Inflammation is regulated by the adenosine derivative molecule, IFC-305, during reversion of cirrhosis in a CCl4 rat model

Vaca, Rebeca Pérez‐Cabeza de; Domínguez‐López, Mariana; Guerrero‐Celis, Nuria; Rodríguez‐Aguilera, Jesús Rafael; Sánchez, Victoria Chagoya de

doi:10.1016/j.intimp.2017.10.019

Cited by 16 publications

(9 citation statements)

References 58 publications

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“…It is known that the extracellular ATP triggers NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, which could lead to the generation of a series of inflammatory cytokines, such as cleaved caspase-1, interleukin (IL)-1β, IL-18, IL-6 and tumor necrosis factor-α (TNF-α) (16,17). Meanwhile, adenosine was reported to be anti-inflammatory, immunosuppressive and have protective effects in sepsis-associated organ injury (18,19). Therefore, CD39 plays a suppressive role in the NLRP3 inflammasome activation and its mediated downstream pro-inflammatory cytokines.…”

Section: Introductionmentioning

confidence: 99%

Overexpressed CD39 mitigates sepsis‑induced kidney epithelial cell injury via suppressing the activation of NLR family pyrin domain containing 3

Yang

Kang

et al. 2019

Int J Mol Med

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Unfettered inflammation is a leading cause of multiple organ failures in sepsis. The anti-inflammatory role of cluster of differentiation (CD)39 has been previously reported. The present study aimed to investigate the role of unfettered inflammation in sepsis-induced acute kidney injury (AKI). Lipopolysaccharide (LPS) was introduced to construct a sepsis mouse model. Kidney function and pathological changes in mice were measured at 12, 24 and 48 h. CD39 overexpression and inhibition vectors were transfected into renal tubular epithelial (HK-2) cells, followed by LPS treatment (10 μg/ml), and the cell viability changes at 24 h after treatment were assessed and the expression of NLR family pyrin domain containing 3 (NLRP3), cleaved caspase-1 and CD39 were determined by performing ELISAs. Cell apoptosis and reactive oxygen species (ROS) levels were determined by flow cytometry. It was found that after LPS administration, kidney injury was the most serious at 24 h in mice. CD39 overexpression could suppress the upregulation of pro-inflammatory cytokines induced by LPS treatment. In addition, the cell apoptosis and ROS level exhibited an obvious decrease, while cell viability increased. The NLRP3 expression and activity also showed a great inhibition in CD39-overexpressed cells. By contrast to CD39 overexpression, CD39 inhibition promoted the activation of the NLRP3 inflammasome. These data indicate the protective role of CD39 in LPS-induced renal tubular epithelial cell damage through inhibiting NLRP3 inflammasome activation and that CD39 might be a potential therapeutic target in sepsis-induced AKI.

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Section: Introductionmentioning

confidence: 99%

Overexpressed CD39 mitigates sepsis‑induced kidney epithelial cell injury via suppressing the activation of NLR family pyrin domain containing 3

Yang

Kang

et al. 2019

Int J Mol Med

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“…The anti-inflammatory role of IFC-305 was also supported by elevation of IL-10, an enhanced metabolic activity of arginase, reduction of NO levels in serum rats, a diminution of the protein levels of inducible nitric oxide synthetase, and an increment of the protein levels of arginase 1 in the liver. These results suggest that the IFC-305 modulates the immune response in cirrhosis and supports the hepatic protective action through an antiinflammatory role, mainly mediated by Kupffer cells [64].…”

Section: Inflammation the Beginning Of Liver Disease And A Key Of Ifmentioning

confidence: 52%

Molecular and Cellular Aspects of Cirrhosis and How an Adenosine Derivative Could Revert Fibrosis

Rodríguez‐Aguilera¹,

Vaca²,

Guerrero‐Celis³

et al. 2019

Liver Cirrhosis - Debates and Current Challenges

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Hepatic fibrosis occurs in response to persistent liver damage and is characterized by an excessive accumulation of extracellular matrix. When the damage is prolonged, there is a chronic inflammation and persistent hepatic fibrosis eventually leads to cirrhosis, where in addition to the scar, there is an important vascular remodeling associated with portal hypertension and, if decompensated, leads to death or can develop hepatocellular carcinoma. We have been studying the pharmacologic functions of adenosine, finding that a derivative of this nucleoside, IFC-305, shows hepatoprotective effects in a CCl 4-induced rat cirrhosis model where it reverses liver fibrosis through modulation of fibrosis-related genes and by ameliorating hepatic function. Furthermore, this compound has the property to rescue cell cycle inhibition in vivo, prevents hepatic stellate cell activation, modulates antiinflammatory macrophage polarization, and favors a chromatin context that could decrease the genomic instability and characteristics of cirrhosis, enabling the recovery of gene expression profile. Here we show results that contribute to the comprehension of molecular and cellular mechanism of cirrhosis, give the opportunity to suggest biomarkers to the early diagnostic of this pathology, and constitute the fundaments to suggest IFC-305 as a coadjuvant for treatment of this disease.

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“…In contrast, the promoter of Col1a1 gene is hypomethylated in cirrhosis but gains DNA methylation upon treatment with IFC-305, correlating with a decrease of Col1a1 transcript and protein level, showing that the treatment restores globally and specifically epigenetic modifications [30]. The microarray analysis also showed modification of immunity genes which where explored in the CCl 4 model; it was found that the IFC-305 compound reduced inflammatory cytokines and increased the anti-inflammatory ones like IL-10, supporting the modulation of the macrophage phenotypes M1 and M2 [31].…”

Section: Introductionmentioning

confidence: 76%

Interaction of Mitochondrial and Epigenetic Regulation in Hepatocellular Carcinoma

Sánchez¹,

Chávez²,

Loyden³

et al. 2018

Liver Cancer

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Hepatocellular carcinoma (HCC) is a pathology preceded mainly by cirrhosis of diverse etiology and is associated with uncontrolled dedifferentiation and cell proliferation processes. Many cellular functions are dependent on mitochondrial function, among which we can mention the enzymatic activity of PARP-1 and sirtuin 1, epigenetic regulation of gene expression, apoptosis, and so on. Mitochondrial dysfunction is related to liver diseases including cirrhosis and HCC; the energetic demand is not properly supplied and mitochondrial morphologic changes have been observed, resulting in an altered metabolism. There is a strong relationship between epigenetics and mitochondrion since the first one is dependent on the correct function of the last one. There is an interest to improve or to maintain mitochondrial integrity in order to prevent or reverse HCC; such is the case of IFC-305 that has a beneficial effect on mitochondrial function in a sequential model of cirrhosis-HCC. In this model, IFC-305 downregulates the expression of PCNA, thymidylate synthase, HGF and its receptor c-Met and upregulates the cell cycle inhibitor p27, thereby decreasing cell proliferation. Both effects, improvement of mitochondria function and reduction of tumor proliferation, suggest its use as HCC chemoprevention or as an adjuvant in chemotherapy.

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Inflammation is regulated by the adenosine derivative molecule, IFC-305, during reversion of cirrhosis in a CCl4 rat model

Cited by 16 publications

References 58 publications

Overexpressed CD39 mitigates sepsis‑induced kidney epithelial cell injury via suppressing the activation of NLR family pyrin domain containing 3

Overexpressed CD39 mitigates sepsis‑induced kidney epithelial cell injury via suppressing the activation of NLR family pyrin domain containing 3

Molecular and Cellular Aspects of Cirrhosis and How an Adenosine Derivative Could Revert Fibrosis

Interaction of Mitochondrial and Epigenetic Regulation in Hepatocellular Carcinoma

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