Hypertrophic scar (HPS) presents as excessive extracellular matrix deposition and abnormal function of fibroblasts. However, there is no single satisfactory method to prevent HPS formation so far. Here, we found that honokiol (HKL), a natural compound isolated from Magnolia tree, had an inhibitory effect on HPS both in vitro and in vivo. Firstly, HKL could dose-dependently down-regulate the mRNA and protein levels of type I collagen, type III collagen, and α-smooth muscle actin (α-SMA) in hypertrophic scar-derived fibroblasts (HSFs). Secondly, HKL suppressed the proliferation, migration abilities of HSFs and inhibited HSFs activation to myofibroblasts, but had no effect on cell apoptosis. Besides, the in vivo rabbit ear scar model further affirmed the inhibitory effects of HKL on collagen deposition, proliferating cell nuclear antigen and α-SMA. Finally, Western blot results showed that HKL reduced the phosphorylation status of Smad2/3, as well as affected the protein levels of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase1. Taken together, this study demonstrated that HKL alleviated HPS by suppressing fibrosis-related molecules and inhibiting HSFs proliferation, migration as well as activation to myofibroblasts via Smad-dependent pathway. Therefore, HKL could be used as a potential agent for treating HPS and other fibrotic diseases.
The
lack of cancer cell specificity and the occurrence of multidrug
resistance (MDR) are two major obstacles in the treatment of hepatocellular
carcinoma (HCC). To tackle these challenges, a novel nanoparticle
(NP)-based drug delivery system (DDS) with a core/shell structure
consisted of d-α-tocopheryl polyethylene glycol 1000
succinate (TPGS)–galactose (Gal)/polydopamine (PDA) is fabricated.
The NP is loaded with doxorubicin (DOX) and a nitric oxide (NO) donor N,N′-di-sec-butyl-N,N′-dinitroso-1,4-phenylenediamine
(BNN) sensitive to heat to afford NO-DOX@PDA-TPGS-Gal. The unique
binding of Gal to asialoglycoprotein receptor (ASGPR) and the pH-sensitive
degradation of NP ensure the targeted transportation of NP into liver
cells and the release of DOX in HCC cells. The near-infrared (NIR)
light further facilitates DOX release and initiates NO generation
from BNN due to the photothermal property of PDA. In addition to the
cytotoxicity contributed by DOX, NO, and heat, TPGS and NO act as
MDR reversal agents to inhibit P-glycoprotein (P-gp)-related efflux
of DOX by HepG2/ADR cells. The combined chemo–photothermal
therapy (chemo-PTT) by NO-DOX@PDA-TPGS-Gal thus shows potent anti-cancer
activity against drug-resistant HCC cells in vitro and in vivo and
significantly prolongs the life span of drug-resistant tumor-bearing
mice. The present work provides a useful strategy for highly targeted
and MDR reversal treatment of HCC.
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