Protective effects of kaerophyllin against liver fibrogenesis in rats

et al. 2014

Pharmaceutical Biology

Context: One approach to protect against liver fibrosis is the use of herb-derived natural compounds, such as hydroxysafflor yellow A (HSYA). The antifibrosis effect of HYSA against liver fibrosis has been investigated; however, its mechanisms have not yet been entirely revealed. Objectives: To study the protective effects of HSYA on liver fibrosis induced by carbon tetrachloride (CCl 4 ) and a high-fat diet (HFD), and to determine the mechanism of action of HSYA. Materials and methods: CCl 4 and HFD were used to mimic liver fibrosis in rats, and serum biochemical indicators were determined. The antifibrosis effects of HSYA were evaluated and its mechanisms were investigated by histopathological analysis, immunohistochemical staining, enzyme-linked immunosorbent assays, real-time-PCR, and western blotting. Results: HSYA reduced CCl 4 -and HFD-mediated liver fibrosis and ameliorated serum biochemical indicator, downregulated the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) (0.31 ± 0.03 protein, 0.59 ± 0.02 mRNA) and transformin growth factor-b1 (TGF-b1) (0.81 ± 0.02 protein, 0.58 ± 0.04 mRNA), and upregulated the expression of peroxisome proliferator-activated receptor-g (PPAR-g) (1.57 ± 0.13 protein, 2.48 ± 0.19 mRNA) and matrix metallopeptidases-2 (MMP-2) (2.31 ± 0.16 protein, 2.79 ± 0.22 mRNA) (p50.01, versus model group). These effects were significantly attenuated by PPAR-g antagonist GW9662 via blocking the phosphorylation of p38 MAPK. Discussion and conclusion: These data demonstrate a novel role for HSYA in inhibiting CCl 4 -and HFD-mediated liver fibrosis, and reveal that PPAR-g and p38 MAPK signaling play pivotal roles in the prevention of liver fibrosis induced by CCl 4 and HFD.

Section: Introductionmentioning

confidence: 99%

Hydroxysafflor yellow A suppresses liver fibrosis induced by carbon tetrachloride with high-fat diet by regulating PPAR-γ/p38 MAPK signaling

et al. 2014

Pharmaceutical Biology

“…Synthetic PPARγ ligands such as 15d-PGJ2 and all-trans retinoic acid (ATRA) inhibited the pro-fibrogenic and pro-inflammatory effects of HSCs (Sharvit et al 2013). In addition, kaerophyllin, a lignan, isolated from traditional Chinese herbs, up-regulated PPARγ expression, inhibited HSC activation in vitro, and protected rat livers from TAA-induced injury and fibrogenesis by inhibiting liver inflammation (Lee et al 2012). A clinical trial indicated that PPARγ-agonists thiazolidinediones significantly improved lobular inflammation, steatosis, and inflammation in patients with NASH (Boettcher et al 2012).…”

Section: Down-regulating Myofibroblast Activation and Ecm Productionmentioning

confidence: 97%

Strategies to prevent and reverse liver fibrosis in humans and laboratory animals

Chen

2015

Arch Toxicol

Liver fibrosis results from chronic damage to the liver in conjunction with various pathways and is mediated by a complex microenvironment. Based on clinical observations, it is now evident that fibrosis is a dynamic, bidirectional process with an inherent capacity for recovery and remodeling. The major mechanisms involved in liver fibrosis include the repetitive injury of hepatocytes, the activation of the inflammatory response after injury stimulation, and the activation and proliferation of hepatic stellate cells (HSCs), which represents the major extracellular matrix (ECM)-producing cells, stimulated by hepatocyte injury and inflammation. The microenvironment in the liver is synergistically regulated abnormal ECM deposition, scar formation, angiogenesis, and fibrogenesis. Moreover, recent studies have clarified novel mechanism in fibrosis such as epigenetic regulation of HSCs, the leptin and PPARγ pathways, the coagulation system, and even autophagy. Uncovering the mechanisms of liver fibrogenesis provides a basis to develop potential therapies to reverse and treat the fibrotic response, thereby improving the outcomes of patients with chronic liver disease. Although both scientific and clinical challenges remain, emerging studies attempt to reveal the ideal anti-fibrotic drug that could be easily delivered to the liver with high specificity and low toxicity. This review highlights the mechanisms, including novel pathways underlying fibrogenesis that may be translated into preventive and treatment strategies, reviews both current and novel agents that target specific pathways or multiple targets, and discusses novel drug delivery systems such as nanotechnology that can be applied in the treatment of liver fibrosis. In addition, we also discuss some current treatment strategies that are being applied in animal models and in clinical trials.

“…For example, intraperitoneal injection of TAA for 6 weeks increased fibrous septa, portal tract, and liver sinusoids as well as α -SMA staining of liver cells, the same as in the CCl 4 model. In the TAA model, administration of kaerophyllin from Bupleurum scorzonerifolium reversed histopathological changes and further reduced the levels of proinflammatory cytokines TNF- α , IL-1 β , and MCP-1 [ 34 ].…”

Section: Animal Models For Liver Fibrosis and Cirrhosismentioning

confidence: 99%

Preclinical Models for Investigation of Herbal Medicines in Liver Diseases: Update and Perspective

Tan

San‐Marina

Evidence-Based Complementary and Alternative Medicine

et al. 2016

Liver disease results from a dynamic pathological process associated with cellular and genetic alterations, which may progress stepwise to liver dysfunction. Commonly, liver disease begins with hepatocyte injury, followed by persistent episodes of cellular regeneration, inflammation, and hepatocyte death that may ultimately lead to nonreversible liver failure. For centuries, herbal remedies have been used for a variety of liver diseases and recent studies have identified the active compounds that may interact with liver disease-associated targets. Further study on the herbal remedies may lead to the formulation of next generation medicines with hepatoprotective, antifibrotic, and anticancer properties. Still, the pharmacological actions of vast majority of herbal remedies remain unknown; thus, extensive preclinical studies are important. In this review, we summarize progress made over the last five years of the most commonly used preclinical models of liver diseases that are used to screen for curative herbal medicines for nonalcoholic fatty liver disease, liver fibrosis/cirrhosis, and liver. We also summarize the proposed mechanisms associated with the observed liver-protective, antifibrotic, and anticancer actions of several promising herbal medicines and discuss the challenges faced in this research field.