COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY A-MOLECULAR & INTEGRATIVE PHYSIOLOGY
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2026
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IF 2.4
Wenyao Lv,Xinzhan Meng,Tianyang Sun,Yuxuan Chen,Weizhong Li,Tao Sheng,Qian Cong,Qiaozhen Yu,Ruitao He,Ruicong He,Yubang Shen,Jianfeng Ren,Junqiang Qiu,Lang Gui,Jiale Li,Xiaoyan Xu
CRISPR/Cas9-mediated knockout of Pik3r1 in grass carp resulted in an 51.8% increase in body weight and a 13.5% increase in body length in F0 mosaic individuals. • The growth enhancement was driven by a unique combination of muscle fiber hypertrophy (22.50% larger area) and hyperplasia (18.90% higher density). • Pik3r1 disruption simultaneously led to a 67.7% reduction in hepatic lipid accumulation, addressing a key metabolic disorder in aquaculture. • Molecular analysis confirmed that the dual phenotype arises from activation of the PI3K/AKT/mTOR cascade and upregulation of PPARα mediated fatty acid oxidation, coupled with suppression of de novo lipogenesis. • The study identifies Pik3r1 as a novel, high-value target for precision breeding to concurrently improve growth yield and metabolic health in grass carp. Grass carp ( Ctenopharyngodon idella ) is a major aquaculture species, yet production efficiency is often constrained by growth performance and metabolic disorders such as hepatic lipid deposition. Conventional selective breeding faces challenges in further improving these complex traits, necessitating precision genetic interventions. In this study, we combined comparative transcriptomics with CRISPR/Cas9 mediated gene disruption to investigate the regulatory role of Pik3r1 . Comparative RNA-seq of fast- and slow-growing individuals together with protein–protein interaction network analysis identified Pik3r1 as a candidate negative regulator of growth. To validate its function, we generated Pik3r1 mosaic F0 mutants by targeting the SH3 domain of Pik3r1 . Disruption of Pik3r1 conferred a profound growth advantage, increasing body weight by 51.8% and body length by 13.5% compared to wild-type controls. Histological analyses revealed that enhanced muscle accretion was driven by both hypertrophy with a 22.50% increase in myofiber cross-sectional area and hyperplasia characterized by an 18.90% rise in fiber density, coupled with a 67.7% reduction in hepatic lipid accumulation. At the molecular level, Pik3r1 disruption relieved the inhibitory effect on the PI3K/AKT/mTOR cascade, with upregulation of PI3K , AKT , mTOR , S6K1 , Myod1 , and Mybpc1 and downregulation of 4ebp1 and Pik3ca in muscle, accompanied by upregulation of PPARα and CPT1a and downregulation of FASN and ACC1 in the liver. Furthermore, a clear genotype phenotype correlation was observed: fish carrying confirmed premature termination codons exhibited substantially greater growth enhancement (77.6% increase in body weight) than those with in-frame mutations. Collectively, our results support Pik3r1 as a key regulator linking somatic growth and lipid metabolism in grass carp, and highlight its potential as a target for molecular breeding aimed at improving yield and carcass quality. Download: Download high-res image (88KB) Download: Download full-size image
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高影响因子
Cell Death & Disease
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2024
·Vol. 15
·期 7
·1-17
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IF 8.1
Wang Yuying,Su Kunqi,Wang Chang,Deng Tao,Liu Xiaofeng,Sun Shiqi,Jiang Yang,Zhang Chunfeng,Xing Baocai,Du Xiaojuan
Chemotherapeutic efficacy is seriously impeded by chemoresistance in more than half of hepatocellular carcinoma (HCC) patients. However, the mechanisms involved in chemotherapy-induced upregulation of chemoresistant genes are not fully understood. Here, this study unravels a novel mechanism controlling nuclear acetyl-CoA production to activate the transcription of chemoresistant genes in HCC. NAT10 is upregulated in HCC tissues and its upregulation is correlated with poor prognosis of HCC patients. NAT10 is also upregulated in chemoresistant HCC cells. Targeting NAT10 increases the cytotoxicity of chemotherapy in HCC cells and mouse xenografts. Upon chemotherapy, NAT10 translocates from the nucleolus to the nucleus to activate the transcription of CYP2C9 and PIK3R1 . Additionally, nuclear acetyl-CoA is specifically upregulated by NAT10. Mechanistically, NAT10 binds with ACLY in the nucleus and acetylates ACLY at K468 to counteract the SQSTM1-mediated degradation upon chemotherapy. ACLY K468-Ac specifically accumulates in the nucleus and increases nuclear acetyl-CoA production to activate the transcription of CYP2C9 and PIK3R1 through enhancing H3K27ac. Importantly, K468 is required for nuclear localization of ACLY. Significantly, ACLY K468-Ac is upregulated in HCC tissues, and ablation of ACLY K468-Ac sensitizes HCC cells and mouse xenografts to chemotherapy. Collectively, these findings identify NAT10 as a novel chemoresistant driver and the blockage of NAT10-mediated ACLY K468-Ac possesses the potential to attenuate HCC chemoresistance.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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PubMed
高影响因子
INTERNATIONAL DENTAL JOURNAL
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2026
·Vol. 76
·期 4
·109587
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IF 5.2
Jingkun Zhang,Li Lin,Huixian Dong,Bingtao Wang,Xiaoshi Chen,Chenhao Wang,Liecong Lin,Jialin Zhong,Guocong Zheng,Qianzhou Jiang
Background The regeneration of functional dentin is a critical clinical goal for preserving tooth vitality after injury, with odontoblastic differentiation of human dental pulp stem cells (hDPSCs) being central to this reparative process. While the long noncoding RNA H19 is recognised as a key regulator of dentin repair, its downstream regulatory network is complex and incompletely mapped. Beyond the previously established H19/miR-140-5p/BMP2 axis, this study identifies a distinct and parallel pathway in which H19 promotes odontoblastic differentiation by downregulating miR-103a-3p, which in turn targets the PIK3R1/AKT and KLF4 signalling cascades. Our findings reveal that these two downstream networks operate independently, further elucidating the multifaceted role of H19 in dentin regeneration. Methodology In this study, we used lentiviral vectors to stably overexpress H19 in hDPSCs. Bioinformatic analysis and dual-luciferase reporter assays were employed to validate the interactions between H19 and miR-103a-3p, as well as between miR-103a-3p and its target mRNAs, including phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) and Kruppel-like factor 4 (KLF4). And qPCR and Western blot were used to investigate the expression pattern of H19 and the potential signalling axis of H19 and key odontogenic markers. Then, alkaline phosphatase and alizarin red S staining were used to evaluate odontogenic differentiation capacity. Finally, a heterotopic pulp regeneration model was established. And HE staining, Masson staining, immunofluorescence and immunohistochemistry were performed to verify the mechanism of H19 regulating odontogenic differentiation in vivo. Results In vitro , H19 promoted odontogenic differentiation of hDPSCs, while miR-103a-3p inhibited them. Both PIK3R1 and KLF4 were identified as direct targets of miR-103a-3p. Ectopic expression of either PIK3R1 or KLF4 restored the odontogenic differentiation capacity of hDPSCs suppressed by miR-103a-3p. Mechanistically, PIK3R1 promoted odontogenesis by activating the PI3K/AKT signalling pathway, whereas KLF4 acted independently as a transcriptional regulator. In vivo , H19 overexpression drove odontoblastic differentiation of hDPSCs by inducing the expression of its downstream targets, PIK3R1 and KLF4. Conclusion Our findings indicated that H19 promoted odontogenic differentiation of hDPSCs by modulating the miR-103a-3p–PIK3R1/AKT and miR-103a-3p–KLF4 axes, underscoring their therapeutic potential for pulp regeneration.
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高影响因子
Arabian Journal of Chemistry
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2024
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IF 5.3
Dong Xie,Guangfu Lv,Yuchen Wang,Wenjing Zhang,Nian Li,Yao Duan,Qing Huang,Ge Chen,Zifeng Pi,Hao Yue
Tenghuang Jiangu Wan (THJGW) is a commonly utilized treatment for osteoarthritis (OA), yet its pharmacodynamic material basis and molecular mechanism remain inadequately understood. This study systematically characterized the in vitro and in vivo chemical components of THJGW using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). The pharmacodynamic material basis of THJGW in the treatment of OA was explored through a target network pharmacology approach and molecular docking technology. Cellular experiments were subsequently employed to validate the molecular mechanisms. Consequently, a total of 134 components from THJGW were identified in vitro , comprising 45 flavonoids, 10 iridoid glycosides, 39 phenylethanoid glycosides, 9 phenylpropanoids, 11 organic acids, 4 phenolics, and 16 other compounds. Additionally, 38 prototype absorbed components in serum were characterized for the purpose of network construction. 11 key components and 10 core targets (VEGFA, STAT3, RELA/NF-κB p65, PIK3R1, PIK3CA, MMP9, MMP1, IL-6, HDAC1, and FGF2) were determined by the target network pharmacology. Through Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, it was found that these intersection targets are associated with various signaling pathways such as pathways in cancer, lipid and atherosclerosis, and prostate cancer. Notably, the lipid and atherosclerosis pathway was closely linked to OA. The molecular docking results demonstrated strong binding affinities of the three core targets: IL-6, STAT3, and RELA/NF-κB p65. These results suggest that these targets may play a significant role for THJGW in treating OA. In vitro experiments showed that THJGW had notable protective effects on LPS-induced RAW264.7 macrophages by reducing levels of TNF-α and IL-6, and inhibiting phosphorylation expression of STAT3 and NF-κB p65 proteins related to the lipid and atherosclerosis pathway. This study provides insight into the pharmacodynamic material basis and mechanism of action for THJGW in the treatment of OA, which provide scientific evidence for the scientific application and improvement of quality standards for THJGW.
研究领域:
药理学
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生物化学
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分子生物学
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中医药
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高影响因子
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