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Journal of Nanobiotechnology Jun 2024Photothermal therapy (PTT) is a promising cancer treatment method due to its ability to induce tumor-specific T cell responses and enhance therapeutic outcomes. However,...
Photothermal therapy (PTT) is a promising cancer treatment method due to its ability to induce tumor-specific T cell responses and enhance therapeutic outcomes. However, incomplete PTT can leave residual tumors that often lead to new metastases and decreased patient survival in clinical scenarios. This is primarily due to the release of ATP, a damage-associated molecular pattern that quickly transforms into the immunosuppressive metabolite adenosine by CD39, prevalent in the tumor microenvironment, thus promoting tumor immune evasion. This study presents a photothermal nanomedicine fabricated by electrostatic adsorption among the Fe-doped polydiaminopyridine (Fe-PDAP), indocyanine green (ICG), and CD39 inhibitor sodium polyoxotungstate (POM-1). The constructed Fe-PDAP@ICG@POM-1 (FIP) can induce tumor PTT and immunogenic cell death when exposed to a near-infrared laser. Significantly, it can inhibit the ATP-adenosine pathway by dual-directional immunometabolic regulation, resulting in increased ATP levels and decreased adenosine synthesis, which ultimately reverses the immunosuppressive microenvironment and increases the susceptibility of immune checkpoint blockade (aPD-1) therapy. With the aid of aPD-1, the dual-directional immunometabolic regulation strategy mediated by FIP can effectively suppress/eradicate primary and distant tumors and evoke long-term solid immunological memory. This study presents an immunometabolic control strategy to offer a salvage option for treating residual tumors following incomplete PTT.
Topics: Animals; Photothermal Therapy; Immunotherapy; Mice; Nanomedicine; Tumor Microenvironment; Cell Line, Tumor; Humans; Indocyanine Green; Neoplasms; Adenosine Triphosphate; Adenosine; Mice, Inbred C57BL; Apyrase; Female; Phototherapy
PubMed: 38915007
DOI: 10.1186/s12951-024-02643-w -
Giornale Italiano Di Cardiologia (2006) Jun 2024
Randomized Controlled Trial
Topics: Humans; Drug-Eluting Stents; Acute Coronary Syndrome; Ticagrelor; Purinergic P2Y Receptor Antagonists; Treatment Outcome; Male; Middle Aged; Platelet Aggregation Inhibitors; Female
PubMed: 38912746
DOI: 10.1714/4287.42692 -
Cellular and Molecular Life Sciences :... Jun 2024N-methyladenosine (mA) is one of the most prevalent and conserved RNA modifications. It controls several biological processes, including the biogenesis and function of...
N-methyladenosine (mA) is one of the most prevalent and conserved RNA modifications. It controls several biological processes, including the biogenesis and function of circular RNAs (circRNAs), which are a class of covalently closed-single stranded RNAs. Several studies have revealed that proteotoxic stress response induction could be a relevant anticancer therapy in Acute Myeloid Leukemia (AML). Furthermore, a strong molecular interaction between the mA mRNA modification factors and the suppression of the proteotoxic stress response has emerged. Since the proteasome inhibition leading to the imbalance in protein homeostasis is strictly linked to the stress response induction, we investigated the role of Bortezomib (Btz) on mA regulation and in particular its impact on the modulation of mA-modified circRNAs expression. Here, we show that treating AML cells with Btz downregulated the expression of the mA regulator WTAP at translational level, mainly because of increased oxidative stress. Indeed, Btz treatment promoted oxidative stress, with ROS generation and HMOX-1 activation and administration of the reducing agent N-acetylcysteine restored WTAP expression. Additionally, we identified mA-modified circRNAs modulated by Btz treatment, including circHIPK3, which is implicated in protein folding and oxidative stress regulation. These results highlight the intricate molecular networks involved in oxidative and ER stress induction in AML cells following proteotoxic stress response, laying the groundwork for future therapeutic strategies targeting these pathways.
Topics: Humans; RNA, Circular; Leukemia, Myeloid, Acute; Adenosine; Oxidative Stress; Bortezomib; Cell Line, Tumor; Reactive Oxygen Species; RNA Splicing Factors; Cell Cycle Proteins; Neoplastic Stem Cells; Heme Oxygenase-1; Protein Serine-Threonine Kinases; Intracellular Signaling Peptides and Proteins
PubMed: 38909325
DOI: 10.1007/s00018-024-05299-9 -
Methods in Molecular Biology (Clifton,... 2024Dynamic and reversible N-methyladenosine (mA) modifications are associated with many essential cellular functions as well as physiological and pathological phenomena....
Dynamic and reversible N-methyladenosine (mA) modifications are associated with many essential cellular functions as well as physiological and pathological phenomena. In-depth study of mA co-functional patterns in epi-transcriptomic data may help to understand its complex regulatory mechanisms. In this chapter, we describe several biclustering mining algorithms for epi-transcriptomic data to discover potential co-functional patterns. The concepts and computational methods discussed in this chapter will be particularly useful for researchers working in related fields. We also aim to introduce new deep learning techniques into the field of co-functional analysis of epi-transcriptomic data.
Topics: Adenosine; Algorithms; Computational Biology; Humans; Transcriptome; Cluster Analysis; Gene Expression Profiling; Deep Learning; Epigenesis, Genetic; Epigenomics; Software
PubMed: 38907925
DOI: 10.1007/978-1-0716-3918-4_19 -
Nucleosides, Nucleotides & Nucleic Acids Jun 2024The chemical synthesis of guanosine nucleosides generates both the and regioisomers, which require careful separation to obtain the desired isomer. To preferentially...
The chemical synthesis of guanosine nucleosides generates both the and regioisomers, which require careful separation to obtain the desired isomer. To preferentially obtain the isomer, a bulky diphenylcarbamoyl (DPC) group can be installed at the position of guanine. However, installation of the DPC group presents a challenging task due to low solubility of the -acetyl protected guanine. Here we report the usage of commercially available 2-amino-6-chloro purine as a new strategy that offers a more efficient route to the synthesis of the guanine phosphoramidite of threose nucleic acid (TNA).
PubMed: 38904107
DOI: 10.1080/15257770.2024.2369688 -
International Journal of Biological... 2024N-methyladenosine (mA) methylation plays a crucial role in various biological processes and the pathogenesis of human diseases. However, its role and mechanism in kidney...
N-methyladenosine (mA) methylation plays a crucial role in various biological processes and the pathogenesis of human diseases. However, its role and mechanism in kidney fibrosis remain elusive. In this study, we show that the overall level of mA methylated RNA was upregulated and the mA methyltransferase METTL3 was induced in kidney tubular epithelial cells in mouse models and human kidney biopsies of chronic kidney disease (CKD). Proximal tubule-specific knockout of METTL3 in mice protected kidneys against developing fibrotic lesions after injury. Conversely, overexpression of METTL3 aggravated kidney fibrosis . Through bioinformatics analysis and experimental validation, we identified β-catenin mRNA as a major target of METTL3-mediated mA modification, which could be recognized by a specific mA reader, the insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3). METTL3 stabilized β-catenin mRNA, increased β-catenin protein and induced its downstream profibrotic genes, whereas either knockdown of IGF2BP3 or inhibiting β-catenin signaling abolished its effects. Collectively, these results indicate that METTL3 promotes kidney fibrosis by stimulating the mA modification of β-catenin mRNA, leading to its stabilization and its downstream profibrotic genes expression. Our findings suggest that targeting METTL3/IGF2BP3/β-catenin pathway may be a novel strategy for the treatment of fibrotic CKD.
Topics: beta Catenin; Animals; Mice; Fibrosis; Humans; Methylation; Methyltransferases; Signal Transduction; Adenosine; Kidney; Male; Mice, Inbred C57BL; Up-Regulation; Renal Insufficiency, Chronic; Mice, Knockout; RNA Methylation
PubMed: 38904026
DOI: 10.7150/ijbs.96233 -
Journal of Translational Medicine Jun 2024KIAA1429, a regulatory subunit of the N-methyladenosine (mA) methyltransferase complex, has been implicated in the progression of various cancers. However, the role of...
BACKGROUND
KIAA1429, a regulatory subunit of the N-methyladenosine (mA) methyltransferase complex, has been implicated in the progression of various cancers. However, the role of KIAA1429 in gastric cancer (GC) and its underlying mechanisms remain elusive. This study aimed to investigate the role of KIAA1429 in GC and to elucidate the underlying mechanisms.
METHODS
The expression patterns and clinical relevance of KIAA1429 in GC were assessed using quantitative real-time PCR (qRT-PCR), Western blotting, immunohistochemistry (IHC), and bioinformatic analysis. In vitro and in vivo loss- and gain-of-function assays, mA dot blot assays, methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA-seq, MeRIP-qPCR, dual luciferase reporter assays, RNA stability assays, RNA immunoprecipitation (RIP) assays, and RNA pull-down assays were performed to investigate the biological functions and underlying molecular mechanisms of KIAA1429 in GC.
RESULTS
Both the mRNA and protein expression of KIAA1429 were greater in GC tissues than in normal gastric tissues. High KIAA1429 expression correlated positively with poor prognosis in GC patients. KIAA1429 not only promoted GC cell proliferation, colony formation, G2/M cell cycle transition, migration, and invasion in vitro but also enhanced GC tumor growth and metastasis in vivo. Mechanistically, KIAA1429 increased the mA level of RASD1 mRNA and enhanced its stability in an mA-YTHDF2-dependent manner, thereby upregulating its expression. RASD1 knockdown partially rescued the KIAA1429 knockdown-induced impairment of pro‑oncogenic ability in GC cells. The expression levels of KIAA1429 and RASD1 were negatively correlated in GC tissues.
CONCLUSIONS
KIAA1429 plays a pro‑oncogenic role in GC by downregulating RASD1 expression through destabilizing RASD1 mRNA in an mA-YTHDF2-dependent manner. KIAA1429 may serve as a prognostic biomarker and therapeutic target for GC.
Topics: Stomach Neoplasms; Humans; RNA, Messenger; Disease Progression; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; RNA-Binding Proteins; Cell Proliferation; Animals; RNA Stability; Adenosine; Male; Mice, Nude; Female; Middle Aged; Cell Movement; Mice; Prognosis; Mice, Inbred BALB C
PubMed: 38902717
DOI: 10.1186/s12967-024-05375-5 -
Environmental Pollution (Barking, Essex... Jun 2024Microplastics are ubiquitous pollutants in the global marine environment. However, few studies have adequately explored the different toxic mechanisms of microplastics...
Microplastics are ubiquitous pollutants in the global marine environment. However, few studies have adequately explored the different toxic mechanisms of microplastics (MPs) and nanoplastics (NPs) in aquatic organisms. The sea cucumber, Apostichopus japonicus, is a key organism in the marine benthic ecosystem due to its crucial roles in biogeochemical cycles and food web. This study investigated the bioaccumulation and adverse effects of polystyrene micro- and nanoplastics (PS-M/NPs) of different sizes (20 μm, 1 μm and 80 nm) in the regenerated intestine of A. japonicus using multi-omics analysis. The results showed that after 30-day exposure at the concentration of 0.1 mg L, PS-MPs and PS-NPs accumulated to 155.41-175.04 μg g and 337.95 μg g, respectively. This excessive accumulation led to increased levels of antioxidases (SOD, CAT, GPx and T-AOC) and reduced activities of immune enzymes (AKP, ACP and T-NOS), indicating oxidative damage and compromised immunity in the regenerated intestine. PS-NPs had more profound negative impacts on cell proliferation and differentiation compared to PS-MPs. Transcriptomic analysis revealed that PS-NPs primarily affected pathways related to cellular components, e.g., ribosome, and oxidative phosphorylation. In comparison, PS-MPs had greater influences on actin-related organization and organic compound metabolism. In the PS-M/NPs-treated groups, differentially expressed metabolites were mainly amino acids, fatty acids, glycerol phospholipid, and purine nucleosides. Additionally, microbial community reconstruction in the regenerated intestine was severely disrupted by the presence of PS-M/NPs. In the PS-NPs group, Burkholderiaceae abundance significantly increased while Rhodobacteraceae abundance decreased. Correlation analyses demonstrated that intestinal regeneration of A. japonicus was closely linked to its enteric microorganisms. These microbiota-host interactions were notably affected by different PS-M/NPs, with PS-NPs exposure causing the most remarkable disruption of mutual symbiosis. The multi-omic approaches used here provide novel insights into the size-dependent toxicity of PS-M/NPs and highlight their detrimental effects on invertebrates in M/NPs-polluted marine benthic ecosystems.
PubMed: 38901819
DOI: 10.1016/j.envpol.2024.124394 -
Microbial Cell Factories Jun 2024Guanosine is a purine nucleoside that is widely used as a raw material for food additives and pharmaceutical products. Microbial fermentation is the main production...
BACKGROUND
Guanosine is a purine nucleoside that is widely used as a raw material for food additives and pharmaceutical products. Microbial fermentation is the main production method of guanosine. However, the guanosine-producing strains possess multiple metabolic pathway interactions and complex regulatory mechanisms. The lack of strains with efficiently producing-guanosine greatly limited industrial application.
RESULTS
We attempted to efficiently produce guanosine in Escherichia coli using systematic metabolic engineering. First, we overexpressed the purine synthesis pathway from Bacillus subtilis and the prs gene, and deleted three genes involved in guanosine catabolism to increase guanosine accumulation. Subsequently, we attenuated purA expression and eliminated feedback and transcription dual inhibition. Then, we modified the metabolic flux of the glycolysis and Entner-Doudoroff (ED) pathways and performed redox cofactors rebalancing. Finally, transporter engineering and enhancing the guanosine synthesis pathway further increased the guanosine titre to 134.9 mg/L. After 72 h of the fed-batch fermentation in shake-flask, the guanosine titre achieved 289.8 mg/L.
CONCLUSIONS
Our results reveal that the guanosine synthesis pathway was successfully optimized by combinatorial metabolic engineering, which could be applicable to the efficient synthesis of other nucleoside products.
Topics: Metabolic Engineering; Guanosine; Escherichia coli; Fermentation; Bacillus subtilis
PubMed: 38898430
DOI: 10.1186/s12934-024-02452-8 -
Nature Communications Jun 2024Archaea possess characteristic membrane-spanning lipids that are thought to contribute to the adaptation to extreme environments. However, the biosynthesis of these...
Archaea possess characteristic membrane-spanning lipids that are thought to contribute to the adaptation to extreme environments. However, the biosynthesis of these lipids is poorly understood. Here, we identify a radical S-adenosyl-L-methionine (SAM) enzyme that synthesizes glycerol monoalkyl glycerol tetraethers (GMGTs). The enzyme, which we name GMGT synthase (Gms), catalyzes the formation of a C(sp)-C(sp) linkage between the two isoprenoid chains of glycerol dialkyl glycerol tetraethers (GDGTs). This conclusion is supported by heterologous expression of gene gms from a GMGT-producing species in a methanogen, as well as demonstration of in vitro activity using purified Gms enzyme. Additionally, we show that genes encoding putative Gms homologs are present in obligate anaerobic archaea and in metagenomes obtained from oxygen-deficient environments, and appear to be absent in metagenomes from oxic settings.
Topics: S-Adenosylmethionine; Archaea; Oxygen; Anaerobiosis; Archaeal Proteins; Glycerol; Metagenome; Phylogeny
PubMed: 38898040
DOI: 10.1038/s41467-024-49650-x