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Antiviral Activity of Chrysin Derivatives against Coxsackievirus B3 in vitro and in vivo.

Song JH, Kwon BE, Jang H, Kang H, Cho S, Park K, Ko HJ, Kim H - Biomol Ther (Seoul) (2015)

Bottom Line: We found that chrysin showed antiviral activity against CVB3 at 10 μM, but exhibited mild cellular cytotoxicity at 50 μM, prompting us to synthesize derivatives of chrysin to increase the antiviral activity and reduce its cytotoxicity.Intraperitoneal injection of CVB3 in BALB/c mice with 1×10(6) TCID50 (50% tissue culture infective dose) of CVB3 induced acute pancreatitis with ablation of acinar cells and increased serum CXCL1 levels, whereas the daily administration of 9 for 5 days significantly alleviated the pancreatic inflammation and reduced the elevation in serum CXCL1 levels.Collectively, we assessed the anti-CVB3 activities of chrysin and its derivatives, and found that among 4-substituted benzyl derivatives, 9 exhibited the highest activity against CVB3 in vivo, and protected mice from CVB3-induced pancreatic damage, simultaneously lowering serum CXCL1 levels.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon 200-701.

ABSTRACT
Chrysin is a 5,7-dihydroxyflavone and was recently shown to potently inhibit enterovirus 71 (EV71) by suppressing viral 3C protease (3C(pro)) activity. In the current study, we investigated whether chrysin also shows antiviral activity against coxsackievirus B3 (CVB3), which belongs to the same genus (Enterovirus) as EV71, and assessed its ability to prevent the resulting acute pancreatitis and myocarditis. We found that chrysin showed antiviral activity against CVB3 at 10 μM, but exhibited mild cellular cytotoxicity at 50 μM, prompting us to synthesize derivatives of chrysin to increase the antiviral activity and reduce its cytotoxicity. Among four 4-substituted benzyl derivatives derived from C(5) benzyl-protected derivatives 7, 9-11 had significant antiviral activity and showed the most potent activity against CVB3 with low cytotoxicity in Vero cells. Intraperitoneal injection of CVB3 in BALB/c mice with 1×10(6) TCID50 (50% tissue culture infective dose) of CVB3 induced acute pancreatitis with ablation of acinar cells and increased serum CXCL1 levels, whereas the daily administration of 9 for 5 days significantly alleviated the pancreatic inflammation and reduced the elevation in serum CXCL1 levels. Collectively, we assessed the anti-CVB3 activities of chrysin and its derivatives, and found that among 4-substituted benzyl derivatives, 9 exhibited the highest activity against CVB3 in vivo, and protected mice from CVB3-induced pancreatic damage, simultaneously lowering serum CXCL1 levels.

No MeSH data available.


Related in: MedlinePlus

Administration of 9 mitigate damage to the pancreas and reduce chemokine levels. (A) 9, 10, and control groups of BALB/c mice were infected with a 1×106 TCID50 (50% tissue culture infective dose) dose of coxsackievirus B3 (CVB3) and then assessed by body weight and survival. (B) Representative hematoxylin and eosin staining (H&E) of pancreas section of (a) uninfected, (b) infected CVB3 and treated (c) 9 and (d) 10 (Scale bar=20 μm). (C) Serum chemokine levels in mice treated with 9 and 10. The sera were taken at day 5 post-infection. Levels of CXCL1 at 5 days were determined in the sera after intraperitoneal infection by the DuoSet Mouse ELISA Kit.
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f4-bt-23-465: Administration of 9 mitigate damage to the pancreas and reduce chemokine levels. (A) 9, 10, and control groups of BALB/c mice were infected with a 1×106 TCID50 (50% tissue culture infective dose) dose of coxsackievirus B3 (CVB3) and then assessed by body weight and survival. (B) Representative hematoxylin and eosin staining (H&E) of pancreas section of (a) uninfected, (b) infected CVB3 and treated (c) 9 and (d) 10 (Scale bar=20 μm). (C) Serum chemokine levels in mice treated with 9 and 10. The sera were taken at day 5 post-infection. Levels of CXCL1 at 5 days were determined in the sera after intraperitoneal infection by the DuoSet Mouse ELISA Kit.

Mentions: To ascertain the antiviral effect of 9 and 10 in vivo, BALB/c mice were intraperitoneally injected with CVB3 at 1×106 tissue culture infectious dose 50% (TCID50). Initially, we monitored the change in body weight of CVB3-infected mice after treatment with 9 and 10. There was a slight weight loss in CVB3-infected mice, but the treatment with 9 and 10 could not significantly prevent the body weight loss after CVB3 infection (Fig. 4A). Next, we assessed the induction of CVB3-associated pancreatitis in mice, since it was well-known that the pancreata of mice are one of the major target organs of CVB3 (Kemball et al., 2010). For the pathological analysis, histology sections were obtained from the pancreata of infected mice. Uninfected pancreata of mice were histologically normal, while after five days of CVB3 infection, they showed almost complete ablation of acinar cells, as well as infiltration of inflammatory cells. However, in CVB3-infected mice, we could find partially intact acinar cells, albeit major parts of the pancreata were also destroyed by CVB3 infection (Fig. 4B).


Antiviral Activity of Chrysin Derivatives against Coxsackievirus B3 in vitro and in vivo.

Song JH, Kwon BE, Jang H, Kang H, Cho S, Park K, Ko HJ, Kim H - Biomol Ther (Seoul) (2015)

Administration of 9 mitigate damage to the pancreas and reduce chemokine levels. (A) 9, 10, and control groups of BALB/c mice were infected with a 1×106 TCID50 (50% tissue culture infective dose) dose of coxsackievirus B3 (CVB3) and then assessed by body weight and survival. (B) Representative hematoxylin and eosin staining (H&E) of pancreas section of (a) uninfected, (b) infected CVB3 and treated (c) 9 and (d) 10 (Scale bar=20 μm). (C) Serum chemokine levels in mice treated with 9 and 10. The sera were taken at day 5 post-infection. Levels of CXCL1 at 5 days were determined in the sera after intraperitoneal infection by the DuoSet Mouse ELISA Kit.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556207&req=5

f4-bt-23-465: Administration of 9 mitigate damage to the pancreas and reduce chemokine levels. (A) 9, 10, and control groups of BALB/c mice were infected with a 1×106 TCID50 (50% tissue culture infective dose) dose of coxsackievirus B3 (CVB3) and then assessed by body weight and survival. (B) Representative hematoxylin and eosin staining (H&E) of pancreas section of (a) uninfected, (b) infected CVB3 and treated (c) 9 and (d) 10 (Scale bar=20 μm). (C) Serum chemokine levels in mice treated with 9 and 10. The sera were taken at day 5 post-infection. Levels of CXCL1 at 5 days were determined in the sera after intraperitoneal infection by the DuoSet Mouse ELISA Kit.
Mentions: To ascertain the antiviral effect of 9 and 10 in vivo, BALB/c mice were intraperitoneally injected with CVB3 at 1×106 tissue culture infectious dose 50% (TCID50). Initially, we monitored the change in body weight of CVB3-infected mice after treatment with 9 and 10. There was a slight weight loss in CVB3-infected mice, but the treatment with 9 and 10 could not significantly prevent the body weight loss after CVB3 infection (Fig. 4A). Next, we assessed the induction of CVB3-associated pancreatitis in mice, since it was well-known that the pancreata of mice are one of the major target organs of CVB3 (Kemball et al., 2010). For the pathological analysis, histology sections were obtained from the pancreata of infected mice. Uninfected pancreata of mice were histologically normal, while after five days of CVB3 infection, they showed almost complete ablation of acinar cells, as well as infiltration of inflammatory cells. However, in CVB3-infected mice, we could find partially intact acinar cells, albeit major parts of the pancreata were also destroyed by CVB3 infection (Fig. 4B).

Bottom Line: We found that chrysin showed antiviral activity against CVB3 at 10 μM, but exhibited mild cellular cytotoxicity at 50 μM, prompting us to synthesize derivatives of chrysin to increase the antiviral activity and reduce its cytotoxicity.Intraperitoneal injection of CVB3 in BALB/c mice with 1×10(6) TCID50 (50% tissue culture infective dose) of CVB3 induced acute pancreatitis with ablation of acinar cells and increased serum CXCL1 levels, whereas the daily administration of 9 for 5 days significantly alleviated the pancreatic inflammation and reduced the elevation in serum CXCL1 levels.Collectively, we assessed the anti-CVB3 activities of chrysin and its derivatives, and found that among 4-substituted benzyl derivatives, 9 exhibited the highest activity against CVB3 in vivo, and protected mice from CVB3-induced pancreatic damage, simultaneously lowering serum CXCL1 levels.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon 200-701.

ABSTRACT
Chrysin is a 5,7-dihydroxyflavone and was recently shown to potently inhibit enterovirus 71 (EV71) by suppressing viral 3C protease (3C(pro)) activity. In the current study, we investigated whether chrysin also shows antiviral activity against coxsackievirus B3 (CVB3), which belongs to the same genus (Enterovirus) as EV71, and assessed its ability to prevent the resulting acute pancreatitis and myocarditis. We found that chrysin showed antiviral activity against CVB3 at 10 μM, but exhibited mild cellular cytotoxicity at 50 μM, prompting us to synthesize derivatives of chrysin to increase the antiviral activity and reduce its cytotoxicity. Among four 4-substituted benzyl derivatives derived from C(5) benzyl-protected derivatives 7, 9-11 had significant antiviral activity and showed the most potent activity against CVB3 with low cytotoxicity in Vero cells. Intraperitoneal injection of CVB3 in BALB/c mice with 1×10(6) TCID50 (50% tissue culture infective dose) of CVB3 induced acute pancreatitis with ablation of acinar cells and increased serum CXCL1 levels, whereas the daily administration of 9 for 5 days significantly alleviated the pancreatic inflammation and reduced the elevation in serum CXCL1 levels. Collectively, we assessed the anti-CVB3 activities of chrysin and its derivatives, and found that among 4-substituted benzyl derivatives, 9 exhibited the highest activity against CVB3 in vivo, and protected mice from CVB3-induced pancreatic damage, simultaneously lowering serum CXCL1 levels.

No MeSH data available.


Related in: MedlinePlus