HSP47: A Therapeutic Target in Pulmonary Fibrosis

Sakamoto, Noriho; Okuno, Daisuke; Tokito, Takatomo; Yura, Hirokazu; Kido, Takashi; Ishimoto, Hiroshi; Tanaka, Yoshimasa; Mukae, Hiroshi

doi:10.3390/biomedicines11092387

Cited by 13 publications

(9 citation statements)

References 106 publications

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“…It has a role in fibrosis in several tissues, and down-regulation would be consistent with decreased fibrosis. 65 On the other hand, Angptl4 was up-regulated in ONH, but down-regulated in TM suggesting it may induce different downstream effectors in each tissue. This is the first study to compare directly the responses of the TM and ONH within the same animal to a given level of IOP.…”

Section: Discussionmentioning

confidence: 99%

Profiling IOP-responsive genes in anterior and posterior ocular tissues in the rat CEI glaucoma model

Lozano,

Yang,

Cepurna

et al. 2024

Preprint

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Purpose: The rat Controlled Elevation of Intraocular pressure (CEI) model allows study of in vivo responses to defined intraocular pressures (IOP). In this study, we use Nanostring technology to investigate in vivo IOP-related gene responses in the trabecular meshwork (TM) and optic nerve head (ONH) simultaneously from the same animals. Methods: Male and female rats (N=35) were subject to CEI for 8-hours at pressures simulating mean, daytime normotensive rat IOP (CEI-20), or 2.5x IOP (CEI-50). Naive animals, receiving no anesthesia or surgical interventions, served as controls. Immediately after CEI, TM and ONH tissues were dissected, RNA isolated, and samples were analyzed with a Nanostring panel containing 770 genes. Post-processing, raw count data were uploaded to Rosalind for differential gene expression analyses. Results: For the TM, 45 IOP-related genes were significant in the 'CEI-50 vs. CEI-20' and 'CEI-50 vs. naive' comparisons, with 15 genes common to both comparisons. Bioinformatics analysis identified Notch and TGFβ pathways to be the most up- and down-regulated KEGG pathways, respectively. For ONH, 22 significantly regulated genes were identified in the 'CEI-50 vs. naive' comparison. Pathway analysis identified 'defense response' and 'immune response' as two significantly upregulated biological process pathways. Conclusions: This study demonstrates the ability to assay IOP-responsive genes in both TM and ONH tissues simultaneously. In the TM, downregulation of TGFβ pathway genes suggest that TM responses may prevent TGFβ-induced extracellular matrix synthesis. For ONH, the initial response to elevated IOP may be protective, with astrocytes playing a key role in these gene responses.

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Section: Discussionmentioning

confidence: 99%

Profiling IOP-responsive genes in anterior and posterior ocular tissues in the rat CEI glaucoma model

Lozano,

Yang,

Cepurna

et al. 2024

Preprint

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“…This natural product warrants better consideration as an insecticidal agent and as an antiadipogenic molecule. The hypothesis that prieurianin binds well to the collagen-binding protein Hsp47 is attractive and opens new perspectives for the design of other compounds with antifibrotic properties because this protein is a major recognized target to combat pulmonary fibrosis and other fibrotic diseases [124][125][126]. Hsp47 inhibitors mediate antifibrotic effects by suppressing the overexpression of collagen and inhibiting the viability and migration of fibroblasts [127].…”

Section: Discussionmentioning

confidence: 99%

Insights into the Mechanism of Action of the Degraded Limonoid Prieurianin

Vergoten,

Bailly

2024

IJMS

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Limonoids are extremely diversified in plants, with many categories of products bearing an intact, rearranged or fragmented oxygenated scaffold. A specific subgroup of fragmented or degraded limonoids derives from the tetranortriterpenoid prieurianin, initially isolated from the tree Trichilia prieuriana but also found in other plants of the Meliaceae family, including the more abundant species Aphanamixis polystachya. Prieurianin-type limonoids include about seventy compounds, among which are dregeanin and rohitukin. Prieurianin and analogs exhibit insecticidal, antimicrobial, antiadipogenic and/or antiparasitic properties but their mechanism of action remains ill-defined at present. Previous studies have shown that prieurianin, initially known as endosidin 1, stabilizes the actin cytoskeleton in plant and mammalian cells via the modulation of the architecture and dynamic of the actin network, most likely via interference with actin-binding proteins. A new mechanistic hypothesis is advanced here based on the recent discovery of the targeting of the chaperone protein Hsp47 by the fragmented limonoid fraxinellone. Molecular modeling suggested that prieurianin and, to a lesser extent dregeanin, can form very stable complexes with Hsp47 at the protein–collagen interface. Hsp-binding may account for the insecticidal action of the product. The present review draws up a new mechanistic portrait of prieurianin and provides an overview of the pharmacological properties of this atypical limonoid and its chemical family.

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“…It has a role in fibrosis in several tissues, and its downregulation is consistent with decreased expression of fibrotic-related genes. 65 On the other hand, Angptl4 was upregulated in ONH but downregulated in TM, suggesting that it may induce different downstream effectors in each tissue.…”

Section: Discussionmentioning

confidence: 99%

Profiling IOP-Responsive Genes in the Trabecular Meshwork and Optic Nerve Head in a Rat Model of Controlled Elevation of Intraocular Pressure

Lozano,

Yang,

Cepurna

et al. 2024

Invest. Ophthalmol. Vis. Sci.

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The rat controlled elevation of intraocular pressure (CEI) model allows study of in vivo responses to short-term exposure to defined intraocular pressures (IOP). In this study, we used NanoString technology to investigate in vivo IOP-related gene responses in the trabecular meshwork (TM) and optic nerve head (ONH) simultaneously from the same animals. METHODS.Male and female rats (N = 35) were subjected to CEI for 8 hours at pressures simulating mean, daytime normotensive rat IOP (CEI-20), or 2.5× IOP (CEI-50). Naïve animals that received no anesthesia or surgical interventions served as controls. Immediately after CEI, TM and ONH tissues were dissected, RNA was isolated, and samples were analyzed with a NanoString panel containing 770 genes. Postprocessing, raw count data were uploaded to ROSALIND for differential gene expression analyses. RESULTS.For the TM, 45 IOP-related genes were significant in the CEI-50 versus CEI-20 and CEI-50 versus naïve comparisons, with 15 genes common to both comparisons. Bioinformatics analysis identified Notch and transforming growth factor beta (TGFβ) pathways to be the most up-and downregulated Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, respectively. For ONH, 22 significantly differentially regulated genes were identified in the CEI-50 versus naïve comparison. Pathway analysis identified defense response and immune response as two significantly upregulated biological process pathways. CONCLUSIONS.This study demonstrated the ability to assay short-term IOP-responsive genes in both TM and ONH tissues simultaneously. In the TM, downregulation of TGFβ pathway genes suggests that TM responses may reduce TGFβ-induced extracellular matrix synthesis. For ONH, the initial response to short-term elevated IOP may be protective.

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HSP47: A Therapeutic Target in Pulmonary Fibrosis

Cited by 13 publications

References 106 publications

Profiling IOP-responsive genes in anterior and posterior ocular tissues in the rat CEI glaucoma model

Profiling IOP-responsive genes in anterior and posterior ocular tissues in the rat CEI glaucoma model

Insights into the Mechanism of Action of the Degraded Limonoid Prieurianin

Profiling IOP-Responsive Genes in the Trabecular Meshwork and Optic Nerve Head in a Rat Model of Controlled Elevation of Intraocular Pressure

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