Implications of CD39 in immune-related diseases

Zeng, Jianrui; Ning, Zhaochen; Wang, Yu‐Zhong; Xiong, Huabao

doi:10.1016/j.intimp.2020.107055

Cited by 23 publications

(21 citation statements)

References 197 publications

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“…In our scRNA-seq analysis, we identified a cluster of CSF1 + CD59 + KIRs-expressing dNK cells (cluster 3) that are predominantly found in normal deciduas. This subpopulation of dNK cells express CD39, an ectonucleoside triphosphate diphosphohydrolase that is regarded as an immunological switch shifting the ATP-mediated pro-inflammatory environment to the adenosine-mediated anti-inflammatory status ( 50 ). CD59 is the main inhibitor of the membrane attack complex, and is involved in the regulation of the function, infiltration, and phenotypes of a variety of immune cells ( 51 ).…”

Section: Resultsmentioning

confidence: 99%

The Immune Atlas of Human Deciduas With Unexplained Recurrent Pregnancy Loss

et al. 2021

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Recurrent pregnancy loss (RPL) is a common fertility problem that affects 1%-2% of couples all over the world. Despite exciting discoveries regarding the important roles of the decidual natural killer cell (dNK) and regulatory T cell in pregnancy, the immune heterogeneity in patients with unexplained recurrent pregnancy loss (URPL) remains elusive. Here, we profiled the transcriptomes of 13,953 CD45+ cells from three normal and three URPL deciduas. Based on our data, the cellular composition revealed three major populations of immune cells including dNK cell, T cell, and macrophage, and four minor populations including monocytes, dendritic cell (DC), mast cell, and B cell. Especially, we identified a subpopulation of CSF1+ CD59+ KIRs-expressing dNK cells in normal deciduas, while the proportion of this subpopulation was decreased in URPL deciduas. We also identified a small subpopulation of activated dDCs that were accumulated mainly in URPL deciduas. Furthermore, our data revealed that in decidua at early pregnancy, CD8+ T cells exhibited cytotoxic properties. The decidual macrophages expressed high levels of both M1 and M2 feature genes, which made them unique to the conventional M1/M2 classification. Our single-cell data revealed the immune heterogeneity in decidua and the potentially pathogenic immune variations in URPL.

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Section: Resultsmentioning

confidence: 99%

The Immune Atlas of Human Deciduas With Unexplained Recurrent Pregnancy Loss

et al. 2021

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“…In the 3-position, a cyano group (10,19,20), an ethylcarboxylic acid ester (1-4, 11-15, 17), or a tert-butylcarboxylic acid ester (5-9, 16, 18, 21-32) was present. Position 2 was substituted with an amino group (1-10), a benzamido residue (11), a thiourea group (12)(13)(14)(15)(16)(17)(18)(19), a cyclized isothiourea group (20), a urea (21)(22)(23)(24)(25)(26)(28)(29)(30)(31)(32), or a carbamate (27) function. R 1 position: A small aliphatic methyl or ethyl substituent resulted in inactive compounds (1, 2, 5, and 6), while a larger, more lipophilic isobutyl residue restored some potency (compound 7); however, a benzyl residue was superior (4,8,10).…”

Section: Structure-activity Relationships (Sars)mentioning

confidence: 99%

“…[10] As the conversion of ATP into adenosine is mainly controlled by CD39 and CD73, these enzymes are potential targets for the treatment of a variety of diseases including inflammation, infection, and cancer. [11][12][13][14][15] Inhibition of CD39 reduces the concentrations of extracellular adenosine and simultaneously increases those of ATP, ADP, and other nucleotides, which abrogates immune escape mechanisms by cancer cells and tissues overexpressing CD39. [13,14] This effect can be increased by ancillary inhibition of CD73, which prevents hydrolysis of AMP, which can also be formed by alternative mechanisms, and thereby further reduces extracellular adenosine levels.…”

Section: Introductionmentioning

confidence: 99%

“…[11][12][13][14][15] Inhibition of CD39 reduces the concentrations of extracellular adenosine and simultaneously increases those of ATP, ADP, and other nucleotides, which abrogates immune escape mechanisms by cancer cells and tissues overexpressing CD39. [13,14] This effect can be increased by ancillary inhibition of CD73, which prevents hydrolysis of AMP, which can also be formed by alternative mechanisms, and thereby further reduces extracellular adenosine levels. [16] Crystal structures are available for rat CD39 (e.g., PDB-ID: 3ZX3) [17] and rat NTPDase2 (e.g., PDB-ID: 4BR5 and 4CD1).…”

Section: Introductionmentioning

confidence: 99%

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2‐Substituted thienotetrahydropyridine derivatives: Allosteric ectonucleotidase inhibitors

Schäkel

Mirza

Pietsch

et al. 2021

Archiv der Pharmazie

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The antithrombotic prodrugs ticlopidine and clopidogrel are thienotetrahydropyridine derivatives that are metabolized in the liver to produce thiols that irreversibly block adenosine diphosphate (ADP)-activated P2Y 12 receptors on thrombocytes. In their native, nonmetabolized form, both drugs were reported to act as inhibitors of ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1, CD39). CD39 catalyzes the extracellular hydrolysis of nucleoside tri-and diphosphates, mainly adenosine 5ʹ-triphosphate (ATP) and ADP, yielding adenosine monophosphate, which is further hydrolyzed by ecto-5ʹ-nucleotidase (CD73) to produce adenosine. While ATP has proinflammatory effects, adenosine is a potent anti-inflammatory, immunosuppressive agent. Inhibitors of CD39 and CD73 have potential as novel checkpoint inhibitors for the immunotherapy of cancer and infection. In the present study, we investigated 2-substituted thienotetrahydropyridine derivatives, structurally related to ticlopidine, as CD39 inhibitors. Due to their substituent on the 2-position, they will not be metabolically transformed into reactive thiols and can, therefore, be expected to be devoid of P2Y 12 receptorantagonistic activity in vivo. Several of the investigated 2-substituted thienotetrahydropyridine derivatives showed concentration-dependent inhibition of CD39.The most potent derivative, 32, showed similar CD39-inhibitory potency to ticlopidine, both acting as allosteric inhibitors. Compound 32 showed an improved selectivity profile: While ticlopidine blocked several NTPDase isoenzymes, 32 was characterized as a novel dual inhibitor of CD39 and CD73.

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“…5 Human ENTPD1 is located at chromosome 10, encoding 510 amino acids weighted 57kDa. 20 ENTPD1 is reportedly as one of the protective factors against diabetic nephropathy 21 and related with vascular damage 22 and inflammation 23 or tumor development. 24 One of the most frequently studied SNP in ENTPD1 was rs6584026, and it was mainly restricted to diabetic/non-diabetic condition in an individual and African-American people with CKD.…”

Section: Introductionmentioning

confidence: 99%

Association of the ENPP1/ENTPD1 Polymorphisms in Hemodialysis Patients

Zhang

Wan

Cheng³

et al. 2021

IJGM

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Introduction: ENPP1 and ENTPD1 are two main enzymes involved in ATP-AMP-ADPadenosine axis, which is associated with lipid metabolism, diabetes mellitus (DM) and renal fibrosis. The single nucleotide polymorphisms (SNPs) of ENPP1 and ENTPD1, rs1044498 and rs6584026, are associated with these factors. This retrospective study aimed to address the two SNPs variants in hemodialysis (HD) patients and analyzes their relations with clinical characteristics. Methods: This study included 543 regular HD patients over 3 months at our center. Overnight fasting peripheral blood sample was taken from each subject to extract the DNA. The genotypes of rs1044498 and rs6584026 were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The basic clinical data were noted such as sex, age, and HD-age, and the main causes of chronic kidney disease (CKD) and the clinical characteristics were collected on average at least three times in half a year. T-test and Chi-test were performed for the statistical analyses. Binary logistic regression was applied for the significant parameters by excluding the confounders, gender, age and HD-age. All statistical tests were considered significant for P<0.05.

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Implications of CD39 in immune-related diseases

Cited by 23 publications

References 197 publications

The Immune Atlas of Human Deciduas With Unexplained Recurrent Pregnancy Loss

The Immune Atlas of Human Deciduas With Unexplained Recurrent Pregnancy Loss

2‐Substituted thienotetrahydropyridine derivatives: Allosteric ectonucleotidase inhibitors

Association of the ENPP1/ENTPD1 Polymorphisms in Hemodialysis Patients

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