Anti-liver fibrosis activity of curcumin/chitosan-coated green silver nanoparticles

Abstract

Liver fibrosis results from the hepatic accumulation of the extracellular matrix accompanied by a failure of the mechanisms responsible for matrix dissolution. Pathogenesis of liver fibrosis is associated with many proteins from different cell types. In the present study, in silico molecular docking analysis revealed that curcumin may inhibit the fibrosis-mediating proteins PDGF, PDGFRB, TIMP-1, and TLR-9 by direct binding. Nano-formulation can overcome curcumin problems, increasing the efficacy of curcumin as a drug by maximizing its solubility and bioavailability, enhancing its membrane permeability, and improving its pharmacokinetics, pharmacodynamics and biodistribution. Therefore, green silver nanoparticles (AgNPs) were synthesized in the presence of sunlight by means of the metabolite of Streptomyces malachiticus, and coated with curcumin-chitosan mixture to serve as a drug delivery tool for curcumin to target CCl4-induced liver fibrosis mouse model. Fibrosis induction significantly increased hepatic gene expression of COL1A1, α-SMA, PDGFRB, and TIMP1, elevated hepatic enzymes, increased histopathological findings, and increased collagen deposition as determined by Mason’s trichrome staining. Treatment with naked AgNPs tended to increase these inflammatory effects, while their coating with chitosan, similar to treatment with curcumin only, did not prevent the fibrogenic effect of CCl4. The induction of liver fibrosis was reversed by concurrent treatment with curcumin/chitosan-coated AgNPs. In this nano form, curcumin was found to be efficient as anti-liver fibrosis drug, maintaining the hepatic architecture and function during fibrosis development. This efficacy can be attributed to its inhibitory role through a direct binding to fibrosis-mediating proteins such as PDGFRB, TIMP-1, TLR-9 and TGF-β.

Remodeling the hepatic fibrotic microenvironment with emerging nanotherapeutics: a comprehensive review

“…Anionic HA-containing NPs LSECs, Tregs Suppressing antigen-specific immune responses [29] AB diblock copolymers NPs LSECs, KCs Leading to immune inflammation [33] Stab2-containing NPs LSECs, Tregs Clearing of lipoproteins [30] Mannose-modified albumin NPs Macrophages TGFβ-siRNA to CD206 + as an anti-fibrotic strategy [37] CMC-containing NPs Macrophages Reducing host immune response [40] PS-containing NPs Macrophages Reducing collagen fiber deposition [42] silk or silicon-containing NPs Macrophages Pro-inflammatory phenotype [69] hydrogel particles M2-polarized macrophages Improving immunocompromised and impaired angiogenesis [108,109] DEX/HA-TK-ART PMs M2-polarized macrophages HIF-1α/NF-κB signaling cascade [90] mLNP-siHMGB1 Macrophages, HSCs Inhibiting the activation of HSCs [38] DSPE-PEG-CeO2 NPs Macrophages, HSCs Reducing inflammation [86] CNF HSCs, macrophages Increasing glycolysis and reprogramming and reducing initiated inflammatory [70] VA-SLNs HSCs Reducing PPARγ/SREBPs-mediated lipid accumulation [61] CS sulfate PMs HSCs Anti-fibrotic strategy [63] CS-coated green silver NPs HSCs Bounding to the fibrogenic protein TGF-β [65] hydrogels HSCs Blocking the TGF-β1/Smad pathway [66] RGD HSCs Inhibiting the proliferation of HSCs [82] Chol-PCX/miRNA NPs HSCs, T cells Disrupting the lipid metabolic network [73,74] GQD HSCs Inhibiting lipid peroxidation, apoptosis, and autophagy [87] CeO2 NPs HSCs Antioxidant effect [85] FPL HSCs Antioxidant effect [88] ChiBil carrying losartan HSCs attenuating iron death [89] PEG-PLGA-containing NPs LSECs, hepatocytes and HSCs Constricting abnormal blood vessels, reducing MVD [99] Self-assembled PMs LSECs, hepatocytes and HSCs Avoiding the hepatotoxicity and side effects [96] NPs laponite HUVECs enhancing HIF-1α and VEGF expression, accelerating neovascularization [110] and mannose receptors (MR) that produce inhibitory acquired immune responses. LSECs regulate adaptive immune responses directly by presenting antigens to T cells and also regulate natural killer T cells (NKT cells) by expressing CXCL16, and the cell surface ligand for CXCR6…”

“…TGFβ signaling is involved in stimulating glycolysis and mitochondrial respiration. Inhibitory effect of curcumin/chitosan-coated green silver NPs directly bound to the fibrogenic protein TGF-β [65]. Mouse livers were decellularized to form liver hydrogels as an injectable biomaterial in the liver, which blocked the TGF-β1/Smad pathway to reduce fibrosis [66] (Table 2).…”

Curcumin-Based Nanomedicines in the Treatment of Inflammatory and Immunomodulated Diseases: An Evidence-Based Comprehensive Review

“…Elzoheiry et al [ 89 ] evaluated the therapeutic effects of CUR encapsulated in green silver NPs (AgNPs), coated or not with CH, in the treatment of liver fibrosis in vivo and in vitro. In the histological analysis of the hepatic tissue, it was possible to observe that the coated and non-coated NPs successfully potentiated the uptake of Cur by the hepatocytes; however, the increase was greater in the coated particles.…”

Human diet‐derived polyphenolic compounds and hepatic diseases: From therapeutic mechanisms to clinical utilization

“…The outcomes indicated effective reversal of hepatic fibrosis attributed to curcumin's capability to interact with proteins involved in fibrosis (PDGFRB, TIMP-1, TLR-9, and TGF-β) (Elzoheiry et al, 2022).…”