BACKGROUND AND PURPOSEHepatic stellate cells (HSCs) are liver-specific pericytes regulating angiogenesis during liver fibrosis. We aimed to elucidate the mechanisms by which hedgehog signalling regulated HSC angiogenic properties and to validate the therapeutic implications.
EXPERIMENTAL APPROACHRats and mice were treated with carbon tetrachloride for in vivo evaluation of hepatic angiogenesis and fibrotic injury. Diversified molecular approaches including real-time PCR, Western blot, luciferase reporter assay, chromatin immunoprecipitation, electrophoretic mobility shift assay and co-immunoprecipitation were used to investigate the underlying mechanisms in vitro.
KEY RESULTSAngiogenesis was concomitant with up-regulation of Smoothened (SMO) and hypoxia inducible factor-1α (HIF-1α) in rat fibrotic liver. The SMO inhibitor cyclopamine and Gli1 inhibitor GANT-58 reduced expression of VEGF and angiopoietin 1 in HSCs and suppressed HSC tubulogenesis capacity. HIF-1α inhibitor PX-478 suppressed HSC angiogenic behaviour, and inhibition of hedgehog decreased HIF-1α expression. Furthermore, heat shock protein 90 (HSP90) was characterized as a direct target gene of canonical hedgehog signalling in HSCs. HSP90 inhibitor 17-AAG reduced HSP90 binding to HIF-1α, down-regulated HIF-1α protein abundance and decreased HIF-1α binding to DNA. 17-AAG also abolished 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG) (a SMO agonist)-enhanced HSC angiogenic properties. Finally, the natural compound ligustrazine was found to inhibit canonical hedgehog signalling leading to suppressed angiogenic properties of HSCs in vitro and ameliorated liver fibrosis and sinusoidal angiogenesis in mice.
CONCLUSION AND IMPLICATIONSWe have provided evidence that the canonical hedgehog pathway controlled HSC-mediated liver angiogenesis. Selective inhibition of HSC hedgehog signalling could be a promising therapeutic approach for hepatic fibrosis.
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Chemotherapy is widely used in the clinic though its benefits are controversial owing to low cancer specificity. Nanovehicles capable of selectively transporting drugs to cancer cells have been energetically pursued to remodel cancer treatment. However, no active targeting nanomedicines have succeeded in clinical translation to date, partly due to either modest targetability or complex fabrication. CD44‐specific A6 short peptide (KPSSPPEE) functionalized polymersomal epirubicin (A6‐PS‐EPI), which boosts targetability and anticancer efficacy toward human multiple myeloma (MM) in vivo, is described. A6‐PS‐EPI encapsulating 11 wt% EPI is small (≈55 nm), robust, reduction‐responsive, and easy to fabricate. Of note, A6 decoration markedly augments the uptake and anticancer activity of PS‐EPI in CD44‐overexpressing LP‐1 MM cells. A6‐PS‐EPI displays remarkable targeting ability to orthotopic LP‐1 MM, causing depleted bone damage and striking survival benefits compared to nontargeted PS‐EPI. Overall, A6‐PS‐EPI, as a simple and intelligent nanotherapeutic, demonstrates high potential for clinical translation.
The ring opening copolymerization of trimethylene carbonate (TMC) and dithiolane trimethylene carbonate (DTC) using acidic and basic organocatalysts, i.e., diphenyl phosphate (DPP) and triazabicyclo[4.4.0]dec-5-ene (TBD), was systemically investigated. Interestingly, DPP and TBD gave rise to completely different polymerization kinetics and copolymer sequences. The copolymerization of TMC and DTC using methoxy poly(ethylene glycol) (mPEG-OH) as an initiator and DPP as a catalyst proceeded in a first-order manner and to near completion in 72 h for both monomers, yielding well-controlled copolymers with random sequences, predictable molar mass, and low dispersity ( M/ M = 1.09-1.19). By contrast, TBD brought about much faster copolymerization of TMC and DTC under similar conditions (high monomer conversion achieved in 2-4 h), to furnish copolymers with controlled molar mass and moderate dispersity ( M/ M = 1.27-1.80). Moreover, polymerization kinetics revealed that DTC was preferentially polymerized followed by first-order polymerization of TMC, leading to blocky copolymers. These results signify that type of organocatalysts has a critical influence on polymerization kinetics of cyclic carbonates, copolymer sequence, and molar mass control.
A hierarchical zeolitic imidazolate framework-8 (micro/meso-ZIF-8) was fabricated by using cetyltrimethylammonium bromide as a structure-controlling agent and l-histidine as co-templates. Compared to the conventional microporous ZIF-8 (micro-ZIF-8), the hierarchical porous structure of micro/meso-ZIF-8 contains micropores and maximum mesopores of around 35.6 nm. The as-prepared hierarchical micro/meso-ZIF-8 featured a large surface area and superior spontaneous adsorption activity than micro-ZIF-8 towards lysozyme (LZM), bovine hemoglobin (BHb) and bovine serum albumin (BSA), and the adsorption capacity increased with the decreasing of the protein size due to the molecule cutoff effects. The maximum adsorption capacity of LZM on micro/meso-ZIF-8 was higher than most of the reported results under similar adsorption conditions. The analyses of adsorption kinetics and thermodynamics implied that the adsorption mechanism mainly involved physical adsorption. Moreover, the micro/meso-ZIF-8 showed good thermal stability against temperature and excellent regeneration ability in the recycling adsorption experiments. This work proposed herein opens a broad application prospect of hierarchical MOFs in biological molecule separation, immobilization and enrichment.
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