Advanced Science
·
2026
·
IF 14.1
Xiuya Guan,Mengkai Lu,Xinhai Cui,Dawei Zhang,Lei Zhang,Lin Lin,Yuan Li,Yuanlong Hu,Chao Li
Atherosclerosis is a chronic inflammatory disease driven by senescent vascular smooth muscle cells (VSMCs). Salvianolic acid A (SAA) exhibits cardiovascular protective effects; however, its role in atherosclerosis remains unclear. This study aimed to investigate the effects and targets of SAA in atherosclerosis. In vitro studies were performed in senescent VSMCs with heat shock protein 90 alpha (HSP90α) overexpression or knockdown, with or without SAA treatment. In vivo, ApoE −/− mice fed a high‐fat diet were treated with SAA and adeno‐associated virus‐mediated VSMC‐specific HSP90α overexpression or knockdown. SAA promoted apoptosis in senescent VSMCs by inhibiting HSP90α. This inhibition promoted ubiquitin‐proteasome‐dependent degradation of protein kinase B (AKT) and activation of PRKR‐Like Endoplasmic Reticulum Kinase (PERK) signaling. SAA increased endoplasmic reticulum‐mitochondrial contacts and mitochondrial calcium uptake. These effects were reversed by HSP90α overexpression. In ApoE −/− mice, SAA reduced the burden of senescent VSMCs, decreased the size of plaque, and increased the stability of the fibrous cap. VSMC‐specific HSP90α knockdown mimicked the protective effects of SAA, whereas HSP90α overexpression reversed SAA‐mediated effects on disease. SAA reduces the burden of senescent VSMCs in atherosclerosis by inhibiting the scaffold function of HSP90α which maintains the AKT‐PERK interaction, to reactivate PERK signaling, thereby alleviating disease progression. Salvianolic acid A (SAA) selectively induces senescent vascular smooth muscle cell apoptosis, alleviating atherosclerosis. Mechanistically, SAA targets heat shock protein 90 alpha (HSP90α) to disrupt the protein inase B (AKT)‐PRKR‐Like Endoplasmic Reticulum Kinase (PERK) scaffold, driving ubiquitin‐proteasome‐dependent AKT degradation. This pathway reactivates PERK signaling, enhances endoplasmic reticulum‐mitochondria contact area, and increases mitochondrial calcium uptake, offering a promising senolytic approach for cardiovascular protection.
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高影响因子
AQUATIC TOXICOLOGY
·
2026
·
IF 4.6
Zhihui Jiang,Yufei Du,Yilin Zhu,Jingyan Wu,Shengming Ma,Shaoting Weng,Kunpeng Zhang
Dimethyl phthalate (DMP), a widespread environmental pollutant, poses serious risks to aquatic organisms. This study investigated the mechanisms of DMP-induced oxidative stress and autophagy in zebrafish gill tissues, and evaluated the protective effect of 1,8-cineole. Zebrafish models were established for DMP exposure alone, 1,8-cineole treatment alone, and combined exposure. Using histopathology, transmission electron microscopy, fluorescence staining, antioxidant enzyme activity assays, real-time quantitative PCR, and Western blot, we systematically analyzed the impacts of DMP on gill morphology, oxidative stress levels, autophagy-related gene and protein expression, and the PI3K/AKT/mTOR signaling pathway. Results revealed that DMP exposure significantly induced oxidative stress and autophagy in gill tissues and suppressed PI3K/AKT/mTOR pathway activity. In contrast, 1,8-cineole treatment effectively alleviated DMP-induced oxidative damage and autophagy activation, while partially restoring PI3K/AKT/mTOR signaling. This study is the first to demonstrate that 1,8-cineole mitigates DMP-induced autophagy injury in gills by modulating the PI3K/AKT/mTOR pathway, offering a theoretical foundation and a potential green strategy for protecting aquatic organisms from phthalate toxicity.
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Foods
·
2026
·Vol. 15
·期 8
·1349
·
IF 6
Xingyuan Peng,Xuan Zheng,Xiyu Li,Xiaona Pang,Junhua Jin,Hui Liu,Hongxing Zhang,Yuanhong Xie
Osteoporosis is a major global health challenge, particularly among aging populations, underscoring the need for safe and effective nutritional interventions. Probiotics and their metabolites have emerged as promising candidates for modulating bone health via the gut-bone axis. In this study, we investigated the effects of a cell-free culture supernatant (CFS) from the food-grade bacteriumLimosilactobacillus fermentumGBE18 on the proliferation, differentiation, and mineralization of MC3T3-E1 pre-osteoblasts. GBE18 CFS exhibited no cytotoxicity at concentrations ranging from 1% to 4% (v/v). Notably, 2% (v/v) CFS significantly enhanced alkaline phosphatase (ALP) activity and extracellular matrix mineralization (p< 0.05). Transcriptomic profiling revealed that differentially expressed genes were enriched in osteoblast-related processes and two key signaling pathways: Wnt/β-catenin and PI3K/Akt. Subsequent qRT-PCR and Western blot analyses confirmed the upregulation of critical regulators (Rspo2,Pdpk1,Malat1) and demonstrated coordinated activation of Akt phosphorylation, β-catenin stabilization, and Runx2 protein expression. Our findings indicate that GBE18 CFS promotes osteogenic differentiation through coordinated modulation of the PI3K/Akt and Wnt/β-catenin pathways. Consequently, this study provides mechanistic evidence supporting the potential application ofL. fermentumGBE18-derived metabolites as functional food ingredients or dietary interventions for bone health and osteoporosis management.
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高影响因子
RSC Advances
·
2026
·Vol. 16
·期 15
·13394
·
IF 6.1
Peng Ning,Fan Yang,Hongyi Cao,Bo Zhou
Sodium Danshensu (SDSS) shows potential in treating diabetic wounds (DWs) owing to its antioxidant, anti-inflammatory, and pro-angiogenesis effects. The specific pharmacological mechanisms of SDSS in achieving the above effects were evaluated. The potential targets of SDSS and DWs were obtained from online databases. Interaction networks were constructed using network pharmacology, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Combined with machine learning, the biological targets were evaluated and prioritized. A high-glucose-induced human umbilical vein endothelial cell (HUVEC) model was established for in vitro studies. A total of 126 shared targets of SDSS and DWs were selected, and the core targets included EGFR, CASP3, SRC, ESR1, JUN, NFKB1, IGF1R, ESR2, AR, and PPARG. KEGG enrichment analysis revealed significant enrichment of the PI3K-AKT signaling pathway ( P < 0.05). Machine learning indicated EGFR as a key target of SDSS in treating DWs. Findings from molecular docking and molecular dynamics simulation confirmed the stable combination of SDSS and EGFR. In vitro experiments indicated that SDSS may activate the PI3K-AKT pathway via EGFR targets, improve the mobility of high-glucose-induced HUVECs, and increase lumen formation (branch number). It promoted catalase production and inhibited the release of malondialdehyde and inflammatory factors including tumor necrosis factor-α and interleukin-6 (all P < 0.05). SDSS activates the PI3K-AKT pathway via EGFR, promotes endothelial cell migration and angiogenesis, and inhibits oxidative stress and the inflammatory response, highlighting its potential in treating DWs. Sodium Danshensu (SDSS) shows potential in treating diabetic wounds (DWs) owing to its antioxidant, anti-inflammatory, and pro-angiogenesis effects.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Zhidan Shi,Xinyi Cheng,Chu Zhang,Jiayi Hu,Xinqi He,Shuting Chen,Hao Wu,Meng Tian,Chuang Yan,Ling He
Alzheimer's disease (AD) is a neurodegenerative disorder with significant sex-related differences, exhibiting a higher incidence rate in elderly women. Tau pathology has been implicated in sex-associated differences in AD susceptibility and disease progression, contributing to differential pathological burden between males and females. Vorinostat (SAHA), a histone deacetylase inhibitor (HDACi) used in cancer treatment, has shown potential therapeutic effects in various neurological and psychiatric disorders; however, the mechanisms underlying its regulation of tau-associated pathology remain poorly understood, with limited evidence regarding its effects in tau-related neurodegenerative conditions. In this study, we investigated the effects of SAHA treatment on an AAV-P301L-Tau-induced tauopathy model. In vivo, we observed that SAHA administration significantly improved p-Tau levels in the hippocampus and cortex of mice, reduced microglial activation and neuronal damage, and alleviated tauopathy-associated cognitive impairments. Our findings revealed sex-associated differences in Tau-related pathological alterations, with female mice exhibiting greater pathological changes and differential responses to SAHA treatment in several molecular and histological indicators. Further combined in vivo and in vitro experiments revealed that SAHA was associated with modulation of the PI3K/AKT/GSK3β signaling pathway, suppression of NF-κB activation, and attenuation of neuroinflammatory responses, including reductions in experimentally measured inflammatory markers such as interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α). These molecular alterations may represent important regulatory components contributing to the neuroprotective effects of SAHA, rather than acting as the sole determinants of its therapeutic efficacy. In summary, these results indicate that SAHA can improve Tau-associated pathological alterations in an AAV-P301L-Tau-induced tauopathy model. The potential mechanisms may involve coordinated regulation of multiple pathological processes, including modulation of Tau phosphorylation, neuroinflammatory responses, and aging-associated signaling pathways. The observed sex-dependent responses to SAHA provide additional insights into the potential influence of biological sex on HDACi-based therapeutic strategies, although the molecular mechanisms underlying these differences require further investigation.
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FITOTERAPIA
·
2026
·
IF 2.9
Qian Sun,Shi-Liu Xu,Shuang-Ning Liu,De-Jian Chen,Zheng-Jun Li,Xiao-Jun Qiu,Xia Yang,Feng-Xiang Zhang,Jian-Xin Chen
SWLDH was firstly confirmed to treat bacterial infection-induced ALI. • PI3K-AKT/NF- κ B and MAPK signaling pathways were confirmed as the core mechanism for SWLDH to treat ALI. • Five potential anti-ALI compounds in SWLDH were identified. Shi-Wei-Long-Dan-Hua capsule (SWLDH) is clinically used to alleviate bacterial or viral infection induced bronchitis. Recent studies have reported its effects on viral infection induced acute lung injury, broadening our understanding of its clinical applications. However, its effects against bacterial infection-induced ALI were still unclear, along with not fully elucidated chemical profile, significantly limiting its clinical application and product improvement. In this work, we aimed to systematically characterize the chemical components in SWLDH and explore its effects and mechanisms against bacterial infection-induced ALI. Results showed that SWLDH (2 g/kg/day) significantly reduced lung index, alleviated pathological injury and depressed cytokine expression in LPS-challenged mice. SWLDH also inhibited LPS-induced over-expression of iNOS and pro-inflammatory cytokines (TNF- α , IL-1 β , IL-6) in RAW264.7 cells. Moreover, 128 chemical components in SWLDH and its 32 prototypes in rats were identified by using UPLC-Q/TOF MS. Network pharmacology and Western blot were used to confirm that SWLDH can alleviate LPS- induced ALI by suppressing pulmonary inflammation and the PI3K-Akt-NF- κ B/MAPK axis. Further, five potential anti-ALI substances in SWLDH were found. This is the first time to comprehensively profile the chemical components in SWLDH and reveal its effects and mechanisms against bacterial infection-induced ALI, providing the potential substances and pharmacological data for further quality improvement and product development. Download: Download high-res image (166KB) Download: Download full-size image
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Cancer Management and Research
·
2025
·
IF 2.6
Mengzhu Chen,Jian Li,Shaodan Hu,Yuhan Wang,Keju Wang,Tan Wang
Background Lung cancer has high incidence and mortality rates. In consideration of the high toxicity and side effects of traditional chemical drugs and drug resistance, researchers have substituted some natural products for anti-lung cancer drugs. Ziziphi spinosae semen (ZSS) is a famous traditional Chinese herb, and ZSS-based formulas have been used against lung cancer in clinic, such as Xiaoyi Sanjie Formula. Jujuboside B (JUB) is one of the main bioactive components in ZSS; however, JUB’s roles in the treatment of lung cancer, and the mechanism have not been well reported.Objective This study intends to evaluate the effects of JUB on the proliferation and migration of non-small cell lung cancer H1299 cells (NC-1299 cells), as well as the potential related regulatory mechanism.Methods The viability, migration and invasive ability of NC-1299 cells were analyzed by CCK8, wound-healing, transwell invasion, and the expression of proteins was analyzed through Western blotting experiments.Results It showed that 160 and 320 μmol/L JUB significantly inhibited the proliferation of NC-1299 cells, reduced the cell migration in the wound healing test, and decreased the cell number of clonal assay (P < 0.05). JUB also significantly inhibited the expression of Vimentin, MMP2, and MMP9 proteins related to the migration and invasion of tumor cells, as well as inhibited the PI3K/AKT and Wnt/β-catenin pathways.Conclusion The results indicate JUB has a significant inhibitory effect on NC-1299 cells, and such inhibitory effect is associated with inhibiting the expression of migration and invasive proteins such as MMP2, as well as inhibiting the PI3K/AKT and Wnt/β-catenin pathways. The findings provide some references for the application of JUB in the substitution of anti-lung cancer drugs.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2026
·
IF 8.5
Yu Cheng,Yao Wen,Zhaohan Wang,Lizhen Yang,Junming Liao,Jieyu Xing,Zheng Liu,Xiaoyan Sheng,Lingli Zhou,Sigui Zhou,Jian Zou,Haiyun Chen
Our previous investigations have revealed that Perilla frutescens -derived polysaccharide PFP50-1 exhibited significant neuroprotective activity by attenuating lipopolysaccharide (LPS)-induced neuroinflammatory responses in microglia. Nonetheless, the protection and mechanisms of its anti-neuroinflammatory activities are still poorly understood. The neuroprotection effects of PFP50-1's underlying mechanisms were evaluated in MPTP-stimulated Parkinson's disease (PD) mice and LPS-induced microglia, respectively. In vitro , PFP50-1 effectively suppressed the excessive release of pro-inflammatory cytokines. Meanwhile, PFP50-1 significantly downregulated the levels of Toll-like receptor 4 (TLR4), myeloid differentiation primary response protein gene 88 (MyD88), nuclear factor kappa-B (NF-κB), p-PI3K (phosphorylated phosphatidylinositol 3-Kinase), and p-Akt (phosphorylated Protein Kinase B). Subsequently, investigations revealed that TLR4 inhibitor (TAK242) and PI3K inhibitor (LY294002) significantly potentiated PFP50-1's inhibitory effects on LPS-induced pro-inflammatory mediators. Moreover, the excessive releases of Caspase-1, IL-18, and IL-1β were reversed by suppressing NLRP3 inflammasome activation. In conditioned medium-stimulated N2a cells, PFP50-1 exhibited a strong neuroprotective effect against neuroinflammation-mediated neurotoxicity by preventing MMP depolarization and ROS production. Notably, PFP50-1 effectively ameliorated MPTP-induced dopaminergic (DA) neuronal degeneration in vivo , which was associated with the downregulation of the TLR4-mediated and PI3K-mediated signaling pathways, as well as the NLRP3 inflammasome. Collectively, our data indicated that PFP50-1's anti-neuroinflammation effect is related to downregulating the TLR4/NF-κB and PI3K/Akt signaling pathways and suppressing NLRP3 inflammasome activation, making it a promising candidate for PD.
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高影响因子
RARE METALS
·
2026
·Vol. 45
·期 9
·e70620
·
IF 12.1
Minghe Jiang,Ruikai Zhu,Shurong Chen,Xuwen Pan,Leiyuan Peng,Yaohui Huang,Wenquan Lv,Mingjing Yin,Xiaoxuan Guan,Mingyang Jiang,Ming Gao,Wei Wang,Yan Liu
en This link goes to a English section zh This link goes to a Chinese section Cisplatin-related acute kidney injury (CP-AKI) is a serious complication of cisplatin (CP) treated patients with cancer with high morbidity and mortality rates. It is directly related to the abnormal accumulation of CP in renal tubular epithelial cells, causing metabolic toxicity, DNA damage, and oxidative stress. Herein, we developed a polyphenol nanozyme (SrEG) by the coordination of strontium ions (Sr 2+ ) and epigallocatechin gallate. It was demonstrated that SrEG, combined with NIR irradiation, exhibited excellent capabilities of scavenging various types of reactive oxygen species (ROS). It was also determined that SrEG + NIR efficiently eliminated intracellular ROS levels, inhibited inflammation related cytokines expression, and induced macrophage M2 directional polarization, thus preventing cellular damage. By intravenous (IV) administration, SrEG was efficiently accumulated in the kidney and gradually degraded. Accordingly, the administration of SrEG + NIR offered the perfect therapeutic effects in CP-AKI rats by inhibiting the PI3K/AKT pathway, thus accelerating kidney function repair. Overall, the strategy of SrEG + NIR showed substantial clinical promise as a potential therapeutic strategy in ROS-related diseases. 摘要 en This link goes to a English section zh This link goes to a Chinese section 顺铂相关的急性肾损伤(CP-AKI)是癌症患者进行顺铂(CP)治疗时的严重并发症,具有较高的致病率和死亡率。CP-AKI与CP在肾小管上皮细胞中的异常积聚直接相关,从而导致代谢毒性、DNA损伤和氧化应激。在此,我们通过锶离子(Sr 2+ )和表没食子儿茶素没食子酸酯的配位开发了一种多酚纳米酶(SrEG)。结果表明,SrEG结合近红外光照展现出优异的清除各种类型活性氧(ROS)的能力。而且SrEG + NIR有效地降低细胞内ROS水平,抑制炎症相关因子的表达,并诱导巨噬细胞M2定向极化,从而防止细胞损伤。通过静脉注射(IV)给药,SrEG在肾脏中有效积聚并逐渐降解。因此,SrEG + NIR的治疗策略通过抑制PI3K/AKT通路,从而加速肾功能修复,为CP-AKI大鼠提供了完美的治疗效果。总体而言,SrEG + NIR作为ROS相关疾病的潜在治疗策略显示出巨大的临床前景。
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高影响因子
INTERNATIONAL UROLOGY AND NEPHROLOGY
·
2023
·
IF 2
Wang Hongjie,Zhang Yunxia,Liu Huan,Li Shuang
Purpose To investigate the role and underlying mechanism of GDF11 on diabetic nephropathy (DN)-related mitochondrial dysfunction and apoptosis. Methods A DN model of rats was established in this study. Human Kidney-2 (HK-2) cells were cultured under high-glucose (HG) condition with or without recombinant GDF11 (rGDF11). Mitochondrial morphology of HK-2 cells was analyzed by transmission electron microscope and MitoTracker Red CMXRos staining. Mitochondrial membrane potential (MMP) and ROS production were monitored using JC-1 assay kit and MitoSOX staining, respectively. Cell apoptosis was detected by TUNEL or flow cytometry assays. Results Herein, we observed that GDF11 was down-regulated in renal cortex and serum of DN rats, which was accompanied by renal mitochondrial morphological abnormalities. In line with the findings in vivo, HK-2 cells exposed to HG presented with mitochondrial morphological alterations and further apoptosis accompanied by GDF11 reduction. In addition, HG promoted a decrease in MMP while an increase in mitochondrial ROS production. Conversely, rGDF11 treatment significantly alleviated these HG-induced mitochondrial defects in HK-2 cells. Meanwhile, HK-2 cell apoptosis induced by HG was simultaneously suppressed by rGDF11. Mechanistically, the decreased levels of p-AKT induced by HG were attenuated after rGDF11 administration. Inhibition of the PI3K/AKT pathway resisted the effects of rGDF11 on the MMP and apoptosis of HK-2 cells. In addition, we identified that GDF11 is a target of miR-32-5p. Up-regulation of miR-32-5p could inhibit the expression of GDF11. Conclusion rGDF11 treatment rescued HG-induced HK-2 cell mitochondrial dysfunction and apoptosis, which may be dependent on the activation of the PI3K/AKT pathway.
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Antioxidants
·
2022
·Vol. 11
·期 9
·1837
·
IF 7.675
Yanling Lin,Qinzhi Zhang,Baofu Xie,Haiyang Jiang,Jianzhong Shen,Shusheng Tang,Chongshan Dai
Chelerythrine (CHE) is a majorly harmful isoquinoline alkaloid ingredient inChelidonium majusthat could trigger potential hepatotoxicity, but the pivotal molecular mechanisms remain largely unknown. In the present study, CHE-induced cytotoxicity and the underlying toxic mechanisms were investigated using human HepG2 cells in vitro. Data showed that CHE treatment (at 1.25–10 μM)-induced cytotoxicity in HepG2 cells is dose-dependent. CHE treatment increased the production of ROS and induced oxidative stress in HepG2 cells. Additionally, CHE treatment triggered the loss of mitochondrial membrane potential, decreased the expression of mitochondrial complexes, upregulated the expression of Bax, CytC, and cleaved-PARP1 proteins and the activities of caspase-9 and caspase-3, and downregulated the expression of Bcl-XL, and HO-1 proteins, finally resulting in cell apoptosis. N-acetylcysteine supplementation significantly inhibited CHE-induced ROS production and apoptosis. Furthermore, CHE treatment significantly downregulated the expression of phosphorylation (p)-Akt (Ser473), p-mTOR (Ser2448), and p-AMPK (Thr172) proteins in HepG2 cells. Pharmacology inhibition of Akt promoted CHE-induced the downregulation of HO-1 protein, caspase activation, and apoptosis. In conclusion, CHE-induced cytotoxicity may involve the inhibition of Akt pathway and the activation of oxidative stress-mediated mitochondrial apoptotic pathway in HepG2 cells. This study sheds new insights into understanding the toxic mechanisms and health risks of CHE.Keywords:chelerythrine;oxidative stress;apoptosis;mitochondrial apoptotic pathway;Akt pathway
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Agriculture-Basel
·
2022
·Vol. 12
·期 7
·988
·
IF 3.408
Yaojun Liu,Wenqiang Shen,Tao Liu,Rainer Mosenthin,Yinghui Bao,Peng Chen,Wenbo Hao,Lihong Zhao,Jianyun Zhang,Cheng Ji,Qiugang Ma
(1) Background: L-carnosine (β-alanyl-L-histidine), a natural dipeptide, exists at relatively high concentrations in skeletal muscles, and has been shown to protect cells from adverse conditions due to its antioxidant, anti-aging, anti-glycation, and buffering properties. Satellite cells (SCs), residing on the myofiber surface, are crucial for muscle post-growth and regeneration. However, the effects of L-carnosine on muscle development of pigs in vivo, on proliferation and growth of SCs in vitro, and the relationship between SCs and muscle development have not yet been investigated. (2) Methods: The objective of this study was to assess the effect of dietary L-carnosine on growth performance andlongissimus dorsimuscle development of pigs in vivo, and to elaborate its molecular mechanisms in vitro using L-carnosine-treated SCs. (3) Results: It was shown that L-carnosine supplementation (0.2 and 2 mM) increased (p< 0.05) SC proliferation and cell percentage in the synthesis (S) phase and decreased cell percentage in the resting (G0)/first gap (G1)/phase. Moreover, average daily gain (ADG) of pigs fed diets containing 0.1% of L-carnosine was higher (p< 0.05) than that of pigs fed diets without L-carnosine, and thelongissimus dorsimuscle weight of pigs assigned to the L-carnosine treatments was 7.95% higher compared to control pigs. Both in thelongissimus dorsimuscle and cultured SCs of pigs, the Akt/mTOR/S6K signaling pathway was activated (p< 0.05), suggesting that L-carnosine improved muscle growth and SC proliferation of pigs. (4) Conclusions: Considering the important role of SCs in post-natal muscle growth, there is evidence that L-carnosine may improve muscle growth of pigs through promoting SC proliferation via activating the Akt/mTOR/S6K signaling pathway.Keywords:L-carnosine;satellite cells;proliferation;mTOR signaling pathway;muscle growth
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