Jian Pi Sheng Sui Gao (JPSSG) alleviation of skeletal myoblast cell apoptosis, oxidative stress, and mitochondrial dysfunction to improve cancer-related fatigue in an AMPK-SIRT1- and HIF-1-dependent manner

Min Xiao; Wei Guo; Chi Zhang; Yukun Zhu; Zhiling Li; Cui Shao; Jiling Jiang; Zhenjiang Yang; Jianyong Zhang; Lizhu Lin

doi:10.21037/atm-22-6611

Jian Pi Sheng Sui Gao (JPSSG) alleviation of skeletal myoblast cell apoptosis, oxidative stress, and mitochondrial dysfunction to improve cancer-related fatigue in an AMPK-SIRT1- and HIF-1-dependent manner

Ann Transl Med. 2023 Feb 15;11(3):156. doi: 10.21037/atm-22-6611.

Authors

Min Xiao^#^{1

2}, Wei Guo^#¹, Chi Zhang¹, Yukun Zhu³, Zhiling Li², Cui Shao¹, Jiling Jiang⁴, Zhenjiang Yang⁵, Jianyong Zhang², Lizhu Lin¹

Affiliations

¹ Clinical Discipline of Integrated Chinese and Western Medicine, The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China.
² Department of Rheumatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China.
³ Department of Science and Education, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China.
⁴ Department of General Surgery, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China.
⁵ Department of Oncology and Hematology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China.

^# Contributed equally.

Abstract

Background: Jian Pi Sheng Sui Gao (JPSSG), a Chinese traditional herbal paste, possesses certain efficacy in patients with cancer-related fatigue (CRF); however, its related mechanism remains unclear. Hence, network pharmacology analysis, followed by in vivo and in vitro experiments were conducted in this study with the aim to evaluate the effect of JPSSG on CRF and clarify its potential mechanism.

Methods: Network pharmacology analysis was performed. Subsequently, 12 mice were injected with CT26 cells to establish CRF mouse models and randomly divided into a model group (n=6) and JPSSG group (n=6); meanwhile, another 6 normal mice served as a control group. Then, 3.0 g/kg JPSSG was given to mice in JPSSG group for 15 days, while mice in the n control and model groups received phosphate-buffered saline (PBS) of the same volume for 15 days. For the in vitro experiment, CT26 conditioned medium (CM) was established; meanwhile, the mitochondrial damage model was constructed through C2C12 myotubes stimulated with H₂O₂. C2C12 myotubes were divided into 5 groups: control group (without treatment), CM group, CM + JPSSG group, H₂O₂ group, and H₂O₂ + JGSSP group.

Results: Network pharmacology analysis identified 87 bioactive compounds and 132 JPSSG-CRF interaction targets. Moreover, according to the Kyoto Encyclopedia of Genes and Genomes enrichment analysis and the subsequent in vivo and in vitro experiments, JPSSG activated adenosine 5'-monophosphate-activated protein kinase-silent-information-regulator factor 2-related-enzyme 1 (AMPK-SIRT1) and hypoxia-inducible factor-1 (HIF-1) signaling pathways during CRF. Moreover, the in vivo experiment showed that JPSSG attenuated CRF in mice, reflected by increased distance traveled, mobile time in open field test, and swimming time in exhaustive swimming test, and decreased absolute rest time and tail suspension test in the JPSSG group (vs. model group). Furthermore, JPSSG upregulated gastrocnemius weight, adenosine triphosphate (ATP), superoxide dismutase (SOD), and the cross-sectional area of the gastrocnemius. With regard to in vitro study, JPSSG elevated cell viability, B-cell lymphoma-2, ATP, SOD, and mitochondrial membrane potential, while it decreased apoptosis rate, cleaved-caspase3, malondialdehyde, and reactive oxygen species in C2C12 myotubes.

Conclusions: JPSSG ameliorates CRF via alleviating skeletal myoblast cell apoptosis, oxidative stress, and mitochondrial dysfunction in an AMPK-SIRT1- and HIF-1-dependent manner.

Keywords: Jian Pi Sheng Sui Gao (JPSSG); cancer-related fatigue (CRF); molecular mechanism; network pharmacology; oxidative stress.