POM-1 inhibits P2 receptors and exhibits anti-inflammatory effects in macrophages

Pimenta-dos-Reis, Gabriela; Torres, Eduardo José Lopes; Quintana, Paula Gabriela; Vidal, Lincon Onorio; Santos, Bárbara Andréa Fortes dos; Lin, Chwan-Fwu; Heise, Norton; Persechini, Pedro M.; Schachter, Julieta

doi:10.1007/s11302-017-9588-x

Cited by 10 publications

(8 citation statements)

References 75 publications

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“…DMSO, present in the wells even in 10% ( v / v ), did not significantly influence the activity of CD39 and CD73. POM-1, an inhibitor of E-NTPDase1-3 enzymes [ 30 ] ( Table 1 ) and antagonist of some P2 purinergic receptors [ 31 ], significantly but incompletely reduced the activity of CD39. Interestingly, POM-1 also inhibited CD73, at least to the same extent as it inhibited CD39.…”

Section: Resultsmentioning

confidence: 99%

A Body of Circumstantial Evidence for the Irreversible Ectonucleotidase Inhibitory Action of FSCPX, an Agent Known as a Selective Irreversible A1 Adenosine Receptor Antagonist So Far

Viczjan

Erdei

Óvári

et al. 2021

IJMS

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In previous studies using isolated, paced guinea pig left atria, we observed that FSCPX, known as a selective A1 adenosine receptor antagonist, paradoxically increased the direct negative inotropic response to A1 adenosine receptor agonists (determined using concentration/effect (E/c) curves) if NBTI, a nucleoside transport inhibitor, was present. Based on mathematical modeling, we hypothesized that FSCPX blunted the cardiac interstitial adenosine accumulation in response to nucleoside transport blockade, probably by inhibiting CD39 and/or CD73, which are the two main enzymes of the interstitial adenosine production in the heart. The goal of the present study was to test this hypothesis. In vitro CD39 and CD73 inhibitor assays were carried out; furthermore, E/c curves were constructed in isolated, paced rat and guinea pig left atria using adenosine, CHA and CPA (two A1 adenosine receptor agonists), FSCPX, NBTI and NBMPR (two nucleoside transport inhibitors), and PSB-12379 (a CD73 inhibitor), measuring the contractile force. We found that FSCPX did not show any inhibitory effect during the in vitro enzyme assays. However, we successfully reproduced the paradox effect of FSCPX in the rat model, mimicked the “paradox” effect of FSCPX with PSB-12379, and demonstrated the lipophilia of FSCPX, which could explain the negative outcome of inhibitor assays with CD39 and CD73 dissolved in a water-based solution. Taken together, these three pieces of indirect evidence are strong enough to indicate that FSCPX possesses an additional action besides the A1 adenosine receptor antagonism, which action may be the inhibition of an ectonucleotidase. Incidentally, we found that POM-1 inhibited CD73, in addition to CD39.

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Section: Resultsmentioning

confidence: 99%

A Body of Circumstantial Evidence for the Irreversible Ectonucleotidase Inhibitory Action of FSCPX, an Agent Known as a Selective Irreversible A1 Adenosine Receptor Antagonist So Far

Viczjan

Erdei

Óvári

et al. 2021

IJMS

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“…Pimenta-Dos-Reis reported that POM-1 inhibits activation of macrophages in mice with sepsis induced by lipopolysaccharide and reduces the levels of related cytokines [ 30 ]. This finding indicates that the effect of POM-1 on the activation or differentiation of TAMs may differ according to the condition.…”

Section: Discussionmentioning

confidence: 99%

The Preventive Effect of the Phenotype of Tumour-Associated Macrophages, Regulated by CD39, on Colon Cancer in Mice

Park

Seo

Piao

et al. 2021

IJMS

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Background: This study was designed to investigate the effect of cluster differentiation (CD)39 and CD73 inhibitors on the expresion of tumour-associated macrophages (TAMs), M1- versus M2-tumour phenotypes in mice with colon cancer. Methods: An in vivo study of co-culture with colon cancer cells and immune cells from the bone marrow (BM) of mice was performed. After the confirmation of the effect of polyoxotungstate (POM-1) as an inhibitor of CD39 on TAMs, the mice were randomly divided into a control group without POM-1 and a study group with POM-1, respectively, after subcutaneous injection of CT26 cells. On day 14 after the injection, the mice were sacrificed, and TAMs were evaluated using fluorescence-activated cell sorting. Results: In the in vivo study, the co-culture with POM-1 significantly increased the apoptosis of CT26 cells. The cell population from the co-culture with POM-1 showed significant increases in the expression of CD11b+ for myeloid cells, lymphocyte antigen 6 complex, locus C (Ly6C+) for monocytes, M1-tumour phenotypes from TAMs, and F4/80+ for macrophages. In the in vivo study, tumour growth in the study group with POM-1 was significantly limited, compared with the control group without POM-1. The expressions of Ly6C+ and major histocompatibility complex class II+ for M1-tumour phenotypes from TAMs on F4/80+ from the tumour tissue in the study group had significantly higher values compared with the control group. Conclusion: The inhibition of CD39 with POM-1 prevented the growth of colon cancer in mice, and it was associated with the increased expression of M1-tumour phenotypes from TAMs in the cancer tissue.

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“…Peritoneal macrophages were obtained by lavage of the peritoneal cavity with 10 ml of Dulbecco's modified Eagle medium (DMEM; Gibco, USA). After isolation from the peritoneal cavity, the monocytes-macrophages pass through an adhesion process and need to be maintained in culture for at least 3 days for stabilization (57). The number of total viable cells of mice, infected with T. muris or not, was determined using trypan blue (Sigma-Aldrich) in a Neubauer chamber.…”

Section: Fig 13mentioning

confidence: 99%

Whipworm Infection Promotes Bacterial Invasion, Intestinal Microbiota Imbalance, and Cellular Immunomodulation

et al. 2020

Self Cite

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Infections with Trichuris trichiura are among the most common causes of intestinal parasitism in children worldwide, and the diagnosis is based on microscopic egg identification in the chronic phase of the infection. During parasitism, the adult worm of the trichurid nematode maintains its anterior region inserted in the intestinal mucosa, which causes serious damage and which may open access for gut microorganisms through the intestinal tissue. The immune-regulatory processes taking place during the evolution of the chronic infection are still not completely understood. By use of the Swiss Webster outbred mouse model, mice were infected with 200 eggs, and tolerance to the establishment of a chronic Trichuris muris infection was induced by the administration of a short pulse of dexamethasone during nematode early larval development. The infected mice presented weight loss, anemia, an imbalance of the microbiota, and intense immunological cell infiltration in the large intestine. It was found that mice have a mixed Th1/Th2/Th17 response, with differences being found among the different anatomical locations. After 45 days of infection, the parasitism induced changes in the microbiota composition and bacterial invasion of the large intestine epithelium. In addition, we describe that the excretory-secretory products from the nematode have anti-inflammatory effects on mouse macrophages cultured in vitro, suggesting that T. muris may modulate the immune response at the site of insertion of the worm inside mouse tissue. The data presented in this study suggest that the host immune state at 45 days postinfection with T. muris during the chronic phase of infection is the result of factors derived from the worm as well as alterations to the microbiota and bacterial invasion. Taken together, these results provide new information about the parasite-host-microbiota relationship and open new treatment possibilities.

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POM-1 inhibits P2 receptors and exhibits anti-inflammatory effects in macrophages

Cited by 10 publications

References 75 publications

A Body of Circumstantial Evidence for the Irreversible Ectonucleotidase Inhibitory Action of FSCPX, an Agent Known as a Selective Irreversible A1 Adenosine Receptor Antagonist So Far

A Body of Circumstantial Evidence for the Irreversible Ectonucleotidase Inhibitory Action of FSCPX, an Agent Known as a Selective Irreversible A1 Adenosine Receptor Antagonist So Far

The Preventive Effect of the Phenotype of Tumour-Associated Macrophages, Regulated by CD39, on Colon Cancer in Mice

Whipworm Infection Promotes Bacterial Invasion, Intestinal Microbiota Imbalance, and Cellular Immunomodulation

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