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<p>Preterm birth (PTB) occurs in 10% of births worldwide and remains the leading cause of neonatal morbidity and mortality. Previously, we reported that N, N-dimethylacetamide (DMA) and N, N-dimethylformamide (DMF) prevent inflammation-induced PTB in a murine model and inhibit the NF-κB inflammatory pathway. Using in vitro and ex vivo models, we show here that two DMA analogs, N,N-diethylaceatmide (DEA) and N, N-dipropylacetamide (DPA), attenuate LPS-stimulated increased secretion of tumor necrosis factor (TNF)-α, IL-6, IL-1, GM-CSF, MCP-1 and IL-10 from RAW 264.7 cells; IL-6, IL-8 and MCP-1 from HTR-8/SVneo cells; and TNF-α, IL-6, GM-CSF, IL-8, MCP-1 and IL-10 from human placental explants. In addition, both analogs inhibited LPS induced up-regulation of nitric oxide (NO) secretion and inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells. Further, both analogs, at 10 mM, inhibited LPS-induced degradation of I<i>k</i>B-⍺ in RAW 264.7 cells, leading to inhibition of the NF-<i>k</i>B pathway. We also found that both analogs inhibited LPS-stimulated NF-<i>k</i>B transcriptional activity but did not affect AP-1 or C/EBP activity. However, neither analog had any effect on the expression of native or phosphorylated forms of JNK1, ERK1/2 and p-38 MAPK. Finally, in a well-established in vivo model of preterm birth, DEA, at 750&#xa0;mg/kg, prevented preterm birth for at least 24&#xa0;h. DEA and DPA have potential as novel therapeutic agents for the prevention of inflammation-induced preterm birth and other inflammatory disorders.</p>

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N,N-Diethylacetamide and N,N-Dipropylacetamide inhibit the NF-kB pathway in in vitro, ex vivo and in vivo models of inflammation-induced preterm birth

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月14日

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  • Samir Gorasiya,
  • Juliet Mushi,
  • Sabesan Yoganathan,
  • Leonard Barasa,
  • Ryan Pekson,
  • Charles R. Ashby Jr.,
  • Sandra E. Reznik

摘要

Preterm birth (PTB) occurs in 10% of births worldwide and remains the leading cause of neonatal morbidity and mortality. Previously, we reported that N, N-dimethylacetamide (DMA) and N, N-dimethylformamide (DMF) prevent inflammation-induced PTB in a murine model and inhibit the NF-κB inflammatory pathway. Using in vitro and ex vivo models, we show here that two DMA analogs, N,N-diethylaceatmide (DEA) and N, N-dipropylacetamide (DPA), attenuate LPS-stimulated increased secretion of tumor necrosis factor (TNF)-α, IL-6, IL-1, GM-CSF, MCP-1 and IL-10 from RAW 264.7 cells; IL-6, IL-8 and MCP-1 from HTR-8/SVneo cells; and TNF-α, IL-6, GM-CSF, IL-8, MCP-1 and IL-10 from human placental explants. In addition, both analogs inhibited LPS induced up-regulation of nitric oxide (NO) secretion and inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells. Further, both analogs, at 10 mM, inhibited LPS-induced degradation of IkB-⍺ in RAW 264.7 cells, leading to inhibition of the NF-kB pathway. We also found that both analogs inhibited LPS-stimulated NF-kB transcriptional activity but did not affect AP-1 or C/EBP activity. However, neither analog had any effect on the expression of native or phosphorylated forms of JNK1, ERK1/2 and p-38 MAPK. Finally, in a well-established in vivo model of preterm birth, DEA, at 750 mg/kg, prevented preterm birth for at least 24 h. DEA and DPA have potential as novel therapeutic agents for the prevention of inflammation-induced preterm birth and other inflammatory disorders.