Plumbagin Suppresses Pulmonary Fibrosis via Inhibition of p300 Histone Acetyltransferase Activity

Lee, Soo Yeon; Kim, Mi Jeong; Jang, Subhin; Lee, Gyeong Eun; Hwang, Soo Yeon; Kwon, Young Joo; Hong, Jung Yeon; Sohn, Myung Hyun; Park, Soo Yeon; Yoon, Ho Geun

doi:10.1089/jmf.2019.4670

Cited by 13 publications

(21 citation statements)

References 43 publications

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“…50 Similarly, plumbagin, which was shown to be an inhibitor of p300, suppresses fibrosis in an idiopathic pulmonary fibrosis model. 51 However, these data do not support a role of steroids, specifically triamcinolone, in counterregulating the effects of TGF-b1 by impacting the histone epigenome. In fact, although the role of triamcinolone as an antifibrotic agent has been recognized for decades, a fully detailed mechanism underlying this widely accepted effect remains elusive.…”

Section: Discussionmentioning

confidence: 90%

Down-Regulation of a Profibrotic Transforming Growth Factor-β1/Cellular Communication Network Factor 2/Matrix Metalloprotease 9 Axis by Triamcinolone Improves Idiopathic Subglottic Stenosis

Treviño-Villarreal

Reynolds

Langston

et al. 2021

The American Journal of Pathology

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Idiopathic subglottic stenosis (iSGS) is a progressive fibrotic disease characterized by life-threatening airway narrowing. Although the molecular underpinnings are unknown, previous reports showing that subglottic serial intralesional steroid injections (SILSIs) improve clinical outcomes suggest a steroidsensitive pathway in iSGS. Herein, a prospective study was conducted to determine the changes in profibrotic markers during SILSI to identify steroid-sensitive profibrotic drivers. Seven newly diagnosed patients with iSGS were recruited for SILSI. Subglottic biopsies before and after SILSI treatments were evaluated for histologic and molecular markers by confocal microscopy and RT-qPCR. At baseline, iSGS subglottises contained abundant vimentin-positive/a-smooth muscle actinenegative fibroblasts, intermingled with a matrix of fibronectin and types I and VI collagen. Transforming growth factor (TGF)-b1 was up-regulated primarily in glandular epithelium. Cellular communication network factor 2 (CCN2) was mainly up-regulated in stromal fibroblasts surrounding TGF-b1epositive glandular structures. SILSI improved iSGS by reducing fibroblast infiltration and increasing matrix remodeling. Mechanistically, SILSI counteracted the effects of TGF-b1 by inducing matrix metalloprotease 9 (MMP9) expression while repressing CCN2 expression, without affecting TGFb1 levels. Treatment of primary iSGS-derived fibroblasts with TGF-b1 recapitulated aspects of the disease in vivo, demonstrating that the induction in CCN2 and repression of MMP9 are caused by changes in histone acetylation induced by TGF-b1. Triamcinolone counteracted the coregulation of these genes by impairing SMAD2/3 binding to promoter regions, and not through histone acetylation. In conclusion, this study shows that SILSI counteracts a dysregulated TGF-b1/CCN2/MMP9 axis involved in iSGS development.

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Section: Discussionmentioning

confidence: 90%

Down-Regulation of a Profibrotic Transforming Growth Factor-β1/Cellular Communication Network Factor 2/Matrix Metalloprotease 9 Axis by Triamcinolone Improves Idiopathic Subglottic Stenosis

Treviño-Villarreal

Reynolds

Langston

et al. 2021

The American Journal of Pathology

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“…PLB has a pleiotropic effect on various cellular functions. Some studies have reported that PLB displays anti-fibrotic properties in the lung, kidney and liver [ 23 , 25 , 32 ]. In this study, our data showed that PLB regulated tissue repair and collagen deposition in TS rats.…”

Section: Discussionmentioning

confidence: 99%

“…Nylon brush was used to brush the inner wall of the trachea back-and-forth for 8 times from tracheostoma to the distal trachea (about 1 cm length), and then the tracheal incision was sutured in the rats of Group (2), (3) and (4) to establish TS model. In Group (4), the rats were intraperitoneally injected with 4 mg/kg/d PLB for five consecutive days (refer to previous literature) [ 23 , 27 ]. PLB (20 mg) was dissolved in 20 μl DMSO first, then diluted in 50 ml normal saline at a final concentration of 0.4 mg/ml.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, it has been reported that PLB can regulate the deposition of collagen in wounded skin and promote wound healing in diabetic animal models [ 22 ]. More recently, it has also been found that PLB can attenuate the proliferation of lung fibroblasts and inhibits the effects of TGF-β1 on lung fibrosis in mice by downregulating P300 [ 23 ]. PLB can also downregulate the overexpression of Smad2 protein caused by lung fibroblasts upon induction with F-828 (a soluble fullerene [C60] derivative) [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

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Plumbagin attenuates traumatic tracheal stenosis in rats and inhibits lung fibroblast proliferation and differentiation via TGF-β1/Smad and Akt/mTOR pathways

et al. 2021

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Traumatic tracheal stenosis (TS) is a serious respiratory disease characterized by hyperplasia of airway granulation. Plumbagin (PLB) is a natural naphthoquinone component with anti-fibrotic properties. This research aimed to explore the roles of PLB in alleviating TS and the underlying mechanisms. For in vitro studies, lung fibroblasts (IMR-90 cells), with/without PLB treatment or TGF-β1 induction, were used. The viability and proliferation of IMR-90 cells were examined by CCK-8 and EdU incorporation assays. The differentiation of IMR-90 cells was assessed by detecting the mRNA and protein expression levels of collagen (COL)-1 and alpha-smooth muscle actin (α-SMA). Besides, immunofluorescence assay was conducted to evaluate the localization of α-SMA in TGF-β1-induced IMR-90 cells. Moreover, the combination of PLB with/without TβRI (SB-431,542), PI3K/Akt (Ly294002) or mTOR (rapamycin) inhibitor was pretreated on IMR-90 cells after TGF-β1 induction. For in vivo studies, a rat model of TS was established. The pathological features and severity of TS were determined by hematoxylin and eosin staining. The protein levels of TGF-β1/Smad and Akt/mTOR pathways were detected for both in vitro and in vivo models. PLB effectively inhibited the proliferation and differentiation of TGF-β1-induced IMR-90 cells, and suppressed TGF-β1/Smad and Akt/mTOR signaling pathways both in vivo and in vitro. Furthermore, PLB reduced the degree of TS in rats. Taken together, our results indicate that PLB regulates lung fibroblast activity and attenuates TS in rats by inhibiting TGF-β1/Smad and Akt/mTOR signaling pathways. In conclusion, this study implies that PLB may serve as a promising therapeutic compound for TS.

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“…[7][8][9]18 Studies have revealed that the level of serum albumin is inversely linked with Aβ deposition and Aβ positivity. 19 Research reports have also shown that Aβ [25][26][27][28][29][30][31][32][33][34][35] can induce in vitro cross-seeding of BSA, resulting in aggregates that were toxic to microglial cells. 20 Moreover, D-ribosemediated glycation of BSA is known to trigger its rapid amyloid formation that generates neurotoxic aggregates.…”

Section: ■ Introductionmentioning

confidence: 99%

Evidence of Anti-amyloid Characteristics of Plumbagin via Inhibition of Protein Aggregation and Disassembly of Protein Fibrils

et al. 2021

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The biological consequences associated with the conversion of soluble proteins into insoluble toxic amyloids are not only limited to the onset of neurodegenerative diseases but also to the potential health risks associated with supplements of protein therapeutic agents as well. Hence, finding inhibitors against amyloid formation is important, and natural product-based anti-amyloid compounds have gained much interest because of their higher efficacy and biocompatibility. Plumbagin has been identified as a potential natural product with multiple medical benefits; however, it remains largely unclear whether plumbagin can act against amyloid formation of proteins. Here, we show that plumbagin can effectively inhibit the temperature-induced amyloid aggregation of important proteins (insulin and serum albumin). Both experimental and computational data revealed that the presence of plumbagin in protein solutions, under aggregating conditions, promotes a direct protein–plumbagin interaction, which is predominantly stabilized by stronger H-bonds and hydrophobic interactions. Plumbagin-mediated retention of the native structures of proteins appears to play a crucial role in preventing their conversion into insoluble β-sheet-rich amyloid aggregates. More importantly, the addition of plumbagin into a suspension of protein fibrils triggered their spontaneous disassembly, promoting the release of soluble proteins. The results highlight that a possible synergistic effect via both the stabilization of protein structures and the restriction of the monomer recruitment at the fibril growth sites could be important for the mechanism of plumbagin’s anti-aggregation effect. These findings may inspire the development of plumbagin-based formulations to benefit both the prevention and treatment of amyloid-related health complications.

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Plumbagin Suppresses Pulmonary Fibrosis via Inhibition of p300 Histone Acetyltransferase Activity

Cited by 13 publications

References 43 publications

Down-Regulation of a Profibrotic Transforming Growth Factor-β1/Cellular Communication Network Factor 2/Matrix Metalloprotease 9 Axis by Triamcinolone Improves Idiopathic Subglottic Stenosis

Down-Regulation of a Profibrotic Transforming Growth Factor-β1/Cellular Communication Network Factor 2/Matrix Metalloprotease 9 Axis by Triamcinolone Improves Idiopathic Subglottic Stenosis

Plumbagin attenuates traumatic tracheal stenosis in rats and inhibits lung fibroblast proliferation and differentiation via TGF-β1/Smad and Akt/mTOR pathways

Evidence of Anti-amyloid Characteristics of Plumbagin via Inhibition of Protein Aggregation and Disassembly of Protein Fibrils

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