JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Jia Li,Ying Zhang,Zhe Su,Tangxiaoxiao He,Ze Chen,Zhiwei Pan,Chao Ding,Zhichao Yu,Lei Bi
Ethnopharmacological relevance With a prevalence reaching 80% in terminal cancer patients,Cancer cachexia (CC) manifests as irreversible skeletal muscle wasting. Presently, there exists no effective therapeutic strategy for managing cancer cachexia. Traditional Chinese medicine (TCM) contributes significantly to the management of CC, enhancing quality of life and potentially prolonging survival in affected patients. Bu-zhong-yi-qi decoction (BYD), a classical Chinese formulation, demonstrates therapeutic potential for tumor-associated conditions and muscle-related disorders. However, its precise pharmacological mechanisms remain to be fully elucidated. Aim of the study To systematically investigate the therapeutic effects and underlying mechanisms of BYD on muscle atrophy caused by CC through an integrated approach combining network pharmacology analysis with comprehensive in vivo and in vitro experimental validation. Materials and methods Network pharmacology analysis was employed to recognize bioactive components, potential therapeutic targets, and associated pathways of BYD. Molecular docking simulations were subsequently performed to evaluate the binding affinity between BYD constituents and key target proteins. The skeletal muscle atrophy model of CC in vivo was established by subcutaneous injection of Lewis lung cancer (LLC) cells. The therapeutic efficacy of BYD was systematically evaluated through a comprehensive assessment of multiple parameters, including carcass weight, gastrocnemius muscle mass, histopathological alterations, the cross-sectional area (CSA) of muscle fibers and inflammatory markers. The muscle atrophy model in vitro was established by C2C12 mouse myoblasts and LLC cells to investigate the underlying mechanisms of BYD. qRT-PCR and Western blot analysis were employed to evaluate the regulatory effects of BYD on both mRNA and protein expression levels of MuRF-1, Atrogin-1 and key molecular components of the JNK/c-JUN signaling pathway. Results Network pharmacology analysis identified 146 bioactive components and 331 corresponding potential targets of BYD. KEGG pathway enrichment analysis revealed significant enrichment of BYD component targets in the MAPK signaling pathway. Molecular docking simulations revealed strong binding affinities between BYD's bioactive components and JUN protein. Experiments in vivo demonstrated that BYD could increase the carcass weight, gastrocnemius muscle mass and CSA of muscle fibers in mice with cachexia. Meanwhile, it could increase C2C12 myotube diameters in vitro . Additionally, BYD down-regulated the mRNA and protein expressions of MuRF-1, Atrogin-1 and JNK/c-JUN signaling pathway in vivo . Conclusions BYD might contribute to ameliorate muscle atrophy induced by CC through suppression of JNK/c-JUN signaling pathway and downregulation of muscle atrophy markers MuRF-1 and Atrogin-1. These findings suggested BYD as a potential therapeutic intervention for CC.
研究领域:
中药学
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肿瘤学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Cachexia Sarcopenia and Muscle
·
2022
·Vol. 13
·期 6
·2740-2751
·
IF 12.063
Fengju Li,Ting Luo,Honghui Rong,Lu Lu,Ling Zhang,Chuanfeng Zheng,Dali Yi,Yi Peng,Enyu Lei,Xiaotao Xiong,Fengchao Wang,Jose M. Garcia,Ji-an Chen
Background Di-(2-ethylhexyl) phthalate (DEHP) and its metabolites can cross the placenta and may cause birth defects and developmental disorders. However, whether maternal DEHP exposure affects skeletal muscle development in the offspring and the pathways involved are unknown. This study investigated the effects of maternal DEHP exposure and the contribution of myostatin (MSTN) to skeletal muscle development in the offspring. Methods Pregnant wild-type and muscle-specific myostatin knockout (MSTN KO) C57BL/6 mice were randomized to receive vehicle (corn oil) or 250 mg/kg DEHP by gavage every other day until their pups were weaned (postnatal day 21 [PND21]). Body weights of the offspring mice were measured longitudinally, and their hindleg muscles were harvested at PD21. Also, C2C12 cells were treated with mono-2-ethylhexyl phthalate (MEHP), the primary metabolite of DEHP, and proteolysis, protein synthesis, and myogenesis markers were measured. The contribution of myostatin to maternal DEHP exposure-induced muscle wasting in the offspring was determined. Results Maternal DEHP exposure reduced body weight growth, myofibre size, and muscle mass in the offspring compared to controls (Quad: 2.70 ± 0.1 vs. 3.38 ± 0.23, Gastroc: 2.29 ± 0.09 vs. 2.81 ± 0.14, Tibialis: 1.01 ± 0.07 vs. 1.25 ± 0.11, mg/tibial length in mm, all P < 0.01, n = 35). Maternal DEHP exposure significantly increased Myostatin expression (2.45 ± 0.41 vs. 0.03 ± 0.00 DEHP vs. controls, P < 0.01, n = 5), Atrogin-1(2.68 ± 0.65 vs. 0.63 ± 0.01, P < 0.05, n = 5), MuRF1 (1.56 ± 0.51 vs. 0.31 ± 0.01, P < 0.05, n = 5), and Smad2/3 phosphorylation (4.12 ± 0.35 vs. 0.49 ± 0.18, P < 0.05), and decreased MyoD (0.27 ± 0.01 vs. 1.52 ± 0.01, P < 0.05, n = 5), Myogenin (0.25 ± 0.03 vs. 1.95 ± 0.56, P < 0.05, n = 5), and AKT phosphorylation (4.12 ± 0.35 vs. 1.00 ± 0.06, P < 0.05, n = 5), in skeletal muscle of the offspring in MSTN flox/flox , but not in MSTN KO mice. Maternal DEHP exposure resulted in up-regulation of CCAAT/enhancer-binding protein δ (C/EBPδ, 4.12 ± 0.35 vs. 1.00 ± 0.19, P < 0.05, n = 5) in skeletal muscle of the offspring in MSTN flox/flox and MSTN KO mice (4.12 ± 0.35 vs. 4.35 ± 0.28, P > 0.05, n = 5). In vitro, C/EBPδ silencing abrogated the MEHP-induced increases in Myostatin, MuRF-1, and Atrogin-1 and decreases in MyoD and Myogenin expression. Conclusions Maternal DEHP exposure impairs skeletal muscle development in the offspring by enhancing the C/EBPδ-myostatin pathway in mice.
研究领域:
发育生物学
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毒理学
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肌肉生理学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
EXPERIMENTAL PHYSIOLOGY
·
2021
·Vol. 106
·期 4
·958-971
·
IF 2.969
Xia Yan,Xuli Gao,Qiaohua Niu,Xin Peng,Jie Zhang,Xiufeng Ma,Yanhong Wei,Huiping Wang,Yunfang Gao,Hui Chang
New Findings What is the central question of this study? The aim was to investigate whether diaphragm hypertrophy and gastrocnemius atrophy during hibernation of Daurian ground squirrels involve differential regulation of protein metabolism and regeneration. What is the main finding and its importance? We clarified the differences in protein metabolism and muscle regenerative potential in the diaphragm and gastrocnemius of hibernating ground squirrels, reflecting the different adaptability of muscles. Are differences in the regulation of protein metabolism and regeneration involved in the different phenotypic adaptation mechanisms of muscle hypertrophy and atrophy in hibernators? Two fast-type muscles (diaphragm and gastrocnemius) in summer active and hibernating Daurian ground squirrels were selected to detect changes in cross-sectional area (CSA) and protein expression indicative of protein synthesis metabolism (protein expression of P-Akt, P-mTORC1, P-S6K1 and P-4E-BP1), protein degradation metabolism (MuRF1, atrogin-1, calpain-1, calpain-2, calpastatin, desmin, troponin T, Beclin1 and LC3-II) and muscle regeneration (MyoD, myogenin and myostatin). In the hibernation group compared with the summer active group, the CSA of the diaphragm muscle increased significantly by 26.1%, whereas the CSA of the gastrocnemius muscle decreased significantly by 20.4%. Our study also indicated that increased protein synthesis, decreased protein degradation and increased muscle regenerative potential contributed to diaphragm muscle hypertrophy, whereas decreased protein synthesis, increased protein degradation and decreased muscle regenerative potential contributed to gastrocnemius muscle atrophy. In conclusion, the differences in muscle regeneration and regulatory pattern of protein metabolism might contribute to the different adaptive changes observed in the diaphragm and gastrocnemius muscles of ground squirrels.
研究领域:
生理学
·
生物化学
·
分子生物学
·
动物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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