Estrogen Deficiency Potentiates Thioacetamide-Induced Hepatic Fibrosis in Sprague-Dawley Rats

Park

et al. 2019

Biology

Recent studies showed that melatonin, a well-known pineal hormone that modulates the circadian rhythm, exerts beneficial effects against liver fibrosis. However, mechanisms for its protective action against the fibrotic processes remain incompletely understood. Here, we aimed to explore the effects of the hormone on transforming growth factor-β1 (TGF-β1)-stimulated epithelial–mesenchymal transition (EMT) in AML12 hepatocytes. Pretreatment with melatonin dose-dependently reversed downregulation of an epithelial marker and upregulation of mesenchymal markers after TGF-β1 stimulation. Additionally, melatonin dose-dependently suppressed an increased phosphorylation of Smad2/3 after TGF-β1 treatment. Besides the canonical Smad signaling pathway, an increase in phosphorylation of extracellular signal-regulated kinase 1/2 and p38 was also dose-dependently attenuated by melatonin. The suppressive effect of the hormone on EMT stimulated by TGF-β1 was not affected by luzindole, an antagonist of melatonin membrane receptors, suggesting that its membrane receptors are not required for the inhibitory action of melatonin. Moreover, melatonin suppressed elevation of intracellular reactive oxygen species (ROS) levels in TGF-β1-treated cells. Finally, TGF-β1-stimulated EMT was also inhibited by the antioxidant N-acetylcysteine. Collectively, these results suggest that melatonin prevents TGF-β1-stimulated EMT through suppression of Smad and mitogen-activated protein kinase signaling cascades by deactivating ROS-dependent mechanisms in a membrane receptor-independent manner.

Section: Discussionsupporting

confidence: 58%

Melatonin Inhibits Transforming Growth Factor-β1-Induced Epithelial–Mesenchymal Transition in AML12 Hepatocytes

Park

et al. 2019

Biology

“…Recently, it has been shown that estradiol influences HSC transdifferentiation/activation. In various models of liver fibrosis caused by carbon tetrachloride (CCl 4 ), dimethylnitrosamine (DMN), or thioacetamide (TAA), treatment with estradiol inhibited HSC proliferation/activation and decreased collagen production [162,163,164,165]. In addition, activated HSCs incubated with estradiol exhibited less myofibroblast-like phenotypes compared with those of vehicle-treated cells [166].…”

Section: Gender Differences In Nafld/nashmentioning

confidence: 99%

Potential Therapeutic Application of Estrogen in Gender Disparity of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis

Lee

Jung

2019

Cells

Nonalcoholic fatty liver disease (NAFLD) caused by fat accumulation in the liver is globally the most common cause of chronic liver disease. Simple steatosis can progress to nonalcoholic steatohepatitis (NASH), a more severe form of NAFLD. The most potent driver for NASH is hepatocyte death induced by lipotoxicity, which triggers inflammation and fibrosis, leading to cirrhosis and/or liver cancer. Despite the significant burden of NAFLD, there is no therapy for NAFLD/NASH. Accumulating evidence indicates gender-related NAFLD progression. A higher incidence of NAFLD is found in men and postmenopausal women than premenopausal women, and the experimental results, showing protective actions of estradiol in liver diseases, suggest that estrogen, as the main female hormone, is associated with the progression of NAFLD/NASH. However, the mechanism explaining the functions of estrogen in NAFLD remains unclear because of the lack of reliable animal models for NASH, the imbalance between the sexes in animal experiments, and subsequent insufficient results. Herein, we reviewed the pathogenesis of NAFLD/NASH focused on gender and proposed a feasible association of estradiol with NAFLD/NASH based on the findings reported thus far. This review would help to expand our knowledge of the gender differences in NAFLD and for developing gender-based treatment strategies for NAFLD/NASH.

“…According to TAA treatment in ovary, accumulation of ECM in stromal cells nearby follicles is indicated in Masson Goldner trichrome staining and also based on decreased total number of follicles and increased number of atretic follicles ( Figure 1 ). Previously, TAA treated ovary induced oxidative stress levels, resulting in imbalance of sex hormones [ 6 ]. ROS acts as an important signaling factor in granulosa cells, but also causes apoptosis when it exceeds normal level [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…Thioacetamide (TAA) is a thinosulfur widely known as hepatotoxin that triggers liver damage by generating ROS [ 5 ]. Oxidative stress in liver induced by TAA can cause a wide spectrum ranging from acute hepatitis to cirrhosis [ 6 ]. TAA is metabolized by hepatic cytochrome (CYP) 450 and generate TAA S-dioxide which is the active product that produce reactive oxygen species (ROS) factors and production of TGF-ß [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Human placenta-derived mesenchymal stem cells trigger repair system in TAA-injured rat model via antioxidant effect

Song

et al. 2020

Aging

Oxidative stress induces damages of various cell types or tissues through a repetitive imbalance between the systemic manifestation of reactive oxygen species (ROS) and detoxification of the reactive intermediates. Thioacetamide (TAA) is well known for causing several degenerative diseases by oxidative stress. However, study of the antioxidant mechanisms of stem cells in TAA-injured rat model is insufficient. Therefore, we investigated the effect of placenta-derived mesenchymal stem cells (PD-MSCs) transplantation on liver and ovary of TAA-injured rat models to study the antioxidant effect in degenerative diseases. In TAA-injured rat model, PD-MSCs engrafted into damaged organ including liver and ovary in PD-MSCs transplanted groups (Tx) compared with non-transplanted groups (NTx) (* p <0.05). Transplanted PD-MSCs reduced inflammatory factors and upregulated oxidative stress factors in Tx compared with NTx (* p <0.05). Also, transplanted PD-MSCs enhanced antioxidants factors and organ functional restoration factors in Tx compared with NTx. These data show that PD-MSC transplantation triggers the regeneration of organ (e.g., liver and ovary) damaged by oxidative stress from TAA treatment via activating antioxidant factors. Therefore, these data suggest the therapeutic potential via antioxidant effect and help understand the therapeutic mechanism of PD-MSCs in damaged tissues such as in liver and reproductive system.