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Biomedicine & Pharmacotherapy =... Feb 2024Diabetic kidney disease (DKD) is a major microvascular complication of diabetes, and hyperglycemic memory associated with diabetes carries the risk of disease... (Review)
Review
Diabetic kidney disease (DKD) is a major microvascular complication of diabetes, and hyperglycemic memory associated with diabetes carries the risk of disease occurrence, even after the termination of blood glucose injury. The existence of hyperglycemic memory supports the concept of an epigenetic mechanism involving n6-methyladenosine (m6A) modification. Several studies have shown that m6A plays a key role in the pathogenesis of DKD. This review addresses the role and mechanism of m6A RNA modification in the progression of DKD, including the regulatory role of m6A modification in pathological processes, such as inflammation, oxidative stress, fibrosis, and non-coding (nc) RNA. This reveals the importance of m6A in the occurrence and development of DKD, suggesting that m6A may play a role in hyperglycemic memory phenomenon. This review also discusses how some gray areas, such as m6A modified multiple enzymes, interact to affect the development of DKD and provides countermeasures. In conclusion, this review enhances our understanding of DKD from the perspective of m6A modifications and provides new targets for future therapeutic strategies. In addition, the insights discussed here support the existence of hyperglycemic memory effects in DKD, which may have far-reaching implications for the development of novel treatments. We hypothesize that m6A RNA modification, as a key factor regulating the development of DKD, provides a new perspective for the in-depth exploration of DKD and provides a novel option for the clinical management of patients with DKD.
Topics: Humans; Diabetic Nephropathies; RNA Methylation; Adenosine; Blood Glucose; Epigenesis, Genetic; RNA; Diabetes Mellitus
PubMed: 38237350
DOI: 10.1016/j.biopha.2024.116185 -
Journal For Immunotherapy of Cancer Aug 2023The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) remains extremely poor. It has been suggested that the adenosine pathway contributes to the...
BACKGROUND
The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) remains extremely poor. It has been suggested that the adenosine pathway contributes to the ability of PDAC to evade the immune system and hence, its resistance to immuno-oncology therapies (IOT), by generating extracellular adenosine (eAdo).
METHODS
Using genetically engineered allograft models of PDAC in syngeneic mice with defined and different immune infiltration and response to IOT and autochthonous tumors in KPC mice we investigated the impact of the adenosine pathway on the PDAC tumor microenvironment (TME). Flow cytometry and imaging mass cytometry (IMC) were used to characterize the subpopulation frequency and spatial distribution of tumor-infiltrating immune cells. Mass spectrometry imaging (MSI) was used to visualize adenosine compartmentalization in the PDAC tumors. RNA sequencing was used to evaluate the influence of the adenosine pathway on the shaping of the immune milieu and correlate our findings to published data sets in human PDAC.
RESULTS
We demonstrated high expression of adenosine pathway components in tumor-infiltrating immune cells (particularly myeloid populations) in the murine models. MSI demonstrated that extracellular adenosine distribution is heterogeneous in tumors, with high concentrations in peri-necrotic, hypoxic regions, associated with rich myeloid infiltration, demonstrated using IMC. Protumorigenic M2 macrophages express high levels of the Adora2a receptor; particularly in the IOT resistant model. Blocking the in vivo formation and function of eAdo (Adoi), using a combination of anti-CD73 antibody and an Adora2a inhibitor slowed tumor growth and reduced metastatic burden. Additionally, blocking the adenosine pathway improved the efficacy of combinations of cytotoxic agents or immunotherapy. Adoi remodeled the TME, by reducing the infiltration of M2 macrophages and regulatory T cells. RNA sequencing analysis showed that genes related to immune modulation, hypoxia and tumor stroma were downregulated following Adoi and a specific adenosine signature derived from this is associated with a poorer prognosis in patients with PDAC.
CONCLUSIONS
The formation of eAdo promotes the development of the immunosuppressive TME in PDAC, contributing to its resistance to conventional and novel therapies. Therefore, inhibition of the adenosine pathway may represent a strategy to modulate the PDAC immune milieu and improve therapy response in patients with PDAC.
Topics: Humans; Mice; Animals; Adenosine; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Immunotherapy; Tumor Microenvironment
PubMed: 37553182
DOI: 10.1136/jitc-2022-006457 -
Pharmacological Research Oct 2023The development of hyperuricemia (HUA) and gout is associated with dysbiosis of the gut microbiota. Quercetin can reduce serum uric acid levels and thus alleviate HUA by...
The development of hyperuricemia (HUA) and gout is associated with dysbiosis of the gut microbiota. Quercetin can reduce serum uric acid levels and thus alleviate HUA by modulating the gut microbiota. However, the detailed mechanisms involved in this process are not fully understood. Here, we showed that quercetin significantly reduced the serum uric acid level in a chicken HUA model by altering the chicken cecal microbiota structure and function and increasing the abundance of Lactobacillus aviarius. An L. aviarius strain, CML180, was isolated from the quercetin-treated chicken gut microbiota. Strain characterization indicated that quercetin promoted the growth of L. aviarius CML180 and increased its adhesion, hydrophobicity, and co-aggregation abilities. Gavage of live L. aviarius CML180 to a mouse model of HUA-established by adenosine and potassium oxonate-reduced the serum uric acid level and alleviated HUA. The ability of L. aviarius CML180 to decrease the level of uric acid was due to its degradation of purine nucleosides, which are the precursors for uric acid production. A nucleoside hydrolase gene, nhy69, was identified from the genome of L. aviarius CML180, and the resulting protein, Nhy69, exhibited strong purine nucleoside-hydrolyzing activity at mesophilic temperature and neutral pH conditions. These findings provide mechanistic insights into the potential of quercetin to treat HUA or gout diseases via a specific gut microbe.
PubMed: 37717681
DOI: 10.1016/j.phrs.2023.106928 -
Journal of the American Chemical Society Nov 2023Queuosine is one of the most complex hypermodified RNA nucleosides found in the Wobble position of tRNAs. In addition to Queuosine itself, several further modified...
Queuosine is one of the most complex hypermodified RNA nucleosides found in the Wobble position of tRNAs. In addition to Queuosine itself, several further modified derivatives are known, where the cyclopentene ring structure is additionally modified by a galactosyl-, a mannosyl-, or a glutamyl-residue. While sugar-modified Queuosine derivatives are found in the tRNAs of vertebrates, glutamylated Queuosine (gluQ) is only known in bacteria. The exact structure of gluQ, particularly with respect to how and where the glutamyl side chain is connected to the Queuosine cyclopentene side chain, is unknown. Here we report the first synthesis of gluQ and, using UHPLC-MS-injection and NMR studies, we show that the isolated natural gluQ is the α-allyl-connected gluQ compound.
Topics: Animals; Nucleoside Q; RNA, Transfer; Bacteria; Cyclopentanes
PubMed: 37967838
DOI: 10.1021/jacs.3c10075 -
Epigenetics Dec 2023The global dynamics in a variety of biological processes can be revealed by mapping transcriptional mA sites, in particular full-transcriptome mA. And individual mA... (Review)
Review
The global dynamics in a variety of biological processes can be revealed by mapping transcriptional mA sites, in particular full-transcriptome mA. And individual mA sites have contributed to biological function, which can be evaluated by stoichiometric information obtained from the single nucleotide resolution. Currently, the identification of mA sites is mainly carried out by experiment and prediction methods, based on high-throughput sequencing and machine learning model respectively. This review summarizes the recent topics and progress made in bioinformatics methods of deciphering the mA methylation, including the experimental detection of mA methylation sites, techniques of data analysis, the way of predicting mA methylation sites, mA methylation databases, and detection of mA modification in circRNA. At the end, the essay makes a brief discussion for the development perspective in this area.
Topics: DNA Methylation; Adenosine; Computational Biology; Machine Learning
PubMed: 36562485
DOI: 10.1080/15592294.2022.2158284 -
Science Advances Aug 2023Understanding mechanisms of epigenetic regulation in embryonic stem cells (ESCs) is of fundamental importance for stem cell and developmental biology. Here, we identify...
Understanding mechanisms of epigenetic regulation in embryonic stem cells (ESCs) is of fundamental importance for stem cell and developmental biology. Here, we identify , a member of the ETS family of transcription factors (TFs), as a marker of ground state pluripotency. We show that is rapidly induced in ground state ESCs and in response to extracellular signal-regulated kinase (ERK) inhibition. We find that SPIC binds to enhancer elements and stabilizes NANOG binding to chromatin, particularly at genes involved in choline/one-carbon (1C) metabolism such as , , and . Gain-of-function and loss-of-function experiments revealed that controls 1C metabolism and the flux of -adenosyl methionine to -adenosyl-L-homocysteine (SAM-to-SAH), thereby, modulating the levels of H3R17me2 and H3K4me3 histone marks in ESCs. Our findings highlight betaine-dependent 1C metabolism as a hallmark of ground state pluripotency primarily activated by SPIC. These findings underscore the role of uncharacterized auxiliary TFs in linking cellular metabolism to epigenetic regulation in ESCs.
Topics: Carbon; Embryonic Stem Cells; Epigenesis, Genetic; Histones; Methylation; S-Adenosylmethionine
PubMed: 37595034
DOI: 10.1126/sciadv.adg7997 -
Cells Feb 2024At the intestinal front, several lines of defense are in place to resist infection and injury, the mucus layer, gut microbiome and strong epithelial junctions, to name a... (Review)
Review
At the intestinal front, several lines of defense are in place to resist infection and injury, the mucus layer, gut microbiome and strong epithelial junctions, to name a few. Their collaboration creates a resilient barrier. In intestinal disorders, such as inflammatory bowel disease (IBD), barrier function is compromised, which results in rampant inflammation and tissue injury. In response to the destruction, the intestinal epithelium releases adenosine, a small but powerful nucleoside that functions as an alarm signal. Amidst the chaos of inflammation, adenosine aims to restore order. Within the scope of its effects is the ability to regulate intestinal epithelial barrier integrity. This review aims to define the contributions of adenosine to mucus production, microbiome-dependent barrier protection, tight junction dynamics, chloride secretion and acid-base balance to reinforce its importance in the intestinal epithelial barrier.
Topics: Humans; Adenosine; Inflammatory Bowel Diseases; Inflammation; Intestinal Mucosa
PubMed: 38474346
DOI: 10.3390/cells13050381 -
JAMA Network Open Mar 2024With the widespread use of anti-SARS-CoV-2 drugs, accumulating data have revealed potential viral load rebound after treatment. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
With the widespread use of anti-SARS-CoV-2 drugs, accumulating data have revealed potential viral load rebound after treatment.
OBJECTIVE
To compare COVID-19 rebound after a standard 5-day course of antiviral treatment with VV116 vs nirmatrelvir-ritonavir.
DESIGN, SETTING, AND PARTICIPANTS
This is a single-center, investigator-blinded, randomized clinical trial conducted in Shanghai, China. Adult patients with mild-to-moderate COVID-19 and within 5 days of SARS-CoV-2 infection were enrolled between December 20, 2022, and January 19, 2023, and randomly allocated to receive either VV116 or nirmatrelvir-ritonavir.
INTERVENTIONS
Participants in the VV116 treatment group received oral 600-mg VV116 tablets every 12 hours on day 1 and 300 mg every 12 hours on days 2 through 5. Participants in the nirmatrelvir-ritonavir treatment group received oral nirmatrelvir-ritonavir tablets with 300 mg of nirmatrelvir plus 100 mg of ritonavir every 12 hours for 5 days. Participants were followed up every other day until day 28 and every week until day 60.
MAIN OUTCOMES AND MEASURES
The primary outcome was viral load rebound (VLR), defined as a half-log increase in viral RNA copies per milliliter compared with treatment completion. Secondary outcomes included a reduction in the cycle threshold value of 1.5 or more, time until VLR, and symptom rebound, defined as an increase of more than 2 points in symptom score compared with treatment completion. The primary outcome and secondary outcomes were analyzed using the full analysis set. Sensitivity analyses were conducted using the per protocol set. Adverse events were analyzed using the safety analysis set.
RESULTS
The full analysis set included 345 participants (mean [SD] age, 53.2 [16.8] years; 175 [50.7%] were men) who received VV116 (n = 165) or nirmatrelvir-ritonavir (n = 180). Viral load rebound occurred in 33 patients (20.0%) in the VV116 group and 39 patients (21.7%) in the nirmatrelvir-ritonavir group (P = .70). Symptom rebound occurred in 41 of 160 patients (25.6%) in the VV116 group and 40 of 163 patients (24.5%) in the nirmatrelvir-ritonavir group (P = .82). Viral whole-genome sequencing of 24 rebound cases revealed the same lineage at baseline and at viral load rebound in each case.
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial of patients with mild-to-moderate COVID-19, viral load rebound and symptom rebound were both common after a standard 5-day course of treatment with either VV116 or nirmatrelvir-ritonavir. Prolongation of treatment duration might be investigated to reduce COVID-19 rebound.
TRIAL REGISTRATION
Chinese Clinical Trial Registry Identifier: ChiCTR2200066811.
Topics: Adult; Male; Humans; Middle Aged; Female; COVID-19; COVID-19 Drug Treatment; China; Ritonavir; SARS-CoV-2; Adenosine; Recurrence
PubMed: 38477921
DOI: 10.1001/jamanetworkopen.2024.1765 -
Cancer Gene Therapy Jun 2024RNA modification, especially N6-methyladenosine, 5-methylcytosine, and N7-methylguanosine methylation, participates in the occurrence and progression of cancer through... (Review)
Review
RNA modification, especially N6-methyladenosine, 5-methylcytosine, and N7-methylguanosine methylation, participates in the occurrence and progression of cancer through multiple pathways. The function and expression of these epigenetic regulators have gradually become a hot topic in cancer research. Mutation and regulation of noncoding RNA, especially lncRNA, play a major role in cancer. Generally, lncRNAs exert tumor-suppressive or oncogenic functions and its dysregulation can promote tumor occurrence and metastasis. In this review, we summarize N6-methyladenosine, 5-methylcytosine, and N7-methylguanosine modifications in lncRNAs. Furthermore, we discuss the relationship between epigenetic RNA modification and lncRNA interaction and cancer progression in various cancers. Therefore, this review gives a comprehensive understanding of the mechanisms by which RNA modification affects the progression of various cancers by regulating lncRNAs, which may shed new light on cancer research and provide new insights into cancer therapy.
Topics: Humans; Neoplasms; RNA, Long Noncoding; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Adenosine; Animals; RNA Processing, Post-Transcriptional
PubMed: 38351139
DOI: 10.1038/s41417-024-00734-2 -
British Journal of Pharmacology Feb 2024Inflammation is a complex pathophysiological process underlying many clinical conditions. Platelets contribute to the thrombo-inflammatory response. Platelet P2Y... (Review)
Review
Inflammation is a complex pathophysiological process underlying many clinical conditions. Platelets contribute to the thrombo-inflammatory response. Platelet P2Y receptors amplify platelet activation, potentiating platelet aggregation, degranulation and shape change. The contents of platelet alpha granules, in particular, act directly on leucocytes, including mediating platelet-leucocyte aggregation and activation via platelet P-selectin. Much evidence for the role of platelet P2Y receptors in inflammation comes from studies using antagonists of these receptors, such as the thienopyridines clopidogrel and prasugrel, and the cyclopentyltriazolopyrimidine ticagrelor, in animal and human experimental models. These suggest that antagonism of P2Y receptors decreases markers of inflammation with some evidence that this reduces incidence of adverse clinical sequelae during inflammatory conditions. Interpretation is complicated by pleiotropic effects such as those of the thienopyridines on circulating leucocyte numbers and of ticagrelor on adenosine reuptake. The available evidence suggests that P2Y receptors are prominent mediators of inflammation and P2Y receptor antagonism as a potentially powerful strategy in a broad range of inflammatory conditions. LINKED ARTICLES: This article is part of a themed issue on Platelet purinergic receptor and non-thrombotic disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.4/issuetoc.
Topics: Animals; Humans; Ticagrelor; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Blood Platelets; Inflammation; Platelet Aggregation; Prasugrel Hydrochloride; Thienopyridines; Receptors, Purinergic P2Y12
PubMed: 37771103
DOI: 10.1111/bph.16256