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A novel imidazopyridine derivative, X22, attenuates sepsis-induced lung and liver injury by inhibiting the inflammatory response in vitro and in vivo.

Ge X, Feng Z, Xu T, Wu B, Chen H, Xu F, Fu L, Shan X, Dai Y, Zhang Y, Liang G - Drug Des Devel Ther (2016)

Bottom Line: In this study, we found a novel imidazopyridine derivative, X22, which has powerful anti-inflammatory activity.We additionally found that pretreatment with X22 reduced the inflammatory pain in the acetic acid and formalin models and reduced the dimethylbenzene-induced ear swelling and acetic acid-increased vascular permeability.Together, these data confirmed that X22 has multiple anti-inflammatory effects and may be a potential therapeutic option in the treatment of inflammatory diseases.

View Article: PubMed Central - PubMed

Affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences; Department of Pulmonary Medicine, The 2nd Affiliated Hospital.

ABSTRACT
Sepsis remains a leading cause of death worldwide. Despite years of extensive research, effective drugs to treat sepsis in the clinic are lacking. In this study, we found a novel imidazopyridine derivative, X22, which has powerful anti-inflammatory activity. X22 dose-dependently inhibited lipopolysaccharide (LPS)-induced proinflammatory cytokine production in mouse primary peritoneal macrophages and RAW 264.7 macrophages. X22 also downregulated the LPS-induced proinflammatory gene expression in vitro. In vivo, X22 exhibited a significant protection against LPS-induced death. Pretreatment or treatment with X22 attenuated the sepsis-induced lung and liver injury by inhibiting the inflammatory response. In addition, X22 showed protection against LPS-induced acute lung injury. We additionally found that pretreatment with X22 reduced the inflammatory pain in the acetic acid and formalin models and reduced the dimethylbenzene-induced ear swelling and acetic acid-increased vascular permeability. Together, these data confirmed that X22 has multiple anti-inflammatory effects and may be a potential therapeutic option in the treatment of inflammatory diseases.

No MeSH data available.


Related in: MedlinePlus

X22 inhibited LPS-induced inflammatory cytokine expression in vitro.Notes: (A and B) MPMs or (C and D) RAW 264.7 macrophages were pretreated with X22 (2.5, 5, 10, 20, and 40 μM) for 30 minutes, followed by incubation with LPS (0.5 μg/mL) for 24 hours. IL-6 and TNF-α levels in the culture medium were measured by ELISA analysis and normalized to the total protein. The results are presented as the percent of LPS control. Each bar represents the mean ± SEM of three independent experiments. Statistical significance relative to the LPS group is indicated, *P<0.05; **P<0.01. (E) MPMs were pretreated with X22 (20 μM) for 30 minutes followed by incubation with LPS (0.5 μg/mL) for 6 hours. The mRNA levels of inflammatory cytokines were quantified by real-time qPCR analysis using β-actin mRNA as the internal control. Each bar represents the mean ± SEM of three to five independent experiments (*P<0.05, **P<0.01 relative to the LPS group).Abbreviations: COX-2, cyclooxygenase-2; DMSO, dimethyl sulfoxide; ELISA, enzyme-linked immunosorbent assay; IL-6, interleukin-6; IL-1β, interleukin-1β; LPS, lipopolysaccharide; qPCR, quantitative polymerase chain reaction; TNF-α, tumor necrosis factor-α; MPMs, mouse peritoneal macrophages; SEM, standard error of mean.
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f3-dddt-10-1947: X22 inhibited LPS-induced inflammatory cytokine expression in vitro.Notes: (A and B) MPMs or (C and D) RAW 264.7 macrophages were pretreated with X22 (2.5, 5, 10, 20, and 40 μM) for 30 minutes, followed by incubation with LPS (0.5 μg/mL) for 24 hours. IL-6 and TNF-α levels in the culture medium were measured by ELISA analysis and normalized to the total protein. The results are presented as the percent of LPS control. Each bar represents the mean ± SEM of three independent experiments. Statistical significance relative to the LPS group is indicated, *P<0.05; **P<0.01. (E) MPMs were pretreated with X22 (20 μM) for 30 minutes followed by incubation with LPS (0.5 μg/mL) for 6 hours. The mRNA levels of inflammatory cytokines were quantified by real-time qPCR analysis using β-actin mRNA as the internal control. Each bar represents the mean ± SEM of three to five independent experiments (*P<0.05, **P<0.01 relative to the LPS group).Abbreviations: COX-2, cyclooxygenase-2; DMSO, dimethyl sulfoxide; ELISA, enzyme-linked immunosorbent assay; IL-6, interleukin-6; IL-1β, interleukin-1β; LPS, lipopolysaccharide; qPCR, quantitative polymerase chain reaction; TNF-α, tumor necrosis factor-α; MPMs, mouse peritoneal macrophages; SEM, standard error of mean.

Mentions: Subsequently, to determine the anti-inflammatory effect of X22, the level of the proinflammatory cytokines, IL-6, and TNF-α, induced by LPS, was monitored in both MPMs and RAW 264.7 macrophages. The MPMs and RAW 264.7 macrophages were treated with LPS (0.5 μg/mL) in the presence or absence of X22 for 24 hours and then the medium was examined for the production of proinflammatory cytokines by ELISA analysis. The data presented in Figure 3A and B revealed that pretreatment with X22 could dose-dependently decrease the LPS-induced production of TNF-α and IL-6 in MPMs. Specifically, the results indicated that the LPS-induced expression of inflammatory cytokines was inhibited the most by X22 at 20 and 40 μM. Similar results were observed in RAW 264.7 macrophages, where X22 also inhibited the LPS-induced TNF-α and IL-6 secretion (Figure 3C and D). After considering the results of the cytotoxicity and the anti-inflammatory activities, the concentration of 20 μM was selected for further studies.


A novel imidazopyridine derivative, X22, attenuates sepsis-induced lung and liver injury by inhibiting the inflammatory response in vitro and in vivo.

Ge X, Feng Z, Xu T, Wu B, Chen H, Xu F, Fu L, Shan X, Dai Y, Zhang Y, Liang G - Drug Des Devel Ther (2016)

X22 inhibited LPS-induced inflammatory cytokine expression in vitro.Notes: (A and B) MPMs or (C and D) RAW 264.7 macrophages were pretreated with X22 (2.5, 5, 10, 20, and 40 μM) for 30 minutes, followed by incubation with LPS (0.5 μg/mL) for 24 hours. IL-6 and TNF-α levels in the culture medium were measured by ELISA analysis and normalized to the total protein. The results are presented as the percent of LPS control. Each bar represents the mean ± SEM of three independent experiments. Statistical significance relative to the LPS group is indicated, *P<0.05; **P<0.01. (E) MPMs were pretreated with X22 (20 μM) for 30 minutes followed by incubation with LPS (0.5 μg/mL) for 6 hours. The mRNA levels of inflammatory cytokines were quantified by real-time qPCR analysis using β-actin mRNA as the internal control. Each bar represents the mean ± SEM of three to five independent experiments (*P<0.05, **P<0.01 relative to the LPS group).Abbreviations: COX-2, cyclooxygenase-2; DMSO, dimethyl sulfoxide; ELISA, enzyme-linked immunosorbent assay; IL-6, interleukin-6; IL-1β, interleukin-1β; LPS, lipopolysaccharide; qPCR, quantitative polymerase chain reaction; TNF-α, tumor necrosis factor-α; MPMs, mouse peritoneal macrophages; SEM, standard error of mean.
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Related In: Results  -  Collection

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f3-dddt-10-1947: X22 inhibited LPS-induced inflammatory cytokine expression in vitro.Notes: (A and B) MPMs or (C and D) RAW 264.7 macrophages were pretreated with X22 (2.5, 5, 10, 20, and 40 μM) for 30 minutes, followed by incubation with LPS (0.5 μg/mL) for 24 hours. IL-6 and TNF-α levels in the culture medium were measured by ELISA analysis and normalized to the total protein. The results are presented as the percent of LPS control. Each bar represents the mean ± SEM of three independent experiments. Statistical significance relative to the LPS group is indicated, *P<0.05; **P<0.01. (E) MPMs were pretreated with X22 (20 μM) for 30 minutes followed by incubation with LPS (0.5 μg/mL) for 6 hours. The mRNA levels of inflammatory cytokines were quantified by real-time qPCR analysis using β-actin mRNA as the internal control. Each bar represents the mean ± SEM of three to five independent experiments (*P<0.05, **P<0.01 relative to the LPS group).Abbreviations: COX-2, cyclooxygenase-2; DMSO, dimethyl sulfoxide; ELISA, enzyme-linked immunosorbent assay; IL-6, interleukin-6; IL-1β, interleukin-1β; LPS, lipopolysaccharide; qPCR, quantitative polymerase chain reaction; TNF-α, tumor necrosis factor-α; MPMs, mouse peritoneal macrophages; SEM, standard error of mean.
Mentions: Subsequently, to determine the anti-inflammatory effect of X22, the level of the proinflammatory cytokines, IL-6, and TNF-α, induced by LPS, was monitored in both MPMs and RAW 264.7 macrophages. The MPMs and RAW 264.7 macrophages were treated with LPS (0.5 μg/mL) in the presence or absence of X22 for 24 hours and then the medium was examined for the production of proinflammatory cytokines by ELISA analysis. The data presented in Figure 3A and B revealed that pretreatment with X22 could dose-dependently decrease the LPS-induced production of TNF-α and IL-6 in MPMs. Specifically, the results indicated that the LPS-induced expression of inflammatory cytokines was inhibited the most by X22 at 20 and 40 μM. Similar results were observed in RAW 264.7 macrophages, where X22 also inhibited the LPS-induced TNF-α and IL-6 secretion (Figure 3C and D). After considering the results of the cytotoxicity and the anti-inflammatory activities, the concentration of 20 μM was selected for further studies.

Bottom Line: In this study, we found a novel imidazopyridine derivative, X22, which has powerful anti-inflammatory activity.We additionally found that pretreatment with X22 reduced the inflammatory pain in the acetic acid and formalin models and reduced the dimethylbenzene-induced ear swelling and acetic acid-increased vascular permeability.Together, these data confirmed that X22 has multiple anti-inflammatory effects and may be a potential therapeutic option in the treatment of inflammatory diseases.

View Article: PubMed Central - PubMed

Affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences; Department of Pulmonary Medicine, The 2nd Affiliated Hospital.

ABSTRACT
Sepsis remains a leading cause of death worldwide. Despite years of extensive research, effective drugs to treat sepsis in the clinic are lacking. In this study, we found a novel imidazopyridine derivative, X22, which has powerful anti-inflammatory activity. X22 dose-dependently inhibited lipopolysaccharide (LPS)-induced proinflammatory cytokine production in mouse primary peritoneal macrophages and RAW 264.7 macrophages. X22 also downregulated the LPS-induced proinflammatory gene expression in vitro. In vivo, X22 exhibited a significant protection against LPS-induced death. Pretreatment or treatment with X22 attenuated the sepsis-induced lung and liver injury by inhibiting the inflammatory response. In addition, X22 showed protection against LPS-induced acute lung injury. We additionally found that pretreatment with X22 reduced the inflammatory pain in the acetic acid and formalin models and reduced the dimethylbenzene-induced ear swelling and acetic acid-increased vascular permeability. Together, these data confirmed that X22 has multiple anti-inflammatory effects and may be a potential therapeutic option in the treatment of inflammatory diseases.

No MeSH data available.


Related in: MedlinePlus