Curcumin- and Cyclopamine-Loaded Liposomes to Enhance Therapeutic Efficacy Against Hepatic Fibrosis

Zhang, Ting; Li, Yanping; Song, Yi; Chen, Xiaoshuang; Li, Jing; Peng, Qiang; He, Jinhan; Fei, Xiaofan

doi:10.2147/dddt.s287442

Cited by 6 publications

(2 citation statements)

References 37 publications

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“…Our results align well with previous reports that highlighted the attenuation of liver fibrosis through abrogation of the Hedgehog pathway ( Jiayuan et al, 2020 ; Zhang et al, 2020 ). Moreover, Michelotti et al (2013) reported that SMO deletion from α-SMA + myofibroblasts caused inhibition of liver fibrosis.…”

Section: Discussionsupporting

confidence: 93%

Hedgehog signaling is a promising target for the treatment of hepatic fibrogenesis: a new management strategy using itraconazole-loaded nanoparticles

Elmorsy,

Saber,

Kira

et al. 2024

Front. Pharmacol.

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Liver fibrosis is a disease with a great global health and economic burden. Existing data highlights itraconazole (ITRCZ) as a potentially effective anti-fibrotic therapy. However, ITRCZ effect is hindered by several limitations, such as poor solubility and bioavailability. This study aimed to formulate and optimize chitosan nanoparticles (Cht NPs) loaded with ITRCZ as a new strategy for managing liver fibrosis. ITRCZ-Cht NPs were optimized utilizing a developed 22 full factorial design. The optimized formula (F3) underwent comprehensive in vitro and in vivo characterization. In vitro assessments revealed that F3 exhibited an entrapment efficiency of 89.65% ± 0.57%, a 169.6 ± 1.77 nm particle size, and a zeta potential of +15.93 ± 0.21 mV. Furthermore, in vitro release studies indicated that the release of ITRCZ from F3 adhered closely to the first-order model, demonstrating a significant enhancement (p-value < 0.05) in cumulative release compared to plain ITRCZ suspension. This formula increased primary hepatocyte survival and decreased LDH activity in vitro. The in vivo evaluation of F3 in a rat model of liver fibrosis revealed improved liver function and structure. ITRCZ-Cht NPs displayed potent antifibrotic effects as revealed by the downregulation of TGF-β, PDGF-BB, and TIMP-1 as well as decreased hydroxyproline content and α-SMA immunoexpression. Anti-inflammatory potential was evident by reduced TNF-α and p65 nuclear translocation. These effects were likely ascribed to the modulation of Hedgehog components SMO, GLI1, and GLI2. These findings theorize ITRCZ-Cht NPs as a promising formulation for treating liver fibrosis. However, further investigations are deemed necessary.

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Section: Discussionsupporting

confidence: 93%

Hedgehog signaling is a promising target for the treatment of hepatic fibrogenesis: a new management strategy using itraconazole-loaded nanoparticles

Elmorsy,

Saber,

Kira

et al. 2024

Front. Pharmacol.

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“…Thus, inhibiting Hh signaling will be an effective therapeutic target. It has been previously reported liver fibrosis was attenuated by Hh inhibitors, such as cyclopamine ( Zhang et al, 2020 ), vismodegib ( Pratap et al, 2012 ), and GANT61 ( Jiayuan et al, 2020 ). The present study showed that GPs suppressed the activation of Hh signaling both in CCl 4 /2-AAF-treated rats and Mdr2 −/− mice.…”

Section: Discussionmentioning

confidence: 99%

Gypenosides ameliorate ductular reaction and liver fibrosis via inhibition of hedgehog signaling

Zhou

et al. 2022

Front. Pharmacol.

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Backgroud and aims: Ductular reaction (DR) is a common pathological change and thought to have a key role in the pathogenesis and progression of liver fibrosis. Our previous study reported Gypenosides (GPs) ameliorated liver fibrosis, however, the anti-fibrotic mechanisms of GPs are still unclear.Methods: Liver fibrosis was induced in rats by carbon tetrachloride combining with 2-acerylaminofluorene (CCl4/2-AAF), and Mdr2 knockout (Mdr2−/−) mice to evaluate the anti-fibrotic role of GPs. In vitro, WB-F344 cells, a hepatic progenitor cells (HPCs) line, with or without Gli1 overexpressing lentiviral vectors, were induced by sodium butyrate (SB) to validate the mechanism of GPs and NPLC0393, the main ingredient of GPs.Results: Both in CCl4/2-AAF-treated rats and Mdr2−/− mice, GPs obviously reduced the deposition of collagen and hydroxyproline content, inhibited the activation of hepatic stellate cells and inflammatory cell infiltration. Notably, GPs reduced the expressions of Epcam, CK19, CK7, Dhh, Smo, Ptch2, Gli1 and Gli2. Furthermore, CK19+ cells co-expressed Gli1, while the number of CK19+/Gli1+ cells was decreased by GPs. In vitro, GPs and NPLC0393 inhibited the differentiation of WB-F344 cells toward a biliary phenotype. Mechanistically, GPs and NPLC0393 protected against DR by inhibiting hedgehog signaling, which was supported by the results that DR, triggered directly by Gli1 overexpressing lentiviral vector was blocked by administration with GPs or NPLC0393.Conclusion: GPs attenuated DR and liver fibrosis by inhibiting hedgehog signaling, which provided more evidences and a novel mechanism of anti-fibrotic effect of GPs.

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The Dual‐Target Nanoparticles with ROS Sensitivity Inhibit the Hedgehog Signaling Pathway and Decrease Oxidative Stress in Activated Hepatic Stellate Cells to Alleviate Liver Fibrosis

Zhang,

Zhang

et al. 2024

Adv Funct Materials

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Liver fibrosis is characterized by excess reactive oxygen species (ROS) production, hepatic stellate cell (HSC) activation, and subsequent extracellular matrix deposition. Since complex pathways regulate HSC activation, the single‐drug therapy efficacy for live fibrosis often falls short of expectations. To address this issue, an HSC‐targeted multifunctional nanoparticle (NP) delivery system co‐loaded with cyclopamine (Cyc; hedgehog inhibitor) and bilirubin (BR; ROS‐scavenger) is designed. The NP, termed RHB, is constructed via chemically conjugating hydrophobic bilirubin to hyaluronic acid (HA), followed by inserting into a cRGDyK peptide modified‐PEG shell. RHB can effectively target activated HSCs in the fibrotic liver by recognizing of the cRGDyK peptide and HA with integrin αvβ3 and CD44 due to their high expression on HSCs. During liver fibrosis, RHB NPs intelligently released Cyc in response to elevated ROS, inhibiting hedgehog signaling and subsequent HSC activation. Meanwhile, RHB NPs exhibited ROS scavenging capability and activated nuclear factor erythroid 2‐related factor 2 (Nrf2) signaling in stimulated HSCs, deactivating HSC. Cyc‐loaded RHB NPs significantly reversed the inflammatory and fibrotic phenotypes in liver fibrotic mice without evident toxicity. In summary, the multifunctional NPs dual‐targeted activated HSCs and deactivated HSC via multiple signaling, effectively ameliorating liver fibrosis, showing great promise for hepatic fibrosis treatment.

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Curcumin- and Cyclopamine-Loaded Liposomes to Enhance Therapeutic Efficacy Against Hepatic Fibrosis

Cited by 6 publications

References 37 publications

Hedgehog signaling is a promising target for the treatment of hepatic fibrogenesis: a new management strategy using itraconazole-loaded nanoparticles

Hedgehog signaling is a promising target for the treatment of hepatic fibrogenesis: a new management strategy using itraconazole-loaded nanoparticles

Gypenosides ameliorate ductular reaction and liver fibrosis via inhibition of hedgehog signaling

The Dual‐Target Nanoparticles with ROS Sensitivity Inhibit the Hedgehog Signaling Pathway and Decrease Oxidative Stress in Activated Hepatic Stellate Cells to Alleviate Liver Fibrosis

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