INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
·
2024
·
IF 3.4
Jiawen Chen,Xiaozhi Xu,Yuru Shao,Xiaohong Bian,Ruiyan Li,Yubin Zhang,Yibei Xiao,Meiling Lu,Qizhou jiang,Yuan Zeng,Fangrong Yan,Junmei Ye,Zhe Li
Doxorubicin (DOX), a widely used chemotherapy agent in cancer treatment, encounters limitations in clinical efficacy due to associated cardiotoxicity. This study aims to explore the role of AKT serine/threonine kinase 2 (AKT2) in mitigating DOX-induced oxidative stress within the heart through both intracellular and extracellular signaling pathways. Utilizing AKT2 knockout (KO) and NRF2 KO murine models, alongside neonatal rat cardiomyocytes (NRCMs), we systematically investigate the impact of AKT2 deficiency on DOX-induced cardiac injury. Our findings reveal that DOX administration induces significant oxidative stress, a primary contributor to cardiac injury. Importantly, Akt2 deficiency exhibits a protective effect by alleviating DOX-induced oxidative stress. Mechanistically, Akt2 deficiency facilitates nuclear translocation of NRF2, thereby suppressing intracellular oxidative stress by promoting the expression of antioxidant genes. Furthermore, We also observed that AKT2 inhibition facilitates superoxide dismutase 2 (SOD2) expression both inside macrophages and SOD2 secretion to the extracellular matrix, which is involved in lowering oxidative stress in cardiomyocytes upon DOX stimulation. The present study underscores the important role of AKT2 in mitigating DOX-induced oxidative stress through both intracellular and extracellular signaling pathways. Additionally, our findings propose promising therapeutic strategies for addressing DOX-induced cardiomyopathy in clinic.
研究领域:
药理学
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心脏病学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
FASEB JOURNAL
·
2025
·Vol. 39
·期 16
·e70901
·
IF 4.2
Yanping Dai,Xiaoqin Gao
Aging-related decline in male fertility is closely associated with impaired sperm quality and dysregulated autophagy/apoptosis in reproductive tissues. This study elucidates the protective role of the AKT2/mTOR/VEGF axis in mitigating age-induced epididymal dysfunction and sperm deterioration. Utilizing iTRAQ proteomics and transcriptome sequencing in young (6-month) versus aged (18-month) rat models, we identified AKT2 and VEGF as key regulators of reproductive aging. Functional validation revealed that AKT2/mTOR/VEGF activation suppressed oxidative stress, preserved mitochondrial membrane potential, and inhibited autophagy/apoptosis in rat epididymal epithelial cells (REECs, cells lining the epididymis involved in sperm maturation and transport) through downstream targets including Bcl-2, Bax, and LC3-II. Notably, extracellular vesicles (EVs) derived from AKT2-activated REECs enhanced sperm motility and reduced sperm DNA fragmentation through reactive oxygen species (ROS) scavenging and autophagy modulation. Pharmacological inhibition of VEGF or AKT2 exacerbated cellular stress responses, while lentivirus-mediated AKT2 overexpression reversed age-related epididymal damage in vivo. Mechanistically, the pathway crosstalk between mTOR-driven VEGF secretion and EV-mediated intercellular communication emerged as a critical mechanism for maintaining sperm viability. These findings establish AKT2/mTOR/VEGF signaling as a central coordinator of epididymal homeostasis and propose EV-based therapies as promising strategies to counteract male reproductive aging. Graphical The AKT2/mTOR/VEGF axis inhibits oxidative stress in REECs, alleviating autophagy and apoptosis. It promotes sperm activity and motility by secreting EVs, reducing sperm autophagy and apoptosis, and thereby increasing the IVF rate.
研究领域:
生殖生物学
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细胞信号传导
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衰老研究
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分子生物学
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泌尿学
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蛋白质组学
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基因组学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL MEDICINE
·
2025
·Vol. 222
·期 3
·e20241147
·
IF 10.6
He Ying,Li Wei,Zhang Meiling,Wang Hui,Lin Peilu,Yu Ying,Huang Bin,Hao Meng,He Jianuo,Kong Weiyao,Luo Dan,Xu Tengteng,Wang Jiaqi,Huang Ying,Zhao Qinwen,Liu Ying,Zhang Jie,Nian Yong,Zhang Lei,Zhu Bo,Yin Chengqian
BRAF mutations drive initiation and progression of various tumors. While BRAF inhibitors are effective in BRAF-mutant melanoma patients, intrinsic or acquired resistance to these therapies is common. Here, we identify non–receptor-type protein tyrosine phosphatase 23 (PTPN23) as an alternative effective target in BRAF-mutant cancer cells. Silencing PTPN23 selectively kills BRAF-mutant melanoma cells but not those with wild-type BRAF. Mechanistically, PTPN23, a catalytically inactive phosphatase, intriguingly induces WNK3-mediated phosphorylation of phosphoinositide 3-kinase class II alpha (PI3KC2α) at serine 329, enhancing its catalytic activity. This activation promotes production of PI(3,4)P2 and subsequent AKT2 activation at endosomes to support cell survival. Genetic or pharmacological targeting of the PTPN23-PI3KC2α-AKT2 signaling axis, alone or in combination with BRAF inhibitors, effectively inhibits the growth of BRAF-mutant melanoma and other cancers in vitro and in vivo. We also demonstrate that melanocyte-specific knockout of PTPN23 significantly inhibits BRAFV600E-driven melanomagenesis. Altogether, our findings demonstrate that targeting PTPN23/PI3KC2α offers a new and viable therapeutic strategy for BRAF-mutant cancers.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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细胞信号传导
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2017
·
IF 2.466
Dandan Chen,Fan Chen,Yitao Xu,Yubin Zhang,Zhe Li,Han Zhang,Tianshu Pan,Yuheng Su,Miyang Wan,Xiaochuan Wang,Junmei Ye
Protein kinase B2 (AKT2) is implicated in diverse process of cardiomyocyte signaling including survival and metabolism. However, the role of AKT2 in myocardium development and the signaling pathway is rarely understood. Therefore, we sought to determine the effect of AKT2 deletion on heart development and its downstream targets. By using experimental animal models and neonatal rat cardiomyocytes (NRCMs), we observed that AKT2 deficiency induces retardation of heart development and increased systemic blood pressure (BP) without affecting cardiac function. Further investigation suggested that deficiency of AKT2 in myocardium results in diminished MEF2A abundance, which induced decreased size of cardiomyocytes. We additionally confirmed that EndoG , which is also regulated by AKT2, is a suppressor of MEF2A in myocardium. Finally, our results proved that AKT2 deficiency impairs the response to β-adrenergic stimuli that normally causes hypertrophy in cardiomyocytes by downregulating MEF2A expression. Our data are the first to show the important role of AKT2 in determining the size of myocardium, its deficiency causes retardation of cardiomyocyte development. We also proved a novel pathway of heart development involving EndoG and MEF2A regulated by AKT2.
研究领域:
心脏病学
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分子生物学
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发育生物学
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DOI
PubMed
高影响因子
AQUACULTURE INTERNATIONAL
·
2024
·
IF 2.2
Cui Jun,Zeng Dan,Guan Peipei,Jiang Ning
Exposure to pathogens induces hyperactivate inflammatory immune responses, oxidative stress and even death in fish. Therefore, suppressing excessive inflammatory responses is a means of treating fish diseases. Scutellariae Radix (SR), an herbal medicine, has anti-inflammatory and antioxidant properties. However, the active ingredients of SR that produce a marked effect and their mechanisms are poorly understood. In this study, 32 active ingredients of SR and their 124 target genes associated with anti-inflammatory effect were screened. These target genes in zebrafish were mainly enriched in biological processes associated with response to stress and stimulus. The KEGG enrichment analysis and pathway–pathway network analysis showed that the MAPK signalling pathway and nine other pathways were the key pathways associated with anti-inflammatory effect. A protein–protein interactions (PPI) network of target genes was constructed, and AKT2 and nine other genes were identified as the hub genes by cytoHubba. Combining the above results, we constructed an active ingredient–hub protein–key pathway network, showing that wogonin-AKT2 was the key regulated module. Molecular docking and SPR-based assays were used to investigate the possible interaction of wogonin with the AKT2 protein. The infected zebrafish and grass carp treated with wogonin displayed a higher survival rate and anti-inflammatory and antioxidant effects than the infected fish without wogonin treatment. Dietary wogonin also enhanced grass carp anti-inflammatory and antioxidant effects. These findings further reveal the molecular biological mechanism by which wogonin from SR exerts anti-inflammatory effects and provide a theoretical basis for the prevention of fish diseases.
研究领域:
生物学
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医学
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药理学
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产品关联
DOI
高影响因子
ADVANCED MATERIALS
·
2025
·
IF 26.8
Shengjie Cui,Xiaowei Wu,Xiaotong Yu,Yiqian Huang,Daixing Zhang,Haotian Chen,Boon Chin Heng,Qing Cai,Yixiang Wang,Yan Gu,Xuliang Deng
Targeted siRNA delivery has been widely used to regulate cell function. However, the rapid degradation of siRNA within macrophages upon delivery severely limits its utility for regulating macrophage function. Here, a novel technique is developed to compact large amounts of siAkt2 strands into delivery nanoparticles, to achieve massive and sustained intracellular release of siAkt2 that overwhelms the degradation capacity of macrophages. Microspheres of RNA complexes are prepared by rolling circle transcription. For better deliverability, siAkt2 microspheres are compacted by cholesterol-modified DNA, and encapsulated by Poly-(L-lactic acid) (PLLA). These PLLA-encapsulated siAkt2-compacted nanoparticles (siAkt2 RNP@PLLA NPs), each containing multiple repeated siAkt2 sequences, displayed long-term stability and maintenance of integrity within body fluids and acidic environments. Extensive endocytosis by RAW 264.7 is followed by continuous massive siAkt2 release into the cytosol, which significantly increased Akt2 gene silencing, metabolic reprogramming, as well as enhanced macrophage alternative polarization to the pro-regenerative M2 phenotype. Local administration of siAkt2 RNP@PLLA NPs in bone defects caused by periodontitis markedly induced macrophage alternative M2 polarization and enhanced bone regeneration. Therefore, the study provides a novel and highly efficient siRNA delivery system for regulating macrophage function, which can be a promising therapeutic strategy for enhancing tissue regeneration.
研究领域:
纳米医学
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免疫治疗
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组织工程
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基因递送
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再生医学
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产品关联
DOI
PubMed
高影响因子
Journal of Biomedical Nanotechnology
·
2019
·Vol. 15
·期 3
·555-570
·
IF 0
Tao Ran,Wang Chengzhang,Zhang Changwei,Li Wenjun,Zhou Hao,Chen Hongxia,Ye Jianzhong
Hepatocellular carcinoma (HCC) is one of the most lethal diseases worldwide. Ginkgo Biloba Leaves polyprenol (GBP) is considered potential efficacy in the treatment of HCC. This study involved oil-in-water type nanoemulsion (NE) loading GBP and Fullerene C60 (C60F)
were prepared by dissolving GBP and C60F in NE using inversed phase emulsification (EIP) with ultrasonic-assisted emulsification (UAE) method. Folic acid (FA) coupled Chitosan (CS) and Graphene oxide (GO) nanocomposites (NCs): FA-CS-GO-NCs were fabricated by ionic cross-linking
of positively charged FA-CS-GO solution conjugates and negative charged NE with TPP. We combined these materials for preparing NCs loading GBP and C60F (GBP-C60F-FA-CS-GO-NCs) based GBP-C60F-NE. GBP-C60F-FA-CS-GO-NCs in the NE were the mean size
was 44.9 nm, PdI was 0.267 and the mean zeta potential was 47.8 mV. And they had good drug loading efficiency, encapsulation efficiency, drug release property and storage stability. In this cytotoxic study, it demonstrated the GBP-C60F-FA-CS-GO-NCs were greater inhibition capacity
on MHCC97H cells compared with GBP-NE, C60F-NE, GBP-C60F-NE, GBP-FA-CS-GO-NCs and C60F-FA-CS-GO-NCs. In this genotoxic study, GBP-C60F-FA-CS-GO-NCs at low C60F concentration showed low genotoxicity on MHCC97H and L02 cells. By comparison,
GBP-C60F-FA-CS-GO-NCs had higher cytotoxicity on MHCC97H than L02 cells. By the cell apoptosis analysis, the results revealed that GBP-C60F-NE and GBP-C60F-FA-CS-GO-NCs could obviously induce MHCC97H cell apoptosis, especially high concentration GBP-C60F-FA-CS-GO-NCs
had the strongest apoptosis inducing ability. The treatment against MHCC97H cells with moderate C60F concentrations of GBP-C60F-FA-CS-GO-NCs effectively inhibited the overexpressions of Akt1 and Akt2, and significantly increased the expression of PTEN. Our results suggest
that PTEN, Akt1 and Akt2 might play an important role in the aspect of GBP-C60F-FA-CS-GO-NCs inhibiting against HCC cells. It provides further evidence to speculation that up-regulated PTEN expression and down-regulated Akt1 and Akt2 expression might be one of the important mechanisms
for GBP-C60F-FA-CS-GO-NCs inhibiting HCC cells. All these results suggest that GBP-C60F-FA-CS-GO-NCs effectively inhibited the HCC malignant development and has potentially important value in the HCC treatment.
研究领域:
纳米技术
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药学
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肿瘤学
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分子生物学
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生物医学工程
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产品关联
DOI
PubMed
ENVIRONMENTAL TOXICOLOGY
·
2023
·
IF 4.5
Peipei Pan,Zina Wen,Feifei Ma,Zhen Lei,Chengshuang Pan,Qianjin Fei,Erpo Tian,Yiyan Wang,Qiqi Zhu,Huitao Li,Xiaoheng Li,Ying Zhong,Ren-Shan Ge,Ren-ai Xu
Bisphenol S (BPS) is a novel bisphenol A (BPA) analogue, a ubiquitous environmental pollutant that disrupts male reproductive system. Whether BPS affects Leydig cell maturation in male puberty remains unclear. Male Sprague–Dawley rats (age of 35 days) were daily gavaged to 0, 1, 10, 100, and 200 mg/kg/day from postnatal days 35–56. BPS at 1–10 mg/kg/day and higher doses markedly reduced serum testosterone and progesterone levels but it at 200 mg/kg/day significantly increased estradiol level. BPS at 100 and 200 mg/kg/day significantly elevated serum luteinizing hormone (LH) levels. BPS at 1–10 mg/kg/day and higher doses significantly reduced inhibin A and inhibin B levels. BPS at 100 and 200 mg/kg/day markedly increased CYP11A1 + Leydig cell number, but did not affect HSD11B1 + (a mature Leydig cell marker) cell number. BPS at 10 mg/kg/day and higher doses significantly downregulated the expression of Cyp11a1 and at 100 and 200 mg/kg/d significantly lowered Cyp17a1 , Hsd11b1 , and Nr5a1 in the testes. BPS at 100 and/or 200 mg/kg/day significantly elevated Lhb in the pituitary. BPS at 100 and 200 mg/kg/day significantly increased the phosphorylation of AKT1, AKT2, and CREB without affecting total AKT1, AKT2, and CREB levels. BPS at 1–100 μM significantly suppressed testosterone production and induced proliferation of primary immature Leydig cells after 24 h of treatment and these actions were reversed by estrogen receptor α antagonist, ICI 182780, and partially reversed by vitamin E. BPS at 0.1–10 μM significantly increased oxidative stress of Leydig cells in vitro. BPS also directly inhibited 17β-hydroxysteroid dehydrogenase 3 activity at 10–100 μM. In conclusion, BPS causes hypergonadotropic androgen deficiency in male rats during pubertal exposure via activating ESR1 and inducing ROS in immature Leydig cells and directly inhibiting 17β-hydroxysteroid dehydrogenase 3 activity.
研究领域:
生殖生物学
·
内分泌学
·
毒理学
·
环境健康
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）