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Journal of Hematology & Oncology May 2024As the most common form of epigenetic regulation by RNA, N methyladenosine (mA) modification is closely involved in physiological processes, such as growth and... (Review)
Review
As the most common form of epigenetic regulation by RNA, N methyladenosine (mA) modification is closely involved in physiological processes, such as growth and development, stem cell renewal and differentiation, and DNA damage response. Meanwhile, its aberrant expression in cancer tissues promotes the development of malignant tumors, as well as plays important roles in proliferation, metastasis, drug resistance, immunity and prognosis. This close association between mA and cancers has garnered substantial attention in recent years. An increasing number of small molecules have emerged as potential agents to target mA regulators for cancer treatment. These molecules target the epigenetic level, enabling precise intervention in RNA modifications and efficiently disrupting the survival mechanisms of tumor cells, thus paving the way for novel approaches in cancer treatment. However, there is currently a lack of a comprehensive review on small molecules targeting mA regulators for anti-tumor. Here, we have comprehensively summarized the classification and functions of mA regulators, elucidating their interactions with the proliferation, metastasis, drug resistance, and immune responses in common cancers. Furthermore, we have provided a comprehensive overview on the development, mode of action, pharmacology and structure-activity relationships of small molecules targeting mA regulators. Our aim is to offer insights for subsequent drug design and optimization, while also providing an outlook on future prospects for small molecule development targeting mA.
Topics: Animals; Humans; Adenosine; Antineoplastic Agents; Epigenesis, Genetic; Neoplasms; Small Molecule Libraries
PubMed: 38711100
DOI: 10.1186/s13045-024-01546-5 -
Haematologica Jan 2024
Topics: Humans; Adenosine
PubMed: 37470140
DOI: 10.3324/haematol.2023.283469 -
International Journal of Molecular... Oct 2023Adenosine, an immunosuppressive metabolite, is produced by adenosine triphosphate (ATP) released from dying or stressed cells and is found at high levels in the tumor... (Review)
Review
Adenosine, an immunosuppressive metabolite, is produced by adenosine triphosphate (ATP) released from dying or stressed cells and is found at high levels in the tumor microenvironment of most solid tumors. It mediates pro-tumor activities by inducing tumor cell proliferation, migration or invasion, tumor tissue angiogenesis, and chemoresistance. In addition, adenosine plays an important role in regulating anti-tumor immune responses and facilitating tumor immune escape. Adenosine receptors are broadly expressed by tumor-infiltrated immune cells, including suppressive tumor-associated macrophages and CD4 regulatory T cells, as well as effector CD4 T cells and CD8 cytotoxic T lymphocytes. Therefore, adenosine is indispensable in down-regulating anti-tumor immune responses in the tumor microenvironment and contributes to tumor progression. This review describes the current progress on the role of adenosine/adenosine receptor pathway in regulating the tumor-infiltrating immune cells that contribute to tumor immune evasion and aims to provide insights into adenosine-targeted tumor immunotherapy.
Topics: Humans; Adenosine; Tumor Microenvironment; Adenosine Triphosphate; Neoplasms; CD8-Positive T-Lymphocytes; T-Lymphocytes, Regulatory; 5'-Nucleotidase
PubMed: 37834375
DOI: 10.3390/ijms241914928 -
Molecular Cell Sep 2023Heritable non-genetic information can regulate a variety of complex phenotypes. However, what specific non-genetic cues are transmitted from parents to their descendants...
Heritable non-genetic information can regulate a variety of complex phenotypes. However, what specific non-genetic cues are transmitted from parents to their descendants are poorly understood. Here, we perform metabolic methyl-labeling experiments to track the heritable transmission of methylation from ancestors to their descendants in the nematode Caenorhabditis elegans (C. elegans). We find heritable methylation in DNA, RNA, proteins, and lipids. We find that parental starvation elicits reduced fertility, increased heat stress resistance, and extended longevity in fed, naïve progeny. This intergenerational hormesis is accompanied by a heritable increase in N6'-dimethyl adenosine (mA) on the 18S ribosomal RNA at adenosines 1735 and 1736. We identified DIMT-1/DIMT1 as the mA and BUD-23/BUD23 as the mG methyltransferases in C. elegans that are both required for intergenerational hormesis, while other rRNA methyltransferases are dispensable. This study labels and tracks heritable non-genetic material across generations and demonstrates the importance of rRNA methylation for regulating epigenetic inheritance.
Topics: Animals; RNA, Ribosomal, 18S; Caenorhabditis elegans; Hormesis; Methyltransferases; Adenosine
PubMed: 37689068
DOI: 10.1016/j.molcel.2023.08.014 -
Neuropharmacology Oct 2023The purinergic system includes P1 and P2 receptors, which are activated by ATP and its metabolites. They are expressed in adult neuronal and glial cells and are crucial... (Review)
Review
The purinergic system includes P1 and P2 receptors, which are activated by ATP and its metabolites. They are expressed in adult neuronal and glial cells and are crucial in brain function, including neuromodulation and neuronal signaling. As P1 and P2 receptors are expressed throughout embryogenesis and development, purinergic signaling also has an important role in the development of the peripheral and central nervous system. In this review, we present the expression pattern and activity of purinergic receptors and of their signaling pathways during embryonic and postnatal development of the nervous system. In particular, we review the involvement of the purinergic signaling in all the crucial steps of brain development i.e. in neural stem cell proliferation, neuronal differentiation and migration as well as in astrogliogenesis and oligodendrogenesis. Then, we review data showing a crucial role of the ATP and adenosine signaling pathways in the formation of the peripheral neuromuscular junction and of central GABAergic and glutamatergic synapses. Finally, we examine the consequences of deregulation of the purinergic system during development and discuss the therapeutic potential of targeting it at adult stage in diseases with reactivation of the ATP and adenosine pathway. This article is part of the Special Issue on "Purinergic Signaling: 50 years".
Topics: Neurons; Receptors, Purinergic; Adenosine; Adenosine Triphosphate; Brain; Cell Proliferation
PubMed: 37348675
DOI: 10.1016/j.neuropharm.2023.109640 -
Frontiers in Immunology 2023Adenosine (Ado) is a well-known immunosuppressive agent that may be released or generated extracellularly by cells, via degrading ATP by the sequential actions of the... (Review)
Review
Adenosine (Ado) is a well-known immunosuppressive agent that may be released or generated extracellularly by cells, via degrading ATP by the sequential actions of the ectonucleotides CD39 and CD73. During inflammation Ado is produced by leukocytes and tissue cells by different means to initiate the healing phase. Ado downregulates the activation and the effector functions of different leukocyte (sub-) populations and stimulates proliferation of fibroblasts for re-establishment of intact tissues. Therefore, the anti-inflammatory actions of Ado are already intrinsically triggered during each episode of inflammation. These tissue-regenerating and inflammation-tempering purposes of Ado can become counterproductive. In chronic inflammation, it is possible that Ado-driven anti-inflammatory actions sustain the inflammation and prevent the final clearance of the tissues from possible pathogens. These chronic infections are characterized by increased tissue damage, remodeling and accumulating DNA damage, and are thus prone for tumor formation. Developing tumors may further enhance immunosuppressive actions by producing Ado by themselves, or by "hijacking" CD39/CD73 cells that had already developed during chronic inflammation. This review describes different and mostly convergent mechanisms of how Ado-induced immune suppression, initially induced in inflammation, can lead to tumor formation and outgrowth.
Topics: Humans; Adenosine; Neoplasms; Adenosine Triphosphate; Inflammation; Anti-Inflammatory Agents
PubMed: 38022572
DOI: 10.3389/fimmu.2023.1258637 -
Nature Communications Jun 2023Phytopathogenic fungi secrete chitin deacetylase (CDA) to escape the host's immunological defense during infection. Here, we showed that the deacetylation activity of...
Phytopathogenic fungi secrete chitin deacetylase (CDA) to escape the host's immunological defense during infection. Here, we showed that the deacetylation activity of CDA toward chitin is essential for fungal virulence. Five crystal structures of two representative and phylogenetically distant phytopathogenic fungal CDAs, VdPDA1 from Verticillium dahliae and Pst_13661 from Puccinia striiformis f. sp. tritici, were obtained in ligand-free and inhibitor-bound forms. These structures suggested that both CDAs have an identical substrate-binding pocket and an Asp-His-His triad for coordinating a transition metal ion. Based on the structural identities, four compounds with a benzohydroxamic acid (BHA) moiety were obtained as phytopathogenic fungal CDA inhibitors. BHA exhibited high effectiveness in attenuating fungal diseases in wheat, soybean, and cotton. Our findings revealed that phytopathogenic fungal CDAs share common structural features, and provided BHA as a lead compound for the design of CDA inhibitors aimed at attenuating crop fungal diseases.
Topics: Humans; Inhibition, Psychological; Amidohydrolases; Chitin; Cladribine; Cytidine Deaminase; Mycoses
PubMed: 37385996
DOI: 10.1038/s41467-023-39562-7 -
Sleep Medicine Mar 2024Sleep is a natural and recurring state of life. Long-term insomnia can lead to physical and mental fatigue, inattention, memory loss, anxiety, depression and other... (Review)
Review
Sleep is a natural and recurring state of life. Long-term insomnia can lead to physical and mental fatigue, inattention, memory loss, anxiety, depression and other symptoms, imposing immense public health and economic burden worldwide. The sleep and awakening regulation system is composed of many nerve nuclei and neurotransmitters in the brain, and it forms a neural network that interacts and restricts each other to regulate the occurrence and maintenance of sleep-wake. Adenosine (AD) is a neurotransmitter in the central nervous system and a driver of sleep. Meanwhile, the functions and mechanisms underlying sleep-promoting effects of adenosine and its receptors are still not entirely clear. However, in recent years, the increasing evidence indicated that adenosine can promote sleep through inhibiting arousal system and activating sleep-promoting system. At the same time, astrocyte-derived adenosine in modulating sleep homeostasis and sleep loss-induced related cognitive and memory deficits plays an important role. This review, therefore, summarizes the current research on the functions and possible mechanisms of adenosine and its receptors in the regulation of sleep and homeostatic control of sleep. Understanding these aspects will provide us better ideas on clinical problems such as insomnia, hypersomnia and other sleep disorders.
Topics: Humans; Adenosine; Sleep Initiation and Maintenance Disorders; Wakefulness; Sleep; Brain; Neurotransmitter Agents
PubMed: 38373361
DOI: 10.1016/j.sleep.2024.02.012 -
Cell Death & Disease Sep 2023Oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) consists of latent and lytic replication phases, both of which are important for the development of KSHV-related...
Oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) consists of latent and lytic replication phases, both of which are important for the development of KSHV-related cancers. As one of the most abundant RNA modifications, N-methyladenosine (mA) and its related complexes regulate KSHV life cycle. However, the role of METTL16, a newly discovered RNA methyltransferase, in KSHV life cycle remains unknown. In this study, we have identified a suppressive role of METTL16 in KSHV lytic replication. METTL16 knockdown increased while METTL16 overexpression reduced KSHV lytic replication. METTL16 binding to and writing of mA on MAT2A transcript are essential for its splicing, maturation and expression. As a rate-limiting enzyme in the methionine-S-adenosylmethionine (SAM) cycle, MAT2A catalyzes the conversion of L-methionine to SAM required for the transmethylation of protein, DNA and RNA, transamination of polyamines, and transsulfuration of cystathionine. Consequently, knockdown or chemical inhibition of MAT2A reduced intracellular SAM level and enhanced KSHV lytic replication. In contrast, SAM treatment was sufficient to inhibit KSHV lytic replication and reverse the effect of the enhanced KSHV lytic program caused by METTL16 or MAT2A knockdown. Mechanistically, METTL16 or MAT2A knockdown increased while SAM treatment decreased the intracellular reactive oxygen species level by altering glutathione level, which is essential for efficient KSHV lytic replication. These findings demonstrate that METTL16 suppresses KSHV lytic replication by modulating the SAM cycle to maintain intracellular SAM level and redox homeostasis, thus illustrating the linkage of KSHV life cycle with specific mA modifications, and cellular metabolic and oxidative conditions.
Topics: S-Adenosylmethionine; Herpesvirus 8, Human; Methionine; Cystathionine; RNA
PubMed: 37673880
DOI: 10.1038/s41419-023-06121-3 -
The Journal of Maternal-fetal &... Dec 2023N6-methyladenosine (m6A) is one of the predominant RNA epigenetic modifications that modify RNAs reversibly and dynamically by "writers" (methyltransferase), "erasers"... (Review)
Review
BACKGROUND
N6-methyladenosine (m6A) is one of the predominant RNA epigenetic modifications that modify RNAs reversibly and dynamically by "writers" (methyltransferase), "erasers" (demethylase), and "readers."
OBJECTIVE
This review aimed to provide a comprehensive understanding of the complexity of m6A regulation in the great obstetrical syndromes to understand its pathogenesis and potential therapeutic targets.
METHODS
The terms "placenta or trophoblast" and "m6A or N6-methyladenosine" were searched in PubMed databases (June 2023).
RESULTS
In this review, we discuss the regulatory role of m6A in the great obstetrical syndromes such as preeclampsia (PE), spontaneous abortion (SA), hyperglycemia in pregnancy (HIP) and fetal growth to emphasize the clinical relevance of m6A dysregulation in pregnancy. We also describe mechanisms that potentially involve the participation of m6A methylation, such as proliferation, invasion, migration, apoptosis, autophagy, endoplasmic reticulum stress, macrophage polarization, and inflammation.
CONCLUSION
We summarize the recent research progress on the role of m6A modification in the great obstetrical syndromes and placental function and provide a brief perspective on its prospective applications.
Topics: Pregnancy; Humans; Female; Placenta; Syndrome; Abortion, Spontaneous; Adenosine; Apoptosis
PubMed: 37474299
DOI: 10.1080/14767058.2023.2234541