Imidacloprid-induced liver fibrosis in quails via activation of the TGF-β1/Smad pathway

Liver fibrosis is an abnormal wound repair response caused by a variety of chronic liver injuries, which is characterized by over-deposition of diffuse extracellular matrix (ECM) and anomalous hyperplasia of connective tissue, and it may further develop into liver cirrhosis, liver failure or liver cancer. To date, chronic liver diseases accompanied with liver fibrosis have caused significant morbidity and mortality in the world with increasing tendency. Although early liver fibrosis has been reported to be reversible, the detailed mechanism of reversing liver fibrosis is still unclear and there is lack of an effective treatment for liver fibrosis. Thus, it is still a top priority for the research and development of anti-fibrosis drugs. In recent years, many strategies have emerged as crucial means to inhibit the occurrence and development of liver fibrosis including anti-inflammation and liver protection, inhibition of hepatic stellate cells (HSCs) activation and proliferation, reduction of ECM overproduction and acceleration of ECM degradation. Moreover, gene therapy has been proved to be a promising anti-fibrosis method. Here, we provide an overview of the relevant targets and drugs under development. We aim to classify and summarize their potential roles in treatment of liver fibrosis, and discuss the challenges and development of anti-fibrosis drugs.

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Liver Fibrosis: Therapeutic Targets and Advances in Drug Therapy.

Sirtuins as endogenous regulators of lung fibrosis: A current perspective

A recent overview on the biological and pharmacological activities of ferulic acid.

Wu-Mei-Wan ameliorates chronic colitis-associated intestinal fibrosis through inhibiting fibroblast activation.

Purpose
Liver fibrosis is a worldwide health issue. Development of effective new drugs for treatment of this disease is of great importance. This study investigated the therapeutic effects of ferulic acid on liver fibrosis in vitro and in vivo.

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Ferulic acid attenuates liver fibrosis and hepatic stellate cell activation via inhibition of TGF-β/Smad signaling pathway.

Objective Osteoarthritis (OA) is characterized by progressive matrix destruction of articular cartilage. This study aimed to investigate the potential antioxidative and chondroprotective effects and underlying mechanism of Icariin (ICA) in interleukin-1 beta (IL-1β)-induced extracellular matrix (ECM) degradation of OA cartilage. Methods Human chondrocyte cell line HC-A was treated with different doses of ICA, and then MTT assay and PI staining were used to estimate ICA-induced chondrocyte apoptosis. Intracellular ROS and superoxide dismutase (SOD) and glutathione peroxidase (GPX) were measured after treatment by IL-1β with or without ICA. The mRNA and protein expression levels of redox transcription factor Nrf2 and the downstream effector SOD-1, SOD-2, NQO-1 and HO-1 were assayed to explore the detailed mechanism by which ICA alleviates ECM degradation. Finally, to expound the role of Nrf2 in ICA-mediated chondroprotection, we specifically depleted Nrf2 in human chondrocytes and then pretreated them with ICA followed by IL-1β. Results ICA had no cytotoxic effects on human chondrocytes and 10-9 M was selected as the optimum concentration. ROS induced by IL-1β could drastically activate matrix-degrading proteases and ICA could significantly rescue the matrix degradation and excess ROS generation caused by IL-1β. We observed that ICA activated the Nrf2/ARE pathway, consequently upregulating the generation of GPX and SOD. Ablation of Nrf2 abrogated the chondroprotective and antioxidative effects of ICA in IL-1β-treated chondrocytes. Conclusion ICA alleviates IL-1β-induced matrix degradation and eliminates ROS by activating the Nrf2/ARE pathway.

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Icariin Alleviates IL-1β-Induced Matrix Degradation By Activating The Nrf2/ARE Pathway In Human Chondrocytes.


 Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to chemoradiation and immune therapies, which is at least in part driven by its immunosuppressive tumor microenvironment (TME) consisting of dense cancer-associated fibroblasts (CAF) and highly suppressed immune cells. Lysine methyltransferase 2D (KMT2D), also known as MLL4 in mice, has been identified as one of the most frequently altered epigenetic regulators in PDAC. Most importantly, KMT2D mutation was found in more than 80% of neoadjuvant-treated PDAC, suggesting that KMT2D loss may be associated with treatment resistance. In human PDAC, low KMT2D protein level is correlated with worse survival. However, it is unknown whether KMT2D loss in PDAC cells modulates the TME. This project aimed to elucidate the role of KMT2D in remodeling the immune and stromal environment in PDAC. We first screened for changes in the immune cell population by performing immunohistochemistry (IHC) stains with human PDAC samples. We found that primary human tumors with low KMT2D expression had increased immunosuppressive tumor-associated neutrophils. xCell digital dissection analysis with The Cancer Genome Atlas (TCGA) data revealed that KMT2D-low PDAC had decreased effector T cell signature and enriched immunosuppressive Treg cell signature. Single-cell RNA sequencing analysis showed that KMT2D-low PDAC had increased suppressive myeloid cells and decreased CD8 T cells. We then generated Ptf1a-Cre; LSL-KrasG12D; Mll4+/+ (KCM+/+) and Ptf1a-Cre; LSL-KrasG12D; Mll4f/f (KCMf/f) mice to model pancreas-specific loss of Mll4 in the background of Kras mutation, a classic PDAC genetic mouse model. All KCM+/+ mice younger than 12 weeks had normal pancreas or low-grade pancreatic intraepithelial neoplasia (PanIN). In contrast, 66% of KCMf/f mice developed high-grade PanIN lesions or PDAC by 12 weeks. Immunohistochemistry staining showed that infiltration of immunosuppressive myeloid cells (tumor-associated macrophages and neutrophils) increased, whereas the presence of CD8+ T cells decreased in Mll4-deficient pancreata. Additionally, myofibroblastic CAFs, defined as PDPN+aSMA+ CAFs, decreased in KCMf/f mice pancreata compared to KCM+/+ pancreata. Mechanistically, we found that KMT2D loss in PDAC cells upregulates the interferon and inflammatory response pathways, including many cytokines and chemokines. These results suggest that KMT2D is a critical tumor suppressor, partly by promoting an immunogenic and tumor-suppressive TME. Cytokines in the interferon and inflammatory response pathways may serve as potential therapeutic targets, especially for treatment-resistant PDACs and KMT2D-deficient PDACs.
 Citation Format: Hong S. Kim, Jing Yang, Shuang Lu, Marina Pasca di Magliano, Kai Ge, Jiaqi Shi. KMT2D loss in pancreatic cancer cells leads to an immunosuppressive tumor microenvironment by upregulating the interferon and inflammatory response pathways [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C037.

Abstract C037: KMT2D loss in pancreatic cancer cells leads to an immunosuppressive tumor microenvironment by upregulating the interferon and inflammatory response pathways

Jing Yang

Papers

Ferulic acid attenuates liver fibrosis and hepatic stellate cell activation via inhibition of TGF-β/Smad signaling pathway.

Icariin Alleviates IL-1β-Induced Matrix Degradation By Activating The Nrf2/ARE Pathway In Human Chondrocytes.

Abstract C037: KMT2D loss in pancreatic cancer cells leads to an immunosuppressive tumor microenvironment by upregulating the interferon and inflammatory response pathways