intravital confocal microscopy. In this review, different methods of image analysis are presented. The use of deep learning algorithms, which enable automated pattern recognition, is explained in detail using our own developments and compared with other established methods.
Topics: Cornea; Dendritic Cells; Humans; Microscopy, Confocal; Ophthalmic Nerve; Deep Learning; Corneal Diseases; Pattern Recognition, Automated; Image Processing, Computer-Assisted; Intravital Microscopy; Algorithms
PubMed: 38941998
DOI: 10.1055/a-2307-0313 -
Journal of Colloid and Interface Science Jun 2024Aqueous zinc batteries (AZBs) with the advantages of safety, low cost, and sustainability are promising candidates for large-scale energy storage devices. However, the...
Aqueous zinc batteries (AZBs) with the advantages of safety, low cost, and sustainability are promising candidates for large-scale energy storage devices. However, the issues of interface side reactions and dendrite growth at the zinc metal anode (ZMA) significantly harm the cycling lifespan of AZBs. In this study, we designed a nano-molecular sieve additive, fullerenol (C(OH)), which possesses a surface rich in hydroxyl groups that can be uniformly dispersed in the aqueous solution, and captures free water in the electrolyte, thereby suppressing the occurrence of interfacial corrosion. Besides, fullerenol can be further reduced to fullerene (C) on the surface of ZMA, holding a unique self-smoothing effect that can inhibit the growth of dendritic Zn. With the synergistic action of these two effects, the fullerenol-contained electrolyte (FE) enables dendrite-free ZMAs. The Zn-Ti half-cell using FE exhibits stable cycling over 2500 times at 5 mA cm with an average Coulombic efficiency as high as 99.8 %. Additionally, the Zn-NaVO cell using this electrolyte displays a capacity retention rate of 100 % after 1000 cycles at -20 °C. This work provides important insights into the molecular design of multifunctional electrolyte additives.
PubMed: 38941928
DOI: 10.1016/j.jcis.2024.06.182 -
Biomedicine & Pharmacotherapy =... Jun 2024Vaccines are an effective intervention for preventing infectious diseases. Currently many vaccine strategies are designed to improve vaccine efficacy by controlling...
Vaccines are an effective intervention for preventing infectious diseases. Currently many vaccine strategies are designed to improve vaccine efficacy by controlling antigen release, typically involving various approaches at the injection site. Yet, strategies for intracellular slow-release of antigens in vaccines are still unexplored. Our study showed that controlling the degradation of antigens in dendritic cells and slowing their transport from early endosomes to lysosomes markedly enhances both antigen-specific T-cell immune responses and germinal center B cell responses. This leads to the establishment of sustained humoral and cellular immunity in vivo imaging and flow cytometry indicated this method not only prolongs antigen retention at the injection site but also enhances antigen concentration in lymph nodes, surpassing traditional Aluminium (Alum) adjuvants. Additionally, we demonstrated that the slow antigen degradation induces stronger follicular helper T cell responses and increases proportions of long-lived plasma cells and memory B cells. Overall, these findings propose that controlling the speed of antigens transport in dendritic cells can significantly boost vaccine efficacy, offering an innovative avenue for developing highly immunogenic next-generation vaccines.
PubMed: 38941888
DOI: 10.1016/j.biopha.2024.117036 -
Annual Review of Immunology Jun 2024Plasmacytoid dendritic cells (pDCs) represent a unique cell type within the innate immune system. Their defining property is the recognition of pathogen-derived nucleic... (Review)
Review
Plasmacytoid dendritic cells (pDCs) represent a unique cell type within the innate immune system. Their defining property is the recognition of pathogen-derived nucleic acids through endosomal Toll-like receptors and the ensuing production of type I interferon and other soluble mediators, which orchestrate innate and adaptive responses. We review several aspects of pDC biology that have recently come to the fore. We discuss emerging questions regarding the lineage affiliation and origin of pDCs and argue that these cells constitute an integral part of the dendritic cell lineage. We emphasize the specific function of pDCs as innate sentinels of virus infection, particularly their recognition of and distinct response to virus-infected cells. This essential evolutionary role of pDCs has been particularly important for the control of coronaviruses, as demonstrated by the recent COVID-19 pandemic. Finally, we highlight the key contribution of pDCs to systemic lupus erythematosus, in which therapeutic targeting of pDCs is currently underway.
Topics: Dendritic Cells; Humans; COVID-19; Animals; Immunity, Innate; SARS-CoV-2; Lupus Erythematosus, Systemic; Toll-Like Receptors; Cell Differentiation; Cell Lineage
PubMed: 38941603
DOI: 10.1146/annurev-immunol-090122-041105 -
Medicine Jun 2024Abdominal aortic aneurysm (AAA) is a cardiovascular disease that seriously threatens human health and brings huge economic burden. At present, its pathogenesis remains...
Abdominal aortic aneurysm (AAA) is a cardiovascular disease that seriously threatens human health and brings huge economic burden. At present, its pathogenesis remains unclear and its treatment is limited to surgical treatment. With the deepening and analysis of studies on the mechanism of ferroptosis, a new idea has been provided for the clinical management of AAA patients, including diagnosis, treatment and prevention. Therefore, this paper aims to construct a competitive endogenous RNA (ceRNA) regulatory axis based on ferroptosis to preliminarily explore the pathogenesis and potential therapeutic targets of AAA. We obtained upregulated and downregulated ferroptosis-related DEGs (FRGs) from GSE144431 dataset and 60 known ferroptosis-related genes. Pearson correlation analysis was used to find aldoketone reductase 1C (AKR1C1) in AAA samples. Enrichment analysis of these genes was performed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Correlation test between immune cells and AKR1C1 was investigated through single-sample gene set enrichment analysis (ssGSEA). The AKR1C1-miRNA pairs were predicted by the TargetScan database and miRWalk database. Circular RNA (CircRNA)-miRNA pairs were selected by the CircInteractome database. Overlapping miRNA between circRNA-miRNA and AKR1C1-miRNA pairs was visualized by Venn diagram. Finally, the circRNA-miRNA-mRNA axis was constructed by searching for upstream circRNA and downstream mRNA of overlapping miRNA. Only one downregulated AKR1C1 gene was found in GSE144431 and 60 ferroptosis-related genes. Functional Enrichment and Pathway Analysis of AKR1C1-related genes were further explored, and it was observed that they were mainly enriched in "response to oxidative stress," "glutathione biosynthetic process" and "nonribosomal peptide biosynthetic process," "Ferroptosis," "Glutathione metabolism" and "Chemical carcinogenesis-reactive oxygen species." They were also found to be significantly associated with most immune cells, including Activated Dendritic cells, CD56dim Natural killer cells, Gamma Delta T cells, Immature B cells, Plasmacytoid dendritic cell, Type 2 T helper cell, Activated CD4 T cell and Type 1 T helper cell. Has_circ_0005073-miRNA-543 and AKR1C1-miRNA-543 were identified by Online Database analysis. Therefore, we have established the has_circ_0005073/miRNA-543/AKR1C1 axis in AAA. We found AKR1C1 was differentially expressed between normal and AAA groups. Based on AKR1C1, we constructed the has_circ_0005073/miRNA-543/AKR1C1 axis to analyze AAA.
Topics: Humans; Aortic Aneurysm, Abdominal; Ferroptosis; MicroRNAs; 20-Hydroxysteroid Dehydrogenases; RNA, Messenger; RNA, Circular; Down-Regulation
PubMed: 38941402
DOI: 10.1097/MD.0000000000038749 -
Investigational New Drugs Jun 2024The present study aimed to clarify the hypothesis that auger emitter I particles in combination with PARP inhibitor Olaparib could inhibit pancreatic cancer progression...
The present study aimed to clarify the hypothesis that auger emitter I particles in combination with PARP inhibitor Olaparib could inhibit pancreatic cancer progression by promoting antitumor immune response. Pancreatic cancer cell line (Panc02) and mice subcutaneously inoculated with Panc02 cells were employed for the in vitro and in vivo experiments, respectively, followed by I and Olaparib administrations. The apoptosis and CRT exposure of Panc02 cells were detected using flow cytometry assay. QRT-PCR, immunofluorescence, immunohistochemical analysis, and western blot were employed to examine mRNA and protein expression. Experimental results showed that I combined with Olaparib induced immunogenic cell death and affected antigen presentation in pancreatic cancer. I in combination with Olaparib influenced T cells and dendritic cells by up-regulating CD4, CD8, CD69, Caspase3, CD86, granzyme B, CD80, and type I interferon (IFN)-γ and down-regulating Ki67 in vivo. The combination also activated the cyclic GMP-AMP synthase stimulator of IFN genes (Sting) pathway in Panc02 cells. Moreover, Sting knockdown alleviated the effect of the combination of I and Olaparib on pancreatic cancer progression. In summary, I in combination with Olaparib inhibited pancreatic cancer progression through promoting antitumor immune responses, which may provide a potential treatment for pancreatic cancer.
PubMed: 38941055
DOI: 10.1007/s10637-024-01454-y