Parthenolide Modulates the NF-κB–Mediated Inflammatory Responses in Experimental Atherosclerosis

López-Franco, Óscar; Hernández-Vargas, Purificación; Ortiz-Muñoz, Guadalupe; Sanjuán, Guillermo; Suzuki, Yusuke; Ortega, Luís; Blanco, Julia; Egido, Jesús; Gómez-Guerrero, Carmen

doi:10.1161/01.atv.0000229659.94020.53

Cited by 92 publications

(86 citation statements)

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“…By Western blots, we observed that 10% FBS induced IκBα  degradation, which may be related to the activation of NF-κB signal pathway and the proliferation of VSMCs stimulated by enriched serum. However, the presence of parthenolide completely antagonized this effect and resulted in upregulation of IκBα protein, which is in agreement with the previous reports showing parthenolide as an inhibitor of NF-κB Sheehan et al, 2002;Hehner et al, 1998;López-Franco et al, 2006). As an inducible isoform of enzyme, Cox-2 is upregulated in response to inflammatory factors and some peptides (Bishop-Bailey et al, 1999).…”

Section: Discussionsupporting

confidence: 92%

“…IκBα is the specific cytoplasmic inhibitory protein of NF-κB, and degradation of IκBα is generally believed to be the critical step for the activation of NF-κB (Brown et al, 1993). A recent study indicated that in vascular smooth muscle cells and monocytes stimulated with lipopolysaccharide (LPS), parthenolide reduced IκBα degradation and NF-κB activation (López-Franco et al, 2006). By Western blots, we observed that 10% FBS induced IκBα  degradation, which may be related to the activation of NF-κB signal pathway and the proliferation of VSMCs stimulated by enriched serum.…”

Section: Discussionmentioning

confidence: 99%

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Parthenolide inhibits proliferation of vascular smooth muscle cells through induction of G0/G1 phase cell cycle arrest

Weng

Sui

Chen

et al. 2009

J. Zhejiang Univ. Sci. B

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Abstract:Objective: This study is to determine the effect of the natural product parthenolide, a sesquiterpene lactone isolated from extracts of the herb Tanacetum parthenium, on the proliferation of vascular smooth muscle cells (VSMCs). Methods: Rat aortic VSMCs were isolated and cultured in vitro, and treated with different concentrations of parthenolide (10, 20 and 30 μmol/L).[ 3 H]thymidine incorporation was used as an index of cell proliferation. Cell cycle progression and distribution were determined by flow cytometric analysis. Furthermore, the expression of several regulatory proteins relevant to VSMC proliferation including IκBα, cyclooxygenase-2 (Cox-2), p21, and p27 was examined to investigate the potential molecular mechanism. Results: Treatment with parthenolide significantly decreased the [ 3 H]thymidine incorporation into DNA by 30%~56% relative to control values in a dose-dependent manner (P<0.05). Addition of parthenolide also increased cell population at G 0 /G 1 phase by 19.2%~65.7% (P<0.05) and decreased cell population at S phase by 50.7%~84.8% (P<0.05), which is consistent with its stimulatory effects on p21 and p27. In addition, parthenolide also increased IκBα expression and reduced Cox-2 expression in a time-dependent manner. Conclusion: Our results show that parthenolide significantly inhibits the VSMC proliferation by inducing G 0 /G 1 cell cycle arrest. IκBα and Cox-2 are likely involved in such inhibitory effect of parthenolide on VSMC proliferation. These findings warrant further investigation on potential therapeutic implications of parthenolide on VSMC proliferation in vivo.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Parthenolide inhibits proliferation of vascular smooth muscle cells through induction of G0/G1 phase cell cycle arrest

Weng

Sui

Chen

et al. 2009

J. Zhejiang Univ. Sci. B

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“…Lesional macrophages (MOMA-2; AbD Serotec, Oxford, U.K.), CD3 T cells, vascular smooth muscle cells (VSMCs) (a-actin-Cy3; Sigma-Aldrich), chemokine (C-C motif) ligand (CCL) 2 (Santa Cruz Biotechnology), CCL5 (Antibodies Online), and tumor necrosis factor a (TNF-a; Santa Cruz Biotechnology) were detected by immunoperoxidase or immunofluorescence. Positive staining was expressed as percentage of total plaque area or number of positive cells per lesion area (26,27). Activated NF-kB in kidney and aorta was detected by Southwestern histochemistry using digoxigenin-labeled probes (26,28 (23).…”

Section: Histological Analysismentioning

confidence: 99%

“…Positive staining was expressed as percentage of total plaque area or number of positive cells per lesion area (26,27). Activated NF-kB in kidney and aorta was detected by Southwestern histochemistry using digoxigenin-labeled probes (26,28 (23). Murine monocyte/macrophage cell line (RAW 264.7, TIB-71; ATCC) was maintained in DMEM with 10% FBS.…”

Section: Histological Analysismentioning

confidence: 99%

Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice

et al. 2015

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Heat shock proteins (HSPs) are induced by cellular stress and function as molecular chaperones that regulate protein folding. Diabetes impairs the function/expression of many HSPs, including HSP70 and HSP90, key regulators of pathological mechanisms involved in diabetes complications. Therefore, we investigated whether pharmacological HSP90 inhibition ameliorates diabetes-associated renal damage and atheroprogression in a mouse model of combined hyperglycemia and hyperlipidemia (streptozotocin-induced diabetic apolipoprotein E-deficient mouse). Treatment of diabetic mice with 17-dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG, 2 and 4 mg/kg, 10 weeks) improved renal function, as evidenced by dose-dependent decreases in albuminuria, renal lesions (mesangial expansion, leukocyte infiltration, and fibrosis), and expression of proinflammatory and profibrotic genes. Furthermore, DMAG significantly reduced atherosclerotic lesions and induced a more stable plaque phenotype, characterized by lower content of lipids, leukocytes, and inflammatory markers, and increased collagen and smooth muscle cell content. Mechanistically, the renoprotective and antiatherosclerotic effects of DMAG are mediated by the induction of protective HSP70 along with inactivation of nuclear factor-kB (NF-kB) and signal transducers and activators of transcription (STAT) and target gene expression, both in diabetic mice and in cultured cells under hyperglycemic and proinflammatory conditions. In conclusion, HSP90 inhibition by DMAG restrains the progression of renal and vascular damage in experimental diabetes, with potential implications for the prevention of diabetes complications.

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“…Estudos anteriores já estabeleceram que a expansão do tecido adiposo, tal como observado na obesidade, está associada a uma resposta inflamatória crônica e em resistência à insulina (123). Recentemente estudos têm implicado o tecido adiposo no processo inflamatório, demonstrando que os adipócitos maduros e pré-adipócitos de origem murina expressam múltiplos TLRs desde TLR1 a TLR9 (124)(125)(126).…”

Section: Discussionunclassified

MyD88: um modulador do perfil inflamatório e metabólico na obesidade experimental.

Castoldi¹

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RESUMOIntrodução: Nos últimos anos, a ativação de receptores da imunidade inata nas células do sistema imune e no tecido adiposo foi descrita como crucial durante o desenvolvimento da obesidade. Além disso, alterações na microbiota intestinal foram relacionadas aos fenótipos inflamatórios e metabólicos na obesidade através do aumento da permeabilidade intestinal, com elevação dos níveis sistêmicos de endotoxina, que colabora para o aumento da inflamação e o desenvolvimento da resistência à insulina. A complexidade do sistema imune nos permite explorar essas vias de sinalização nos diversos órgãos, tecidos e células. Por isso formulamos a hipótese de que MyD88 regularia o desenvolvimento da obesidade, desempenhando um papel importante no tecido adiposo contribuindo para a resistência à insulina. Nos macrófagos, a sinalização via MyD88 favoreceria um perfil pró-inflamatório, e ainda, regularia alterações na microbiota intestinal que por sua vez estariam contribuindo nesse processo através de alterações na permeabilidade intestinal. Objetivo: Estudar a relação entre a obesidade e inflamação, focando no papel da molécula adaptadora MyD88 e sua importância no tecido adiposo, macrófagos, intestino e na modulação da microbiota intestinal. Métodos: Utilizamos camundongos C57BL/6, deficientes de MyD88 (KO), Adiponectina cre+ MyD88 flox +/+ e Lisozima cre+ MyD88 flox +/+ alimentados com dieta hiperlipídica e avaliamos os perfis metabólicos e inflamatórios, permeabilidade intestinal e alterações na microbiota intestinal. Ainda em um modelo de transplante de microbiota estudamos o possível papel da microbiota no desenvolvimento da obesidade. Resultados: Verificamos que camundongos MyD88 KO ganharam mais peso comparados aos camundongos WT, são mais intolerantes à glicose e resistentes à insulina. Porém, ao analisarmos o perfil inflamatório no tecido adiposo e sistêmico, observamos significativa diminuição de IL-1β, TNF-α e IL-6 bem como diminuição na fosforilação das vias de sinalização pró-inflamatórias nos camundongos MyD88 KO obesos. No tecido adiposo, há um predomínio de macrófagos de perfil M1. Além disso, observamos menor inflamação no intestino, porém, a permeabilidade intestinal estava aumentada. A microbiota dos camundongos MyD88 KO foi capaz de induzir resistência à insulina nos camundongos WT, aumentou a permeabilidade intestinal e inflamação no tecido adiposo. A depleção de MyD88 no tecido adiposo não alterou o perfil metabólico dos camundongos comparados aos controles. No entanto, a depleção de MyD88 nos macrófagos, protegeu os camundongos do ganho de peso, resistência à insulina e do aumento da permeabilidade intestinal. Observamos maior polarização M2 no tecido adiposo desses camundongos. Ainda, camundongos MyD88 KO obesos não foram capazes de montar uma resposta inflamatória em resposta à sepse. No entanto, no tecido adiposo dos camundongos MyD88 KO obesos, observamos um aumento significativo da expressão de Dectina-1 e IFN-β, o que poderia explicar a resistência à insulina com a ausência da inflamação clássi...

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Parthenolide Modulates the NF-κB–Mediated Inflammatory Responses in Experimental Atherosclerosis

Abstract: NF-kappaB inhibition by PTN retards atherosclerotic lesions in apoE mice, by reducing lesion size and changing plaque composition. This natural compound could represent a novel therapeutic approach to inflammation during vascular damage.

Cited by 92 publications

References 49 publications

Parthenolide inhibits proliferation of vascular smooth muscle cells through induction of G0/G1 phase cell cycle arrest

Parthenolide inhibits proliferation of vascular smooth muscle cells through induction of G0/G1 phase cell cycle arrest

Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice

MyD88: um modulador do perfil inflamatório e metabólico na obesidade experimental.

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