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. 2020 Oct 24;21(21):7894.
doi: 10.3390/ijms21217894.

Polydeoxyribonucleotide Exerts Protective Effect Against CCl4-Induced Acute Liver Injury Through Inactivation of NF-κB/MAPK Signaling Pathway in Mice

Il-Gyu Ko  1 , Jun-Jang Jin  1 , Lakkyong Hwang  1 , Sang-Hoon Kim  1 , Chang-Ju Kim  1 , Jin Hee Han  2 , Seunghwan Lee  3 , Ha Il Kim  4 , Hyun Phil Shin  4 , Jung Won Jeon  4
Affiliations

Polydeoxyribonucleotide Exerts Protective Effect Against CCl4-Induced Acute Liver Injury Through Inactivation of NF-κB/MAPK Signaling Pathway in Mice

Il-Gyu Ko et al. Int J Mol Sci. .

Abstract

Acute liver injury (ALI) causes life-threatening clinical problem, and its underlying etiology includes inflammation and apoptosis. An adenosine A2A receptor agonist, polydeoxyribonucleotide (PDRN), exhibits anti-inflammatory and anti-apoptotic effects by inhibiting the secretion of pro-inflammatory cytokines. In the current study, the protective effect of PDRN against carbon tetrachloride (CCl4)-induced ALI was investigated using mice. For the induction of ALI, mice received intraperitoneal injection of CCl4 twice over seven days. Mice from the PDRN-treated groups received an intraperitoneal injection of 200 μL saline containing PDRN (8 mg/kg), once a day for seven days, starting on day 1 after the first CCl4 injection. In order to confirm that the action of PDRN occurs through the adenosine A2A receptor, 8 mg/kg 3,7-dimethyl-1-propargylxanthine (DMPX), an adenosine A2A receptor antagonist, was treated with PDRN. Administration of CCl4 impaired liver tissue and increased the liver index and histopathologic score. The expression of pro-inflammatory cytokines was increased, and apoptosis was induced by the administration of CCl4. Administration of CCl4 activated nuclear factor-kappa B (NF-κB) and facilitated phosphorylation of signaling factors in mitogen-activated protein kinase (MAPK). In contrast, PDRN treatment suppressed the secretion of pro-inflammatory cytokines and inhibited apoptosis. PDRN treatment inactivated NF-κB and suppressed phosphorylation of signaling factors in MAPK. As a result, liver index and histopathologic score were reduced by PDRN treatment. When PDRN was treated with DMPX, the anti-inflammatory and anti-apoptotic effect of PDRN disappeared. Therefore, PDRN can be used as an effective therapeutic agent for acute liver damage.

Keywords: acute liver injury; apoptosis; inflammation; mitogen-activated protein kinase; nuclear factor-kappa B; polydeoxyribonucleotide.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Level of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and expression of cytochrome P450 2E1 (CYP2E1) and uncoupling protein 2 (UCP2). (A) Concentration of AST and ALT in serum. (B) Representative expression of CYP2E1 and UCP2 in liver tissue. CON, control group; CCl4, CCl4-injection group; CCl4-PDRN, CCl4-injection and polydeoxyribonucleotide (PDRN)-treated group; CCl4-PDRN+DMPX, CCl4-injection and PDRN with 3,7-dimethyl-1-propargylxanthine (DMPX)-treated group. * indicates p < 0.05 when compared with the control group. # indicates p < 0.05 when compared with the CCl4-injection group.
Figure 2
Figure 2
Change in morphology, histology, and liver index. (A) Morphological and histological change in the liver. (B) Body weight change during the experiment. (C) Liver weight in each group. (D) Liver index in each group. (E) Histopathological score in each group. (CV) Central vein, (PV) portal vein. Block arrows indicate recovery from hepatocyte necrosis. □: Measurement before experiment, ▨: Measurement at the end of the experiment. CON, control group; CCl4, CCl4-injection group; CCl4-PDRN, CCl4-injection and polydeoxyribonucleotide (PDRN)-treated group; CCl4-PDRN+DMPX, CCl4-injection and PDRN with 3,7-dimethyl-1-propargylxanthine (DMPX)-treated group. * indicates p < 0.05 when compared with the control group. # indicates p < 0.05 when compared with the CCl4-injection group.
Figure 3
Figure 3
Level of pro-inflammatory cytokines. Left panel: Concentration of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in serum. Right panel: Expression of TNF-α, IL-1β, and IL-6 in liver tissue. CON, control group; CCl4, CCl4-injection group; CCl4-PDRN, CCl4-injection and polydeoxyribonucleotide (PDRN)-treated group; CCl4-PDRN+DMPX, CCl4-injection and PDRN with 3,7-dimethyl-1-propargylxanthine (DMPX)-treated group. * indicates p < 0.05 when compared with the control group. # indicates p < 0.05 when compared with the CCl4-injection group.
Figure 4
Figure 4
Expression of nuclear factor (NF)-κB and cascade factors of mitogen-activated protein kinase (MAPK). Upper left panel: Representative expression of NF-κB, NF-κB inhibitor (IκB)-α, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p-38. Upper right panel: Relative expression of NF-κB and relative ratio of phosphorylated IκB-α (p-IκB-α) to IκB-α. Lower panel: Relative ratio of phosphorylated ERK (p-ERK) to ERK, phosphorylated JNK (p-JNK) to JNK and phosphorylated p-38 (p-p-38) to p-38. CON, control group; CCl4, CCl4-injection group; CCl4-PDRN, CCl4-injection and polydeoxyribonucleotide (PDRN)-treated group; CCl4-PDRN+DMPX, CCl4-injection and PDRN with 3,7-dimethyl-1-propargylxanthine (DMPX)-treated group. * indicates p < 0.05 when compared with the control group. # indicates p < 0.05 when compared with the CCl4-injection group.
Figure 5
Figure 5
Expression of cyclic adenosine-3′,5′-monophosphate (cAMP), cAMP response element-binding protein (CREB) and protein kinase A (PKA). (A) Concentration of cAMP in serum and liver tissue. (B) Relative ratio of phosphorylated CREP (p-CREB) to CREB in liver tissue. (C) Relative ratio of phosphorylated PKA (p-PKA) to PKA in liver tissue. CON, control group; CCl4, CCl4-injection group; CCl4-PDRN, CCl4-injection and polydeoxyribonucleotide (PDRN)-treated group; CCl4-PDRN+DMPX, CCl4-injection and PDRN with 3,7-dimethyl-1-propargylxanthine (DMPX)-treated group. * indicates p < 0.05 when compared with the control group. # indicates p < 0.05 when compared with the CCl4-injection group.
Figure 6
Figure 6
Cell death by apoptosis in liver tissue. (A) Representative expression of cleaved caspase-3 and cleaved caspase-9 in liver tissue. (B) Relative ratio of Bcl-2-associated X protein (Bax) to B-cell lymphoma-2 (Bcl-2) in liver tissue. CON, control group; CCl4, CCl4-injection group; CCl4-PDRN, CCl4-injection and polydeoxyribonucleotide (PDRN)-treated group; CCl4-PDRN+DMPX, CCl4-injection and PDRN with 3,7-dimethyl-1-propargylxanthine (DMPX)-treated group. * indicates p < 0.05 when compared with the control group. # indicates p < 0.05 when compared with the CCl4-injection group.
Figure 7
Figure 7
Experimental schedule.
See this image and copyright information in PMC

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