Non-alcoholic fatty liver disease (NAFLD) embraces several forms of liver disorders involving fat disposition in hepatocytes ranging from simple steatosis to the severe stage, namely, non-alcoholic steatohepatitis (NASH). Recently, several experimental in vivo animal models for NAFLD/NASH have been established. However, no reproducible experimental animal model displays the full spectrum of pathophysiological, histological, molecular, and clinical features associated with human NAFLD/NASH progression. Although methionine-choline-deficient (MCD) diet and high-fat diet (HFD) models can mimic histological and metabolic abnormalities of human disease, respectively, the molecular signaling pathways are extremely important for understanding the pathogenesis of the disease. This review aimed to assess the differences in gene expression patterns and NAFLD/NASH progression pathways among the most common dietary animal models, i.e., HFD- and MCD diet-fed animals. Studies showed that the HFD and MCD diet could induce either up- or downregulation of the expression of genes and proteins that are involved in lipid metabolism, inflammation, oxidative stress, and fibrogenesis pathways. Interestingly, the MCD diet model could spontaneously develop liver fibrosis within two to four weeks and has significant effects on the expression of genes that encode proteins and enzymes involved in the liver fibrogenesis pathway. However, such effects in the HFD model were found to occur after 24 weeks with insulin resistance but appear to cause less severe fibrosis. In conclusion, assessing the abnormal gene expression patterns caused by different diet types provides valuable information regarding the molecular mechanisms of NAFLD/NASH and predicts the clinical progression of the disease. However, expression profiling studies concerning genetic variants involved in the development and progression of NAFLD/NASH should be conducted.
Thymoquinone (TQ) is a quinone derived from the black seed Nigella sativa and has been extensively studied in pharmaceutical and nutraceutical research due to its therapeutic potential and pharmacological properties. Although the chemopreventive and potential anticancer effects of TQ have been reported, its limited solubility and poor delivery remain the major limitations. In this study, we aimed to characterize the inclusion complexes of TQ with Sulfobutylether-β-cyclodextrin (SBE-β-CD) at four different temperatures (293–318 K). Additionally, we compared the antiproliferative activity of TQ alone to TQ complexed with SBE-β-CD on six different cancer cell lines, including colon, breast, and liver cancer cells (HCT-116, HT-29, MDA-MB-231, MCF-7, SK-BR-3, and HepG2), using an MTT assay. We calculated the thermodynamic parameters (ΔH, ΔS, and ΔG) using the van’t Holf equation. The inclusion complexes were characterized by X-ray diffraction (XRD), Fourier transforms infrared (FT-IR), and molecular dynamics using the PM6 model. Our findings revealed that the solubility of TQ was improved by ≥60 folds, allowing TQ to penetrate completely into the cavity of SBE-β-CD. The IC50 values of TQ/SBE-β-CD ranged from 0.1 ± 0.01 µg/mL against SK-BR-3 human breast cancer cells to 1.2 ± 0.16 µg/mL against HCT-116 human colorectal cancer cells, depending on the cell line. In comparison, the IC50 values of TQ alone ranged from 0.2 ± 0.01 µg/mL to 4.7 ± 0.21 µg/mL. Overall, our results suggest that SBE-β-CD can enhance the anticancer effect of TQ by increasing its solubility and bioavailability and cellular uptake. However, further studies are necessary to fully understand the underlying mechanisms and potential side effects of using SBE-β-CD as a drug delivery system for TQ.
Polyethylene glycol (PEG) coated Poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) for cancer treatment are biocompatible, nonimmunogenic and accumulate in tumour sites due to the enhanced permeability and retention (EPR). Doxorubicin (DOX) is a potent but cardiotoxic anticancer agent. Hyaluronic acid (HA) occurs naturally in the extra-cellar matrix and binds to CD44 receptors which are overexpressed in cancer metastasis, proven to be characteristic of cancer stem cells and responsible for multidrug resistance. In this study, an athymic mice model of breast cancer metastasis was developed using red fluorescent protein (RFP)-labelled triple negative cancer cells. The animals were divided into four treatment groups (Control, HA-PEG-PLGA nanoparticles, PEG-PLGA nanoparticles, and Free DOX). The tumour size growth was assessed until day 25 when animals were sacrificed. Mice treated with HA-PEG-PLGA NPs inhibited tumour growth. The tumour growth at day 25 (118% ± 13.0) was significantly (p < 0.05) less than PEG-PLGA NPs (376% ± 590 and control (826% ± 970). Fluorescent microscopy revealed that HA-PEG-PLGA NPs had significantly (p < 0.05) less metastasis in liver, spleen, colon, and lungs as compared to control and to Free DOX groups. The efficacy of HA-PEG-PLGA NPs was proven in vivo. Further pharmacokinetic and toxicity studies are required for this formulation to be ready for clinical research.
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