Background: One of the primary drivers of liver fibrosis is the excessive accumulation of extracellular matrix (ECM), primarily caused by the over-proliferation of hepatic star-shaped cells (HSCs). The activation of HSCs by transforming growth factor beta (TGF-β) has a critical role in initiating fibrosis. Recent studies have suggested that miRNA-133a significantly ...

Background: Atherosclerosis remains the leading cause of mortality worldwide, highlighting the urgent need for innovative treatments targeting chronic inflammation. Recent research indicates that quercetin (QCT) and curcumin, two naturally occurring compounds, have potential therapeutic benefits in cardiovascular diseases. Objectives: This study focuses on the novel synthesis of nano-quercetin (N-QCT) encapsulated in solid lipid nanoparticles (SLNs) and investigates the synergistic cardioprotective effects of N-QCT and curcumin on human vascular smooth muscle cells (VSMCs). The underlying molecular mechanisms, particularly the involvement of the TGF-β signaling pathway in VSMCs, are explored. Methods: The VSMCs, including TGF-β-stimulated VSMCs, were treated with N-QCT, curcumin, or a combination of both. The MTT assay was performed to evaluate the cytotoxic effects of these treatments. The cytotoxicity of various concentrations of curcumin and QCT was used to calculate the Combination Index (CI), with CI analysis quantifying synergy or antagonism. Furthermore, following TGF-β stimulation, antioxidant enzyme activity, nuclear transcription factor erythroid 2-related factor (Nrf2) mRNA expression, reactive oxygen species (ROS) production, NADPH oxidases (NOX) expression, and extracellular signal-regulated kinase (Erk)1/2 phosphorylation were measured in the treated VSMCs. Results: The N-QCT and curcumin significantly influenced Nrf2 mRNA expression and upregulated downstream antioxidant enzymes, including HO-1, GPx, and SOD1. The combination treatment further enhanced Nrf2 protein expression and modulated Erk1/2 phosphorylation. Notably, the synergistic effect of the combination produced pronounced cardioprotective outcomes, characterized by reduced ROS production and decreased phosphorylation of Erk1/2 via the TGF-β/NOX/Erk1/2 and ROS/Nrf2 signaling pathways. Conclusions: The findings demonstrate that the combination of QCT encapsulated in SLNs and curcumin synergistically reduces oxidative stress and inflammation in TGF-β-stimulated VSMCs. This effect is achieved through the inhibition of ROS/Erk1/2 signaling and the activation of Nrf2 and antioxidant enzymes. These natural compounds, when used together, represent a promising therapeutic approach for mitigating the inflammatory processes associated with atherosclerosis.

Background: Liver fibrosis, associated with hepatic stellate cells (HSCs), occurs when a healthy liver sustains damage, thereby impairing its function. NADPH oxidases (NOXs), specifically isoforms 1, 2, and 4, play a role in reactive oxygen species (ROS) production during hepatic injuries, resulting in fibrosis. Curcumin has shown strong potential in mitigating liver ...

One of the primary drivers of liver fibrosis is the excessive accumulation of ECM, primarily caused by the over-proliferation of HSCs. The activation of HSCs by TGF-β has a critical role in initiating fibrosis. Recent studies have suggested that miRNA-133a significantly regulates the fibrogenesis process, which its downregulation is associated with the fibrosis progression. Understanding the role of miRNA-133a provides potential therapeutic insights for targeting TGF-β signaling and mitigating liver fibrosis. We investigated whether exosomes could attenuate liver fibrosis by enhancing the antifibrotic effects of miR-133a. The LX-2 cell line was treated with TGF-β for 24 hours, followed by an additional 24 hours of treatment with exosomes. After this treatment period, we assessed the mRNA expression levels of α-SMA, collagen 1, and miR-133a, as well as the protein levels of p-Smad3. TGF-β exposure significantly increased the expression level of α-SMA and collagen 1 genes and elevated the levels of p-Smad3 protein. Additionally, it resulted in a significant downregulation of miR-133a compared to the control group. Exosome administration effectively reduced the TGF-β-induced upregulation of p-Smad3, α-SMA, and collagen 1 genes, but increased miR-133a expression levels. Our findings indicate that by partially mitigating the downregulation of miR-133a, exosomes can effectively inhibit the persistent activation of HSCs. Furthermore, in the context of in vitro liver fibrosis, exosomes can suppress the TGF-β/Smad3 pathway, reducing the accumulation of ECM.

Background: Hepatocellular carcinoma (HCC) is the most prevalent type of liver malignancy worldwide. Traditional cancer treatments, such as chemotherapy and radiotherapy, often pose significant risks, including potential organ damage and, in severe cases, death. Etoposide (ETO), a commonly used chemotherapeutic agent, is not exempt from these complications. Combinational therapies have been explored for years as promising strategies to enhance treatment efficacy while mitigating adverse side effects. Stem cell-derived exosomes, recognized for their therapeutic potential, have emerged as valuable tools in cancer treatment due to their anti-cancer properties. Objectives: The present study investigates the potential synergistic effects between stem cell-derived exosomes and ETO in inducing apoptosis in HepG2 HCC cells. Methods: Cell apoptosis was evaluated using Annexin V/PI staining along with caspase-3 and -9 activity assays. Gene expression of Bax and Bcl-2 was measured by qRT-PCR, while p53 protein levels were assessed using western blotting. Results: Treatment with both stem cell-derived exosomes (100 µg/mL) and ETO (10 µM) significantly reduced HepG2 cell viability and induced apoptosis (16.2%) compared to either treatment alone. Caspase-9 and -3 activities increased to 69% and 64%, respectively, under combined treatment, versus 33% and 31% with exosomes and 51% and 39% with ETO alone. Bax expression rose by 3.6-fold, and Bcl-2 decreased to 0.44-fold upon co-treatment, leading to a markedly elevated Bax/Bcl-2 ratio. Moreover, p53 protein levels increased 3.24-fold, highlighting the enhanced apoptotic signaling. These results confirm a synergistic effect between exosomes and ETO. Conclusions: Our findings reveal that stem cell-derived exosomes exhibit synergistic effects when co-treated with ETO in HepG2 cells. Building on these results, we conclude that further investigation of this combination could lead to the development of a promising anti-cancer therapy for HCC.