Dataset Information

Cryptotanshinone is a candidate therapeutic agent for interstitial lung disease associated with a BRICHOS-domain mutation of SFTPC.

ABSTRACT: Interstitial lung disease (ILD) represents a large group of diseases characterized by chronic inflammation and fibrosis of the lungs, for which therapeutic options are limited. Among several causative genes of familial ILD with autosomal dominant inheritance, the mutations in the BRICHOS domain of SFTPC cause protein accumulation and endoplasmic reticulum stress by misfolding its proprotein. Through a screening system using these two phenotypes in HEK293 cells and evaluation using alveolar epithelial type 2 (AT2) cells differentiated from patient-derived induced pluripotent stem cells (iPSCs), we identified Cryptotanshinone (CPT) as a potential therapeutic agent for ILD. CPT decreased cell death induced by mutant SFTPC overexpression in A549 and HEK293 cells and ameliorated the bleomycin-induced contraction of the matrix in fibroblast-dependent alveolar organoids derived from iPSCs with SFTPC mutation. CPT and this screening strategy can apply to abnormal protein-folding-associated ILD and other protein-misfolding diseases.

SUBMITTER: Hosokawa M

PROVIDER: S-EPMC10494175 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cryptotanshinone is a candidate therapeutic agent for interstitial lung disease associated with a BRICHOS-domain mutation of <i>SFTPC</i>.

Hosokawa Motoyasu M Mikawa Ryuta R Hagiwara Atsuko A Okuno Yukiko Y Awaya Tomonari T Yamamoto Yuki Y Takahashi Senye S Yamaki Haruka H Osawa Mitsujiro M Setoguchi Yasuhiro Y Saito Megumu K MK Abe Shinji S Hirai Toyohiro T Gotoh Shimpei S Hagiwara Masatoshi M

iScience 20230825 10

Interstitial lung disease (ILD) represents a large group of diseases characterized by chronic inflammation and fibrosis of the lungs, for which therapeutic options are limited. Among several causative genes of familial ILD with autosomal dominant inheritance, the mutations in the BRICHOS domain of <i>SFTPC</i> cause protein accumulation and endoplasmic reticulum stress by misfolding its proprotein. Through a screening system using these two phenotypes in HEK293 cells and evaluation using alveola ...[more]

PMID: 37701577

Similar Datasets

Project description:Hepatocellular carcinoma (HCC) is a fatal and dominant form of liver cancer that currently has no effective treatment or positive prognosis. In this study, we explored the antitumor effects of cryptotanshinone (CPT) against HCC and the molecular mechanisms underlying these effects using a systems pharmacology and experimental validation approach. First, we identified a total of 296 CPT targets, 239 of which were also HCC-related targets. We elucidated the mechanisms by which CPT affects HCC through multiple network analysis, including CPT-target network analysis, protein-protein interaction network analysis, target-function network analysis, and pathway enrichment analysis. In addition, we found that CPT induced apoptosis in Huh7 and MHCC97-H ells due to increased levels of cleaved PARP, Bax, and cleaved caspase-3 and decreased Bcl-2 expression. CPT also induced autophagy in HCC cells by increasing LC3-II conversion and the expression of Beclin1 and ATG5, while decreasing the expression of p62/SQSTM1. Autophagy inhibitors (3-methyladenine and chloroquine) enhanced CPT-induced proliferation and apoptosis, suggesting that CPT-induced autophagy may protect HCC cells against cell death. Furthermore, CPT was found to inhibit the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. Interestingly, activation of PI3K by insulin-like growth factor-I inhibited CPT-induced apoptosis and autophagy, suggesting that the PI3K/AKT/mTOR signaling pathway is involved in both CPT-induced apoptosis and autophagy. Finally, CPT was found to inhibit the growth of Huh7 xenograft tumors. In conclusion, we first demonstrated the antitumor effects of CPT in Huh7 and MHCC97-H cells, both in vitro and in vivo. We elucidated the potential antitumor mechanism of CPT, which involved inducing apoptosis and autophagy by inhibiting the PI3K/Akt/mTOR signaling pathway. Our findings may provide valuable insights into the clinical application of CPT, serving as a potential candidate therapeutic agent for HCC treatment.

Dataset Information

Cryptotanshinone is a candidate therapeutic agent for interstitial lung disease associated with a BRICHOS-domain mutation of SFTPC.

Publications

Cryptotanshinone is a candidate therapeutic agent for interstitial lung disease associated with a BRICHOS-domain mutation of <i>SFTPC</i>.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets