Geranylgeranylacetone attenuates fibrogenic activity and induces apoptosis in cultured human hepatic stellate cells and reduces liver fibrosis in carbon tetrachloride-treated mice

Senoo, Takemasa; Sasaki, Ryu; Akazawa, Yuko; Ichikawa, Tatsuki; Miuma, Satoshi; Miyaaki, Hisamitsu; Taura, Naota; Nakao, Kazuwa

doi:10.1186/s12876-018-0761-7

Cited by 13 publications

(11 citation statements)

References 29 publications

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“…In many cases, the cytotoxicity of copper complexes originates from the generation of ROS driven by the metal. Meanwhile, ROS plays a significant role in apoptosis activation by many chemotherapeutical drugs and radiation treatments [36, 37]. In the case of abnormal metabolism and signaling, tumor cells are well adapted to the unbalanced redox state through improved antioxidant capacity and oncogenic signaling pathways [22].…”

Section: Resultsmentioning

confidence: 99%

TPP-related mitochondrial targeting copper (II) complex induces p53-dependent apoptosis in hepatoma cells through ROS-mediated activation of Drp1

Guo

Jin

et al. 2019

Cell Commun Signal

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BackgroundIn recent years, copper complexes have gradually become the focus of potential anticancer drugs due to their available redox properties and low toxicity. In this study, a novel mitochondrion-targeting copper (II) complex, [Cu (ttpy-tpp)Br2] Br (simplified as CTB), is first synthesized by our group. CTB with tri-phenyl-phosphine (TPP), a targeting and lipophilic group, can cross the cytoplasmic and mitochondrial membranes of tumor cells. The present study aims to investigate how CTB affects mitochondrial functions and exerts its anti-tumor activity in hepatoma cells.MethodsMultiple molecular experiments including Flow cytometry, Western blot, Immunofluorescence, Tracker staining, Transmission Electron Microscopy and Molecular docking simulation were used to elucidate the underlying mechanisms. Human hepatoma cells were subcutaneously injected into right armpit of male nude mice for evaluating the effects of CTB in vivo.ResultsCTB induced apoptosis via collapse of mitochondrial membrane potential (MMP), ROS production, Bax mitochondrial aggregation as well as cytochrome c release, indicating that CTB-induced apoptosis was associated with mitochondrial pathway in human hepatoma cells. Mechanistic study revealed that ROS-related mitochondrial translocation of p53 was involved in CTB-mediated apoptosis. Simultaneously, elevated mitochondrial Drp1 levels were also observed, and interruption of Drp1 activation played critical role in p53-dependent apoptosis. CTB also strongly suppressed the growth of liver cancer xenografts in vivo.ConclusionIn human hepatoma cells, CTB primarily induces mitochondrial dysfunction and promotes accumulation of ROS, leading to activation of Drp1. These stimulation signals accelerate mitochondrial accumulation of p53 and lead to the eventual apoptosis. Our research shows that CTB merits further evaluation as a chemotherapeutic agent for the treatment of Hepatocellular carcinoma (HCC).

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Section: Resultsmentioning

confidence: 99%

TPP-related mitochondrial targeting copper (II) complex induces p53-dependent apoptosis in hepatoma cells through ROS-mediated activation of Drp1

Guo

Jin

et al. 2019

Cell Commun Signal

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“…These findings indicated that DC-IL10 could inhibit the inflammatory response and the activation of HSCs by regulating the imbalance of Treg/Th17 in liver fibrosis. Inhibiting the activation of HSCs has become a critical treatment strategy for liver fibrosis [26]. Previous investigations have confirmed that the TGF- β /smad signaling pathway plays an important role in the activation of HSCs and is considered as a crucial mechanism during the progress of liver fibrosis [27].…”

Section: Discussionmentioning

confidence: 99%

Interleukin 10 Gene-Modified Bone Marrow-Derived Dendritic Cells Attenuate Liver Fibrosis in Mice by Inducing Regulatory T Cells and Inhibiting the TGF-β/Smad Signaling Pathway

Tang

Yang

et al. 2019

Mediators of Inflammation

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Aim To explore the therapeutic effects and mechanisms of interleukin 10 gene-modified bone marrow-derived dendritic cells (DC-IL10) on liver fibrosis. Methods In vitro, BMDCs were transfected with lentiviral-interleukin 10-GFP (LV-IL10-GFP) at the MOI of 1 : 40. Then, the phenotype (MHCII, CD80, and CD86) and allo-stimulatory ability of DC-IL10 were identified by flow cytometry, and the levels of IL-10 and IL-12 (p70) secreted into the culture supernatants were quantified by ELISA. In vivo, DC-IL10 was injected into mice with CCl4-induced liver fibrosis through the tail vein. Lymphocytes were isolated to investigate the differentiation of T cells, and serum and liver tissue were collected for biochemical, cytokine, histopathologic, immune-histochemical, and Western blot analyzes. Results In vitro, the expressions of MHCII, CD80, and CD86 in DC-IL10 were significantly suppressed, allogeneic CD4+T cells incubated with DC-IL10 showed a lower proliferative response, and the levels of IL-10 and IL-12 (p70) secreted into the DC-IL10 culture supernatants were significantly increased and decreased, respectively. In vivo, regulatory T cells (Tregs) were significantly increased, while ALT, AST, and inflammatory cytokines were significantly reduced in the DC-IL10 treatment group, and the degree of hepatic fibrosis was obviously reversed. The TGF-β/smad pathway was inhibited following DC-IL10 treatment compared to the liver fibrosis group. Conclusion IL-10 genetic modification of BMDCs may maintain DC in the state of tolerance and allow DC to induce T cell hyporesponsiveness or tolerance. DC-IL10 suppressed liver fibrosis by inducing Treg production and inhibiting the TGF-β/smad signaling pathway.

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“…We previously reported that GGA induces endoplasmic reticulum (ER) stress in hepatoma cells and hepatic stellate cells 22 . Additionally, it has been reported that ER stress reduces hepatic transcriptional factors 23 .…”

Section: Resultsmentioning

confidence: 99%

“…30 Senoo et al also reported that GGA induced ER stress in hepatoma and stellate cells. 22 Additionally, Vachirayonsti et al reported that HNF4α was downregulated during ER stress. 23 Similarly, in our study, GGA treatment induced ER stress.…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported that GGA induces endoplasmic reticulum (ER) stress in hepatoma cells and hepatic stellate cells. 22 Additionally, it has been reported that ER stress reduces hepatic transcriptional factors. 23 We speculated that HBV promoter and enhancer activity is inhibited by comprehensive suppression of transcriptional factors through ER stress caused by GGA treatment.…”

Section: Geranylgeranylacetone Treatment Decreases Hepatitis B Virus Promoter and Enhancer Activitiesmentioning

confidence: 99%

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Geranylgeranylacetone decreases the production of hepatitis B virus‐related antigen by comprehensive downregulation of mRNA transcription activity

Haraguchi

Miuma

Yamamoto

et al. 2021

J of Gastro and Hepatol

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Background and Aim: Elimination of hepatitis B virus (HBV) is infrequently achieved with current therapies. Therefore, more effective anti-HBV therapy is needed. We previously reported that geranylgeranylacetone (GGA) showed anti-hepatitis C virus activity in human hepatoma cells. In this study, we examined the anti-HBV activity of GGA. Methods: We used HepG2.2.15.7 cells, PXB cells infected with HBV, Huh7 cells transfected with linear HBV, and PLC/PRF/5 cells as HBV-infected hepatocyte models. After GGA treatment, HBV-related antigen was measured by chemiluminescent immunoassay. HBV-related mRNA was examined by Northern blot. cccDNA and endoplasmic reticulum stress markers were measured by real-time polymerase chain reaction. The activities of HBV promoters and enhancer regions were examined using luciferase vectors. Results: After GGA treatment, hepatitis B surface antigen and hepatitis B e antigen secretion was decreased in all HBV-infected hepatocyte models. HBV-related mRNA was also decreased by GGA treatment, although cccDNA levels were not affected. Additionally, the activity of HBV S1 and S2 promoter region and Enhancer 1/Enhancer 2/core promoter region was reduced by GGA treatment. The mRNA expression of the main transcription factors, hepatocyte nuclear factor 3 and 4 and CCAAT/enhancer binding protein, was also decreased. Further, the expression levels of endoplasmic reticulum stress markers were increased by GGA treatment, which reflected the change in HBV-related antigen secretion. Conclusions: Geranylgeranylacetone treatment reduces HBV-related protein levels by suppressing comprehensive downregulation of HBV promoter and enhancer activity, which might be caused by decreased hepatic transcription factor expression. GGA treatment may enhance anti-HBV effects in combination with other therapies.

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Geranylgeranylacetone attenuates fibrogenic activity and induces apoptosis in cultured human hepatic stellate cells and reduces liver fibrosis in carbon tetrachloride-treated mice

Cited by 13 publications

References 29 publications

TPP-related mitochondrial targeting copper (II) complex induces p53-dependent apoptosis in hepatoma cells through ROS-mediated activation of Drp1

TPP-related mitochondrial targeting copper (II) complex induces p53-dependent apoptosis in hepatoma cells through ROS-mediated activation of Drp1

Interleukin 10 Gene-Modified Bone Marrow-Derived Dendritic Cells Attenuate Liver Fibrosis in Mice by Inducing Regulatory T Cells and Inhibiting the TGF-β/Smad Signaling Pathway

Geranylgeranylacetone decreases the production of hepatitis B virus‐related antigen by comprehensive downregulation of mRNA transcription activity

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