Autophagy
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2025
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IF 14.3
Minghong Leng,Fenghe Yang,Junhui Zhao,Yufei Xiong,Yiqing Zhou,Mingyang Zhao,Shi Jia,Limei Liu,Qiaoxia Zheng,Lebin Gan,Jingjing Ye,Ming Zheng
Endurance exercise triggers adaptive responses especially in slow-twitch myofibers of skeletal muscles, leading to the remodeling of myofiber structure and the mitochondrial network. However, molecular mechanisms underlying these adaptive responses, with a focus on the fiber type-specific perspective, remains largely unknown. In this study we analyzed the alterations of transcriptomics and metabolomics in distinct skeletal myofibers in response to endurance exercise. We determined that genes associated with sphingolipid metabolism, namely those encoding SPHK1, S1PR1, and S1PR2, are enriched in slow-twitch but not fast-twitch myofibers from both mouse and human skeletal muscles, and found that the SPHK1-S1PR pathway is essential for adaptive responses of slow-twitch to endurance exercise. Importantly, we demonstrate that endurance exercise causes the accumulation of ceramides on stressed mitochondria, and the mitophagic degradation of ceramides results in an increase of the sphingosine-1-phosphate (S1P) level. The elevated S1P thereby facilitates mitochondrial adaptation and enhances endurance capacity via the SPHK1-S1PR1/S1PR2 axis in slow-twitch muscles. Moreover, administration of S1P improves endurance performance in muscle atrophy mice by emulating these adaptive responses. Our findings reveal that the SPHK1-S1P-S1PR1/S1PR2 axis through mitophagic degradation of ceramides in slow-twitch myofibers is the central mediator to endurance exercise and highlight a potential therapeutic target for ameliorating muscle atrophy diseases.Abbreviations CQ: chloroquine; DMD: Duchenne muscular dystrophy; EDL: extensor digitorum longus; FCCP: carbonyl cyanide p-trifluoromethoxyphenyl hydrazone; FUNDC1: FUN14 domain containing 1; GTEx: genotype-tissue expression; MYH: myosin heavy chain; mtDNA: mitochondrial DNA; PPARGC1A/PGC-1α: peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; RG: red gastrocnemius; S1P: sphingosine-1-phosphate; S1PR: sphingosine-1-phosphate receptor; Sol: soleus; SPHK1: sphingosine kinase 1; TA: tibialis anterior; WG: white gastrocnemius
研究领域:
运动生理学
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分子生物学
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代谢组学
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肌肉生物学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Jingli Xiong,Ziyu Long,Jiayi Ma,Huilian Jiang,Jiewen Ye,Zhijun Zeng,Yongan Liao,Beini Lao,Yuan Zhou,Yang Yu,Jiuyao Zhou
WLS attenuates cisplatin-induced AKI by ameliorating renal dysfunction, suppressing inflammation, and inhibiting ferroptosis. • Mechanistically, WLS upregulates S1P levels, activates the S1PR2/GPX4 axis, and promotes the interaction between S1PR2 and GPX4. • Tubule-specific deletion of S1pr2 markedly attenuates the renoprotective and anti-ferroptosis effects of WLS, exacerbating AKI, underscoring S1PR2 as a critical therapeutic target. Background Acute kidney injury (AKI) is a critical clinical syndrome with limited curative therapies. Tubular epithelial cell death is a central event in AKI progression in which ferroptosis plays a pivotal role. Pharmacological inhibition of ferroptosis attenuates renal inflammation and preserves kidney function, positioning it as a promising therapeutic strategy for AKI. Wuling powder (WLS) is a classic formula used for kidney diseases; however, whether it confers renoprotection by modulating ferroptosis in AKI remains unclear. Purpose To investigate whether WLS attenuates cisplatin-induced AKI by inhibiting ferroptosis and to elucidate the underlying mechanism. Methods AKI models were established in mice and mouse renal tubular epithelial cells using cisplatin. Renal function, histopathology, inflammatory responses, and ferroptosis-related markers were assessed. Potential targets were screened, and the regulatory mechanism was defined. Renal tubule-specific S1pr2 knockout mice were generated to validate the functional role of the identified pathway. Results WLS treatment significantly attenuated cisplatin-induced AKI, as evidenced by improved renal function and histology, suppressed inflammation, and inhibited ferroptosis. Mechanistically, WLS upregulated S1P levels, activated the S1PR2/GPX4 axis, and promoted their interaction. Tubule-specific S1pr2 deletion exacerbated renal injury and ferroptosis, and largely abolished the renoprotective effects of WLS. Conclusion WLS alleviates cisplatin-induced AKI by activating the S1PR2/GPX4 axis, thereby inhibiting ferroptosis, reducing inflammation, and improving renal function. These findings reveal a novel mechanism of WLS and identify the S1PR2/GPX4 axis as a promising therapeutic target for AKI. Download: Download high-res image (194KB) Download: Download full-size image
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DOI
高影响因子
EXPERIMENTAL NEUROLOGY
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2026
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IF 4.8
Song Liu,Yi Lv
Background Intestinal flora imbalance after intracerebral hemorrhage (ICH) aggravates neuroinflammation and secondary brain injury through the gut-brain axis, although the specific mechanism remains unclear. This study focuses on the regulatory effects of Muribaculaceae and β-muricholic acid (β-MA, a primary bile acid) on neurological injury after ICH, aiming to reveal the molecular mechanism by which it improves the prognosis of ICH through the sphingosine-1-phosphate receptor 2 (S1PR2). Methods A mouse ICH model was constructed by collagenase induction to evaluate the changes in gut microbiota diversity and metabolites. After intervention with Muribaculum intestinale (MI), neurological function was assessed by behavioral tests, and pathological changes of brain tissue were analyzed by Hematoxylin-Eosin and Nissl staining. Subsequently, intestinal barrier function, inflammatory factors, and total bile acid (TBA) levels were examined in ICH mice. In addition, cell viability, apoptosis, oxidative stress, inflammatory factors, and β-MA levels were analyzed in the heme-induced SH-SY5Y cell model. Molecular docking and drug affinity responsiveness target stability (DARTS) were used to analyze the interaction between β-MA and S1PR2. Intervention with a S1PR2 agonist (CYM-5520) was used to further verify the mechanism. Results Altered gut microbiota composition, elevated lipopolysaccharide levels, reduced expression of tight junction proteins, inflammatory activation, and disrupted bile acid metabolism were observed in ICH mice. Supplementation with MI ameliorated neural damage, cerebral edema, and neuronal loss in an intake dose-responsive manner, enhanced intestinal barrier integrity, and increased TBA levels. As a primary bile acid, β-MA directly mitigated hemin-induced oxidative stress and inflammation in neural cells. Mechanistically, β-MA downregulated the expression of S1PR2, but overexpression of S1PR2 counteracted the protective effects of β-MA. Furthermore, the administration of CYM-5520 attenuated the neuroprotective effects conferred by MI in vivo . Conclusion Muribaculaceae alleviated neurological injury after ICH by upregulating β-MA levels, thereby inhibiting the S1PR2 signaling pathway. This research offers a novel approach to treating ICH by focusing on the gut microbiota-bile acid metabolism-neuroprotection axis.
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2021
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IF 6.514
Dongdong Luo,Zhikun Guo,Xuecui Zhao,Lijuan Wu,Xiaochun Liu,Yingzhi Zhang,Yuhang Zhang,Zirong Deng,Xianjun Qu,Shuxiang Cui,Shengbiao Wan
Sphingosine-1-phosphate receptor 2 (S1PR2) has been identified as a brand-new GPCR target for designing antagonists to reverse 5-FU resistance. We herein report the structural optimization and structure-activity relationship of JTE-013 derivatives as S1PR2 antagonists. Compound 9d was the most potent S1PR2 antagonist (K D = 34.8 nM) among developed compounds. Here, compound 9d could significantly inhibit the expression of dihydropyrimidine dehydrogenase (DPD) to reverse 5-FU-resistance in HCT116 DPD and SW620/5-FU cells. Further mechanism studies demonstrated that compound 9d not only inhibited S1PR2 but also affected the transcription of S1PR2. In addition, compound 9d also showed acceptable selectivity to normal cells (NCM460). Importantly, compound 9d with suitable pharmacokinetic properties could significantly reverse 5-FU-resistance in the HCT116 DPD and SW620/5-FU xenograft models without obvious toxicity, in which the inhibition rates of 5-FU were increased from 23.97% to 65.29% and 27.23% to 60.81%, respectively. Further immunohistochemistry and western blotting analysis also demonstrated that compound 9d significantly decreases the expression of DPD in tumor and liver tissues. These results indicated that compound 9d is a promising lead compound to reverse 5-FU-resistance for colorectal cancer therapy.
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PubMed
高影响因子
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