Inhibition of nuclear factor- B activation by IRFI 042, protects against endotoxin-induced shock

Altavilla, Domenica; Squadrito, Giovanni; Minutoli, Letteria; Deodato, Barbara; Bova, Antonino; Sardella, Alberto; Seminara, Paolo; Passaniti, Maria; Urna, Giuseppe; S, Venuti; Caputi, Achille P.; Squadrito, Francesco

doi:10.1016/s0008-6363(02)00276-6

Cited by 49 publications

(39 citation statements)

References 19 publications

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“…As such, NFκB inhibition has been proposed as a potential therapy for patients with septic shock (Rahman and Fazal, 2011;Wheeler et al, 2009). However, pre-clinical studies provide conflicting evidence on whether NFκB inhibition attenuates or exacerbates endotoxemic shock (Altavilla et al, 2002;Courtine et al, 2011;Everhart et al, 2006;Fujihara et al, 2000;Gadjeva et al, 2004;Greten et al, 2007;Kisseleva et al, 2006;Lawrence et al, 2005;Liu et al, 1997;Matsuda et al, 2004;Sha et al, 1995;Sheehan et al, 2002;Ulloa et al, 2002). It is not surprising that completely inhibiting NFκB activity would have both beneficial and detrimental consequences.…”

Section: Introductionmentioning

confidence: 99%

Inhibiting IκBβ–NFκB signaling attenuates the expression of select pro-inflammatory genes

McKenna

Wright

2015

Journal of Cell Science

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Multiple mediators of septic shock are regulated by the transcription factor nuclear factor κB (NFκB). However, complete NFκB inhibition can exacerbate disease, necessitating evaluation of targeted strategies to attenuate the pro-inflammatory response. Here, we demonstrate that in murine macrophages, low-dose NFκB inhibitors specifically attenuates lipopolysaccharide (LPS)-induced IκBβ degradation and the expression of a select subset of target genes (encoding IL1β, IL6, IL12β). Gain-and loss-of-function experiments demonstrate the necessary and sufficient role of inhibitor of NFκB family member IκBβ (also known as NFKBIB) in the expression of these genes. Furthermore, both fibroblasts and macrophages isolated from IκBβ overexpressing mice demonstrate attenuated LPS-induced IκBβ-NFκB signaling and IL1β, IL6 and IL12β expression. Further confirming the role of IκBβ and its NFκB subunit binding partner cRel in LPS-induced gene expression, pre-treatment of wild-type mouse embryonic fibroblasts with a cell-permeable peptide containing the cRel nuclear localization sequence attenuated IL6 expression. We prove that LPS-induced IκBβ-NFκB signaling can be selectively modulated to attenuate the expression of select pro-inflammatory target genes, thus providing therapeutic insights for patients exposed to systemic inflammatory stress.

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Section: Introductionmentioning

confidence: 99%

Inhibiting IκBβ–NFκB signaling attenuates the expression of select pro-inflammatory genes

McKenna

Wright

2015

Journal of Cell Science

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“…When each of these solvent extracts (100 mg/kg) was pretreated with the LPS/D-GalN-induced lethality model, the groups of mice pretreated with the ethyl acetate and water extracts showed higher survival rates, 80% each, than others with the control value of 20% (Table 1). The ethyl acetate extract was further chromatographed on a silica gel column, a preparative TLC and a reverse-phase gel column to afford twelve lignan compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Their structures were characterized as sarisan (1), erythro-austrobailignan-6 (2), meso-dihydroguaiaretic acid (3), saucerneol B (4), manassantin B (5), manassantin A (6), rel-(8R,8ЈR)-dimethyl-(7S,7ЈR)-bis(3,4-methylenedioxyphenyl)tetrahydro-furan (7), (ϩ)-saururinone (8), sauchinone (9), sauchinone B (10), nectandrin B (11), and machilin D (12).…”

Section: Resultsmentioning

confidence: 99%

“…6) Loss of hepatic function is one of the hallmarks of the development of multiple-organ failure associated with severe sepsis. 7,8) There have been reports that the synthetic compounds IRFI 042, 9) tyrphostin AG 126, 10) and SR 27388 11) show significant protection against lethality due to septic shock, and lysophosphatidylcholine (LPC) can effectively prevent and treat sepsis and microbial infections. 12) Recently, protective compounds against sepsis have been reported from medicinal plants.…”

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confidence: 99%

Protective Effect of Lignans against Sepsis from the Roots of <i>Saururus chinensis</i>

Seo

Lee

Kim

et al. 2008

Biological & Pharmaceutical Bulletin

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Lipopolysaccharide (LPS) is an endotoxin which induces septic shock syndrome and stimulates the production of inflammatory mediators such as NO, tumor necrosis factor-a (TNF-a), interleukins, prostanoids and leukotrienes. [1][2][3] These mediators frequently result from excessive stimulation of the host immune system through complex signal transductions and lead to hypotension and multiorgan dysfunction with a high mortality rate. 4,5) In patients with sepsis, TNF-a plays a major role in the associated systemic toxicity.6) Loss of hepatic function is one of the hallmarks of the development of multiple-organ failure associated with severe sepsis. 7,8) There have been reports that the synthetic compounds IRFI 042, 9) tyrphostin AG 126, 10) and SR 27388 11) show significant protection against lethality due to septic shock, and lysophosphatidylcholine (LPC) can effectively prevent and treat sepsis and microbial infections. 12) Recently, protective compounds against sepsis have been reported from medicinal plants. 13,14) The protective activity against sepsis-induced lethality of the methanol extracts of about 100 Korean medicinal plants was determined based on the sepsis model induced by lipopolysaccharide/D-galactosamine, from which Saururus chinensis (Saururaceae) was chosen as one of the active plants. Saururus chinensis (Saururaceae) is a perennial herbaceous plant with potential therapeutic utility in treatment of various diseases such as edema, jaundice, gonorrhea, anti-pyretic, diuretic, and anti-inflammatory agents in Korean folk medicine.15) Previous chemical studies of the genus Saururus have shown the presence of more than 20 lignans, [16][17][18][19] some of which exhibited neuroleptic, 20) hepatoprotective, 21) and antifeedant activities. 22) A triene, 12,13-dehydrogeranylgeraniol, was recently demonstrated to inhibit intracellular reactive oxygen species (ROS)-catalyzed oxidation within HL-60 cells.23) Different types of compounds have also been isolated from Saururus species including aristolactams, flavonoids, anthraquinones, and fruanoditerpenes. [24][25][26][27] In this paper, the isolation and activity of twelve known lignans as anti-septic shock agents from the roots of this plant are described. MATERIALS AND METHODS General ProceduresMelting points were measured by Fisher-Johns melting point apparatus and are uncorrected. Optical rotations were measured using a JASCO DIP-1000 (Tokyo, Japan) automatic digital polarimeter. The NMR spectra were recorded on a Bruker 250 MHz (DMX 250, Germany) spectrometer using Bruker's standard pulse program. Samples were dissolved in CDCl 3 -d 1 or CD 3 OD, and chemical-shifts were reported in ppm downfield from TMS. The FABMS spectrum was measured by VG TRIO 2A mass spectrometer. Stationary phases for column chromatography (Silica gel 60, 70-230 and 230-400 mesh and Lichroprep RP-18 gel, 40-63 mm, Merck) and TLC plates (Silica-gel 60 F 254 and RP-18 F 254, 0.25 mm, Merck) were purchased from Merck KGaA (Darmstadt, Germany). Spots were detected under UV radiation ...

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“…3) Loss of hepatic function is one of the hallmarks of the development of multiple-organ failure associated with severe sepsis. 4,5) There have been reports that the synthetic compounds IRFI 042, 6) tyrphostin AG 126, 7) and SR 27388 8) show significant protection against lethality due to septic shock, and lysophosphatidylcholine (LPC) can effectively prevent and treat sepsis and microbial infections. 9) Recently, protective compounds against sepsis have been reported from medicinal plants.…”

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confidence: 99%

Agents Protecting against Sepsis from the Roots of Angelica dahurica

Song

Kim

et al. 2005

Biological & Pharmaceutical Bulletin

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Inhibition of nuclear factor- B activation by IRFI 042, protects against endotoxin-induced shock

Abstract: These data suggest that IRFI 042 blocks the activation of NF-kappaB, reduces TNF-alpha mRNA levels, and finally reverses endotoxic shock.

Cited by 49 publications

References 19 publications

Inhibiting IκBβ–NFκB signaling attenuates the expression of select pro-inflammatory genes

Inhibiting IκBβ–NFκB signaling attenuates the expression of select pro-inflammatory genes

Protective Effect of Lignans against Sepsis from the Roots of <i>Saururus chinensis</i>

Agents Protecting against Sepsis from the Roots of Angelica dahurica

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