Potentiating dual-directional immunometabolic regulation with nanomedicine to enhance anti-tumor immunotherapy following incomplete photothermal ablation.

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.

Compartmentalization of adenosine metabolism in cancer cells and its modulation during acute hypoxia.

Extracellular adenosine mediates diverse anti-inflammatory, angiogenic and vasoactive effects, and has become an important therapeutic target for cancer, which has been translated into clinical trials. This study was designed to comprehensively assess adenosine metabolism in prostate and breast cancer cells. We identified cellular adenosine turnover as a complex cascade, comprising (1) the ectoenzymatic breakdown of ATP via sequential ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1, officially known as ENPP1), ecto-5'-nucleotidase (CD73, also known as NT5E), and adenosine deaminase reactions, and ATP re-synthesis through a counteracting adenylate kinase and members of the nucleoside diphosphate kinase (NDPK, also known as NME/NM23) family; (2) the uptake of nucleotide-derived adenosine via equilibrative nucleoside transporters; and (3) the intracellular adenosine phosphorylation into ATP by adenosine kinase and other nucleotide kinases. The exposure of cancer cells to 1% O2 for 24 h triggered an ∼2-fold upregulation of CD73, without affecting nucleoside transporters, adenosine kinase activity and cellular ATP content. The ability of adenosine to inhibit the tumor-initiating potential of breast cancer cells via a receptor-independent mechanism was confirmed in vivo using a xenograft mouse model. The existence of redundant pathways controlling extracellular and intracellular adenosine provides a sufficient justification for reexamination of the current concepts of cellular purine homeostasis and signaling in cancer.This article has an associated First Person interview with the first author of the paper.

Adenosine Metabolism in the Cerebral Cortex from Several Mice Models during Aging.

Adenosine is a neuromodulator that has been involved in aging and neurodegenerative diseases as Alzheimer's disease (AD). In the present work, we analyzed the possible modulation of purine metabolites, 5'nucleotidase (5'NT) and adenosine deaminase (ADA) activities, and adenosine monophosphate (AMP)-activated protein kinase (AMPK) and its phosphorylated form during aging in the cerebral cortex. Three murine models were used: senescence-accelerated mouse-resistant 1 (SAMR1, normal senescence), senescence-accelerated mouse-prone 8 (SAMP8, a model of AD), and the wild-type C57BL/6J (model of aging) mice strains. Glutamate and excitatory amino acid transporter 2 (EAAT2) levels were also measured in these animals. HPLC, Western blotting, and enzymatic activity evaluation were performed to this aim. 5'-Nucleotidase (5'NT) activity was decreased at six months and recovered at 12 months in SAMP8 while opposite effects were observed in SAMR1 at the same age, and no changes in C57BL/6J mice. ADA activity significantly decreased from 3 to 12 months in the SAMR1 mice strain, while a significant decrease from 6 to 12 months was observed in the SAMP8 mice strain. Regarding purine metabolites, xanthine and guanosine levels were increased at six months in SAMR1 without significant differences in SAMP8 mice. In C57BL/6J mice, inosine and xanthine were increased, while adenosine decreased, from 4 to 24 months. The AMPK level was decreased at six months in SAMP8 without significant changes nor in SAMR1 or C57BL/6J strains. Glutamate and EAAT2 levels were also modulated during aging. Our data show a different modulation of adenosine metabolism participants in the cerebral cortex of these animal models. Interestingly, the main differences between SAMR1 and SAMP8 mice were found at six months of age, SAMP8 being the most affected strain. As SAMP8 is an AD model, results suggest that adenosinergic metabolism is involved in the neurodegeneration of AD.

Dual-Cascade Activatable Nanopotentiators Reshaping Adenosine Metabolism for Sono-Chemodynamic-Immunotherapy of Deep Tumors.

Immunotherapy is an attractive treatment strategy for cancer, while its efficiency and safety need to be improved. A dual-cascade activatable nanopotentiator for sonodynamic therapy (SDT) and chemodynamic therapy (CDT)-cooperated immunotherapy of deep tumors via reshaping adenosine metabolism is herein reported. This nanopotentiator (NPMCA ) is constructed through crosslinking adenosine deaminase (ADA) with chlorin e6 (Ce6)-conjugated manganese dioxide (MnO2 ) nanoparticles via a reactive oxygen species (ROS)-cleavable linker. In the tumor microenvironment with ultrasound (US) irradiation, NPMCA mediates CDT and SDT concurrently in deep tumors covered with 2-cm tissues to produce abundant ROS, which results in dual-cascade scissoring of ROS-cleavable linkers to activate ADA within NCMCA to block adenosine metabolism. Moreover, immunogenic cell death (ICD) of dying tumor cells and upregulation of the stimulator of interferon genes (STING) is triggered by the generated ROS and Mn2+ from NPMCA , respectively, leading to activation of antitumor immune response. The potency of immune response is further reinforced by reducing the accumulation of adenosine in tumor microenvironment by the activated ADA. As a result, NPMCA enables CDT and SDT-cooperated immunotherapy, showing an obviously improved therapeutic efficacy to inhibit the growths of bilateral tumors, in which the primary tumors are covered with 2-cm tissues.

A prognostic signature based on adenosine metabolism related genes for ovarian cancer.

Background: Ovarian cancer is one of the most common cause of cancer death in women due to its late diagnosis and susceptibility to drug resistance. Adenosine (ADO) signaling plays a key role in immune activity and tumor progression. In this study, we constructed a signature of ADO metabolism related genes expression in patients with ovarian cancer. Methods: A total of 372 ovarian cancer patients from TCGA was used as training set and 1,137 patients from six GEO datasets were as validation set. The gene expression and drug response inhibitory concentration values for ovarian cancer cell line from GDSC were used for drug sensitivity analysis. The non-negative matrix factorization algorithm and ssGSVA were used to construct the ADO score. Results: Patients with high ADO score had shorter overall survival (OS) than those with low ADO score in both training set (HR = 1.42, 95% CI, 1.06-1.88) and validation sets (pooled HR = 1.24, 95% CI = 1.02-1.51). In GSEA analysis, genes in ATP synthesis related pathways were enriched in the low ADO score group (adjusted P value = 0.02). Further, we observed that the high ADO score group had significantly higher levels of most cancer hallmark signatures (all adjusted P values < 0.01) and T cell dysfunction and exclusion signatures than the low ADO score group (all adjusted P values < 0.001). Patients with lower ADO score tended to be sensitive to common drugs including Olaparib and Paclitaxel (adjusted P values = 0.05 and 0.04, respectively). Conclusions: In conclusion, the established ADO signature could be used as a prognostic biomarker to stratify ovarian cancer patients and had the potential to guide the drug exploitation and personalized therapy selection.

Adenosine kinase deficiency presenting with tortuous cervical arteries: A risk factor for recurrent stroke.

Adenosine kinase (ADK) deficiency is a very rare inborn error of methionine and adenosine metabolism. It is characterized by developmental delay, hypotonia, epilepsy, facial dysmorphism, failure to thrive, transient liver dysfunction with cholestasis, recurrent hypoglycemia, and cardiac defects. Only 26 cases (16 families) of ADK deficiency have been published since its identification in 2011. Vascular abnormalities in cervical arteries and cerebral stroke have never been reported in this condition. Here, we describe two patients with ADK deficiency and vascular tortuosity leading to stroke in one of them. ADK deficiency is a rare inborn error of methionine metabolism with a complex phenotype that might be associated with cerebrovascular abnormalities and stroke.

Adenosine metabolism, immunity and joint health.

The purine nucleoside adenosine is a present in most body fluids where it regulates a wide variety of physiologic and pharmacologic processes. Adenosine mediates its effects through activating 4 G protein-coupled receptors expressed on the cell membrane: A1, A2A, A2B, and A3. The adenosine receptors are widely distributed in the body, and tissues with high expression include immune tissues, cartilage, bone, heart, and brain. Here we review the source and metabolism of adenosine and the role of adenosine in regulating immunity and cartilage biology.

Isolation and substrate specificity of an adenine nucleoside phosphorylase from adult Schistosoma mansoni.

An adenine nucleoside phosphorylase (ANP, EC none) activity was identified and partially purified from extracts of Schistosoma mansoni by chromatofocussing column chromatography and molecular sieving. The enzyme is distinct from purine nucleoside phosphorylase (PNP, EC 2.4.2.1). ANP is specific for adenine nucleosides which includes adenosine analogs modified in the aglycone, pentose or both moieties. (e.g. 2'-deoxyadenosine, 5'-deoxy-5'-methylthioadenosine, 5'-deoxy-5'-iodo-2-fluoroadenosine, etc.) The enzyme is also distinct from the mammalian 5'-deoxy-5'-methylthioadenosine phosphorylase (MTAP, EC 2.4.2.28) in that it is able of the phosphorolysis of 2'-deoxyadenosine while mammalian MTAP cannot. Because of ANP unique substrate specificity, the enzyme could play a role as a target for chemotherapy of these parasites. Cytotoxic analogs may be designed as subversive substrates that are selectively activated only by the schistosomal ANP.

Adenine and adenosine salvage in Leishmania donovani.

6-aminopurine metabolism in Leishmania is unique among trypanosomatid pathogens since this genus expresses two distinct routes for adenine salvage: adenine phosphoribosyltransferase (APRT) and adenine deaminase (AAH). To evaluate the relative contributions of APRT and AAH, adenine salvage was evaluated in Δaprt, Δaah, and Δaprt/Δaah null mutants of L. donovani. The data confirm that AAH plays the dominant role in adenine metabolism in L. donovani, although either enzyme alone is sufficient for salvage. Adenosine salvage was also evaluated in a cohort of null mutants. Adenosine is also primarily converted to hypoxanthine, either intracellularly or extracellularly, but can also be phosphorylated to the nucleotide level by adenosine kinase when the predominant pathways are genetically or pharmacologically blocked. These data provide genetic verification for the relative contributions of 6-aminopurine metabolizing pathways in L. donovani and demonstrate that all of the pathways can function under appropriate conditions of genetic or pharmacologic perturbation.

Adenosina desaminase: uma enzima extraordinária e onipresente Adenosina desaminase: uma enzima extraordinária e onipresente / Adenosine deaminase: an extraordinary and omnipresent enzyme

Depois de introduzir os conceitos básicos da enzima adenosina desaminase (ADA), uma breve discussão sobre a estrutura, o mecanismo enzimático, terapia genética e potencial utilização terapêutica de inibidores de ADA são apresentados. O estudo da ADA é muito mais complexo do que simplesmente seu papel como biomarcador diagnóstico para tuberculose pleural que veio revolucionar o setor de diagnóstico na medicina clínica nos últimos anos. O aumento de sua atividade no líquido pleural, e em outros líquidos orgânicos, impede que o paciente na maioria dos casos com síndrome do derrame pleural por tuberculose seja submetido a procedimentos cirúrgicos invasivos com possíveis complicações potencialmente fatais AU.

After introducing the basic concepts of ADA, a brief discussion on the structure, enzymatic mechanism, gene therapy and potential therapeutic use of ADA inhibitors are presented. The study of the ADA is much more complex than simply its role as a biomarker for pleural tuberculosis that has revolutionized the diagnostic in clinical medicine in recent years. The increase in its activity in the pleural fluid, and other body fluids, prevents the patient in most cases with pleural effusion tuberculosis is subjected to invasive surgical procedures with possible life-threatening complications. AU