Mechanism Study of GanDouLing Mitigating Liver Fibrosis in Wilson’s Disease via Regulating the PI3K/AKT/mTOR Pathway to Activate Autophagy

Shao-Peng Huang; Sen Chen; Huan Wu; An Zhou; Huai-Zhou Jiang; Hai Bian; Yun-Lai Wang; Zheng-Rong Zhang; Yi-Kang Cai; Hui Jiang; Peng Wu

doi:doi:10.11648/j.ajcem.20231104.12

Research Article |

Mechanism Study of GanDouLing Mitigating Liver Fibrosis in Wilson’s Disease via Regulating the PI3K/AKT/mTOR Pathway to Activate Autophagy

Shao-Peng Huang, Sen Chen, Huan Wu, An Zhou, Huai-Zhou Jiang, Hai Bian, Yun-Lai Wang, Zheng-Rong Zhang, Yi-Kang Cai, Hui Jiang, Peng Wu

Published in American Journal of Clinical and Experimental Medicine (Volume 11, Issue 4)

Received: 27 September 2023 Accepted: 25 October 2023 Published: 30 October 2023

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Abstract

The hepatic copper accumulation characteristic of Wilson's disease (WD) leads to activation of hepatic stellate cells, extracellular matrix deposition, and the progression to liver fibrosis (LF), with specific therapeutic interventions for this condition notably deficient. Increasing evidence suggests the potential utility of GanDouLing (GDL) in addressing WD-related LF. In this study, the pharmacological effects of GDL on WD and LF were assessed by establishing a copper-induced human hepatic stellate cell (LX-2) model and elucidating potential mechanisms underlying GDL treatment. The findings indicate that GDL treatment significantly attenuates the viability of copper-induced LX-2 cells and reduces the expression of fibrotic markers. This inhibitory effect is mediated through the PAM pathway, as it can be reversed by activators such as IGF-1 or MHY1485. Furthermore, GDL treatment downregulates critical components of the PAM pathway at both mRNA and protein levels. Molecular docking simulations further confirm the strong affinity and stable binding between active constituents of GDL, such as luteolin and vestitol, and their target proteins (AKT1, PIK3CA, mTOR). In copper-induced LX-2 cells, GDL treatment upregulates autophagic indicators, including LC3, Beclin-1, and AO, while downregulating p62. TEM experiments reveal that GDL treatment increases the presence of autophagosomes in copper-induced LX-2 cells, thereby ameliorating mitochondrial damage. In conclusion, GDL exerts its inhibitory effects on copper-induced LX-2 cell activation by downregulating the PAM pathway. These findings provide a novel approach for addressing LF related to WD and support the utilization of herbal-based supplements and alternative therapies.

Published in	American Journal of Clinical and Experimental Medicine (Volume 11, Issue 4)
DOI	10.11648/j.ajcem.20231104.12
Page(s)	73-85
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2024. Published by Science Publishing Group

Keywords

GanDouLing, Wilson Disease-Associated Liver Fibrosis, Autophagy, PI3K/AKT/mTOR Pathway

References

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Cite This Article

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APA Style

Shao-Peng Huang, Sen Chen, Huan Wu, An Zhou, Huai-Zhou Jiang, et al. (2023). Mechanism Study of GanDouLing Mitigating Liver Fibrosis in Wilson’s Disease via Regulating the PI3K/AKT/mTOR Pathway to Activate Autophagy. American Journal of Clinical and Experimental Medicine, 11(4), 73-85. https://doi.org/10.11648/j.ajcem.20231104.12

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ACS Style

Shao-Peng Huang; Sen Chen; Huan Wu; An Zhou; Huai-Zhou Jiang, et al. Mechanism Study of GanDouLing Mitigating Liver Fibrosis in Wilson’s Disease via Regulating the PI3K/AKT/mTOR Pathway to Activate Autophagy. Am. J. Clin. Exp. Med. 2023, 11(4), 73-85. doi: 10.11648/j.ajcem.20231104.12

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AMA Style

Shao-Peng Huang, Sen Chen, Huan Wu, An Zhou, Huai-Zhou Jiang, et al. Mechanism Study of GanDouLing Mitigating Liver Fibrosis in Wilson’s Disease via Regulating the PI3K/AKT/mTOR Pathway to Activate Autophagy. Am J Clin Exp Med. 2023;11(4):73-85. doi: 10.11648/j.ajcem.20231104.12

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@article{10.11648/j.ajcem.20231104.12,
  author = {Shao-Peng Huang and Sen Chen and Huan Wu and An Zhou and Huai-Zhou Jiang and Hai Bian and Yun-Lai Wang and Zheng-Rong Zhang and Yi-Kang Cai and Hui Jiang and Peng Wu},
  title = {Mechanism Study of GanDouLing Mitigating Liver Fibrosis in Wilson’s Disease via Regulating the PI3K/AKT/mTOR Pathway to Activate Autophagy},
  journal = {American Journal of Clinical and Experimental Medicine},
  volume = {11},
  number = {4},
  pages = {73-85},
  doi = {10.11648/j.ajcem.20231104.12},
  url = {https://doi.org/10.11648/j.ajcem.20231104.12},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ajcem.20231104.12},
  abstract = {The hepatic copper accumulation characteristic of Wilson's disease (WD) leads to activation of hepatic stellate cells, extracellular matrix deposition, and the progression to liver fibrosis (LF), with specific therapeutic interventions for this condition notably deficient. Increasing evidence suggests the potential utility of GanDouLing (GDL) in addressing WD-related LF. In this study, the pharmacological effects of GDL on WD and LF were assessed by establishing a copper-induced human hepatic stellate cell (LX-2) model and elucidating potential mechanisms underlying GDL treatment. The findings indicate that GDL treatment significantly attenuates the viability of copper-induced LX-2 cells and reduces the expression of fibrotic markers. This inhibitory effect is mediated through the PAM pathway, as it can be reversed by activators such as IGF-1 or MHY1485. Furthermore, GDL treatment downregulates critical components of the PAM pathway at both mRNA and protein levels. Molecular docking simulations further confirm the strong affinity and stable binding between active constituents of GDL, such as luteolin and vestitol, and their target proteins (AKT1, PIK3CA, mTOR). In copper-induced LX-2 cells, GDL treatment upregulates autophagic indicators, including LC3, Beclin-1, and AO, while downregulating p62. TEM experiments reveal that GDL treatment increases the presence of autophagosomes in copper-induced LX-2 cells, thereby ameliorating mitochondrial damage. In conclusion, GDL exerts its inhibitory effects on copper-induced LX-2 cell activation by downregulating the PAM pathway. These findings provide a novel approach for addressing LF related to WD and support the utilization of herbal-based supplements and alternative therapies.},
 year = {2023}
}

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TY  - JOUR
T1  - Mechanism Study of GanDouLing Mitigating Liver Fibrosis in Wilson’s Disease via Regulating the PI3K/AKT/mTOR Pathway to Activate Autophagy
AU  - Shao-Peng Huang
AU  - Sen Chen
AU  - Huan Wu
AU  - An Zhou
AU  - Huai-Zhou Jiang
AU  - Hai Bian
AU  - Yun-Lai Wang
AU  - Zheng-Rong Zhang
AU  - Yi-Kang Cai
AU  - Hui Jiang
AU  - Peng Wu
Y1  - 2023/10/30
PY  - 2023
N1  - https://doi.org/10.11648/j.ajcem.20231104.12
DO  - 10.11648/j.ajcem.20231104.12
T2  - American Journal of Clinical and Experimental Medicine
JF  - American Journal of Clinical and Experimental Medicine
JO  - American Journal of Clinical and Experimental Medicine
SP  - 73
EP  - 85
PB  - Science Publishing Group
SN  - 2330-8133
UR  - https://doi.org/10.11648/j.ajcem.20231104.12
AB  - The hepatic copper accumulation characteristic of Wilson's disease (WD) leads to activation of hepatic stellate cells, extracellular matrix deposition, and the progression to liver fibrosis (LF), with specific therapeutic interventions for this condition notably deficient. Increasing evidence suggests the potential utility of GanDouLing (GDL) in addressing WD-related LF. In this study, the pharmacological effects of GDL on WD and LF were assessed by establishing a copper-induced human hepatic stellate cell (LX-2) model and elucidating potential mechanisms underlying GDL treatment. The findings indicate that GDL treatment significantly attenuates the viability of copper-induced LX-2 cells and reduces the expression of fibrotic markers. This inhibitory effect is mediated through the PAM pathway, as it can be reversed by activators such as IGF-1 or MHY1485. Furthermore, GDL treatment downregulates critical components of the PAM pathway at both mRNA and protein levels. Molecular docking simulations further confirm the strong affinity and stable binding between active constituents of GDL, such as luteolin and vestitol, and their target proteins (AKT1, PIK3CA, mTOR). In copper-induced LX-2 cells, GDL treatment upregulates autophagic indicators, including LC3, Beclin-1, and AO, while downregulating p62. TEM experiments reveal that GDL treatment increases the presence of autophagosomes in copper-induced LX-2 cells, thereby ameliorating mitochondrial damage. In conclusion, GDL exerts its inhibitory effects on copper-induced LX-2 cell activation by downregulating the PAM pathway. These findings provide a novel approach for addressing LF related to WD and support the utilization of herbal-based supplements and alternative therapies.
VL  - 11
IS  - 4
ER  -

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Author Information

Shao-Peng Huang

School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
Sen Chen

School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
Huan Wu

The Experimental Research Center, Anhui University of Chinese Medicine, Hefei, China
An Zhou

The Experimental Research Center, Anhui University of Chinese Medicine, Hefei, China
Huai-Zhou Jiang

The Experimental Research Center, Anhui University of Chinese Medicine, Hefei, China
Hai Bian

College of Integrated Traditional Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
Yun-Lai Wang

School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
Zheng-Rong Zhang

The Experimental Research Center, Anhui University of Chinese Medicine, Hefei, China
Yi-Kang Cai

College of Integrated Traditional Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
Hui Jiang

Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
Peng Wu

College of Integrated Traditional Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China

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APA Style

Shao-Peng Huang, Sen Chen, Huan Wu, An Zhou, Huai-Zhou Jiang, et al. (2023). Mechanism Study of GanDouLing Mitigating Liver Fibrosis in Wilson’s Disease via Regulating the PI3K/AKT/mTOR Pathway to Activate Autophagy. American Journal of Clinical and Experimental Medicine, 11(4), 73-85. https://doi.org/10.11648/j.ajcem.20231104.12

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ACS Style

Shao-Peng Huang; Sen Chen; Huan Wu; An Zhou; Huai-Zhou Jiang, et al. Mechanism Study of GanDouLing Mitigating Liver Fibrosis in Wilson’s Disease via Regulating the PI3K/AKT/mTOR Pathway to Activate Autophagy. Am. J. Clin. Exp. Med. 2023, 11(4), 73-85. doi: 10.11648/j.ajcem.20231104.12

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AMA Style

Shao-Peng Huang, Sen Chen, Huan Wu, An Zhou, Huai-Zhou Jiang, et al. Mechanism Study of GanDouLing Mitigating Liver Fibrosis in Wilson’s Disease via Regulating the PI3K/AKT/mTOR Pathway to Activate Autophagy. Am J Clin Exp Med. 2023;11(4):73-85. doi: 10.11648/j.ajcem.20231104.12

Copy | Download

@article{10.11648/j.ajcem.20231104.12,
  author = {Shao-Peng Huang and Sen Chen and Huan Wu and An Zhou and Huai-Zhou Jiang and Hai Bian and Yun-Lai Wang and Zheng-Rong Zhang and Yi-Kang Cai and Hui Jiang and Peng Wu},
  title = {Mechanism Study of GanDouLing Mitigating Liver Fibrosis in Wilson’s Disease via Regulating the PI3K/AKT/mTOR Pathway to Activate Autophagy},
  journal = {American Journal of Clinical and Experimental Medicine},
  volume = {11},
  number = {4},
  pages = {73-85},
  doi = {10.11648/j.ajcem.20231104.12},
  url = {https://doi.org/10.11648/j.ajcem.20231104.12},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ajcem.20231104.12},
  abstract = {The hepatic copper accumulation characteristic of Wilson's disease (WD) leads to activation of hepatic stellate cells, extracellular matrix deposition, and the progression to liver fibrosis (LF), with specific therapeutic interventions for this condition notably deficient. Increasing evidence suggests the potential utility of GanDouLing (GDL) in addressing WD-related LF. In this study, the pharmacological effects of GDL on WD and LF were assessed by establishing a copper-induced human hepatic stellate cell (LX-2) model and elucidating potential mechanisms underlying GDL treatment. The findings indicate that GDL treatment significantly attenuates the viability of copper-induced LX-2 cells and reduces the expression of fibrotic markers. This inhibitory effect is mediated through the PAM pathway, as it can be reversed by activators such as IGF-1 or MHY1485. Furthermore, GDL treatment downregulates critical components of the PAM pathway at both mRNA and protein levels. Molecular docking simulations further confirm the strong affinity and stable binding between active constituents of GDL, such as luteolin and vestitol, and their target proteins (AKT1, PIK3CA, mTOR). In copper-induced LX-2 cells, GDL treatment upregulates autophagic indicators, including LC3, Beclin-1, and AO, while downregulating p62. TEM experiments reveal that GDL treatment increases the presence of autophagosomes in copper-induced LX-2 cells, thereby ameliorating mitochondrial damage. In conclusion, GDL exerts its inhibitory effects on copper-induced LX-2 cell activation by downregulating the PAM pathway. These findings provide a novel approach for addressing LF related to WD and support the utilization of herbal-based supplements and alternative therapies.},
 year = {2023}
}

Copy | Download

TY  - JOUR
T1  - Mechanism Study of GanDouLing Mitigating Liver Fibrosis in Wilson’s Disease via Regulating the PI3K/AKT/mTOR Pathway to Activate Autophagy
AU  - Shao-Peng Huang
AU  - Sen Chen
AU  - Huan Wu
AU  - An Zhou
AU  - Huai-Zhou Jiang
AU  - Hai Bian
AU  - Yun-Lai Wang
AU  - Zheng-Rong Zhang
AU  - Yi-Kang Cai
AU  - Hui Jiang
AU  - Peng Wu
Y1  - 2023/10/30
PY  - 2023
N1  - https://doi.org/10.11648/j.ajcem.20231104.12
DO  - 10.11648/j.ajcem.20231104.12
T2  - American Journal of Clinical and Experimental Medicine
JF  - American Journal of Clinical and Experimental Medicine
JO  - American Journal of Clinical and Experimental Medicine
SP  - 73
EP  - 85
PB  - Science Publishing Group
SN  - 2330-8133
UR  - https://doi.org/10.11648/j.ajcem.20231104.12
AB  - The hepatic copper accumulation characteristic of Wilson's disease (WD) leads to activation of hepatic stellate cells, extracellular matrix deposition, and the progression to liver fibrosis (LF), with specific therapeutic interventions for this condition notably deficient. Increasing evidence suggests the potential utility of GanDouLing (GDL) in addressing WD-related LF. In this study, the pharmacological effects of GDL on WD and LF were assessed by establishing a copper-induced human hepatic stellate cell (LX-2) model and elucidating potential mechanisms underlying GDL treatment. The findings indicate that GDL treatment significantly attenuates the viability of copper-induced LX-2 cells and reduces the expression of fibrotic markers. This inhibitory effect is mediated through the PAM pathway, as it can be reversed by activators such as IGF-1 or MHY1485. Furthermore, GDL treatment downregulates critical components of the PAM pathway at both mRNA and protein levels. Molecular docking simulations further confirm the strong affinity and stable binding between active constituents of GDL, such as luteolin and vestitol, and their target proteins (AKT1, PIK3CA, mTOR). In copper-induced LX-2 cells, GDL treatment upregulates autophagic indicators, including LC3, Beclin-1, and AO, while downregulating p62. TEM experiments reveal that GDL treatment increases the presence of autophagosomes in copper-induced LX-2 cells, thereby ameliorating mitochondrial damage. In conclusion, GDL exerts its inhibitory effects on copper-induced LX-2 cell activation by downregulating the PAM pathway. These findings provide a novel approach for addressing LF related to WD and support the utilization of herbal-based supplements and alternative therapies.
VL  - 11
IS  - 4
ER  -

Copy | Download