Experimental Hematology & Oncology
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2025
·Vol. 14
·期 1
·1-19
·
IF 13.5
Shan Guangyao,Bian Yunyi,Ren Shencheng,Hu Zhengyang,Pan Binyang,Zeng Dejun,Zheng Zhaolin,Fan Hong,Bi Guoshu,Yao Guangyu,Zhan Cheng
Background Ferroptosis, a regulated cell death driven by iron-dependent lipid peroxidation, is associated with chemoresistance in lung adenocarcinoma (LUAD). This study aims to investigate the role of sarcosine in ferroptosis and its underlying mechanisms.Methods An RSL3-induced ferroptosis model was used to screen a library of 889 human endogenous metabolites and metabolomic profiling was harnessed to identify metabolites associated with ferroptosis. Cell viability, lipid-reactive oxygen species (ROS), ferrous iron, malondialdehyde (MDA), and mitochondrial integrity were assessed to evaluate sarcosine’s effects on ferroptosis. Metabolic fate was studied using 15N-labeled sarcosine. Next, we used untargeted metabolomic profiling and next-generation sequencing to dissect metabolic and transcriptomic changes upon sarcosine supplementation. The effects of sarcosine on ferroptosis and chemotherapy were further validated in patient-derived organoids (PDOs), xenograft models, and LUAD tissues.Results Sarcosine emerged as a potent ferroptosis inducer in the metabolic library screening, which was further confirmed via cell viability, lipid-ROS, ferrous iron, and MDA measurements. Metabolic flux analysis showed limited conversion of sarcosine to other metabolites in LUAD cells, while untargeted metabolomic profiling and seahorse assays indicated a metabolic shift from glycolysis to oxidative phosphorylation. Sarcosine enhanced pyruvate dehydrogenase activity to generate more ROS by interacting with PDK4, reducing PDHA1 phosphorylation. As a co-activator of N-methyl-D-aspartate receptor (NMDAR), sarcosine also exerted its pro-ferroptosis effect via regulating ferrous export through the NMDAR/MXD3/SLC40A1 axis. Given the significance of ferroptosis in chemotherapy, we validated that sarcosine enhanced the sensitization of cisplatin by promoting ferroptosis in LUAD cells, PDOs, and xenograft models.Conclusion Sarcosine promotes ferroptosis and enhances chemosensitivity, suggesting its potential as a therapeutic agent in treating LUAD.
研究领域:
肿瘤学
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代谢组学
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细胞生物学
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DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR LIFE SCIENCES
·
2024
·Vol. 81
·期 1
·1-24
·
IF 6.2
Hong Ling,Xiao Shan,Diao Lianghui,Lian Ruochun,Chen Cong,Zeng Yong,Liu Su
Polycystic ovary syndrome (PCOS) is a complex common endocrine disorder affecting women of reproductive age. Ovulatory dysfunction is recognized as a primary infertile factor, however, even when ovulation is medically induced and restored, PCOS patients continue to experience reduced cumulative pregnancy rates and a higher spontaneous miscarriage rate. Hyperandrogenism, a hallmark feature of PCOS, affects ovarian folliculogenesis, endometrial receptivity, and the establishment and maintenance of pregnancy. Decidualization denotes the transformation that the stromal compart of the endometrium must undergo to accommodate pregnancy, driven by the rising progesterone levels and local cAMP production. However, studies on the impact of hyperandrogenism on decidualization are limited. In this study, we observed that primary endometrial stromal cells from women with PCOS exhibit abnormal responses to progesterone during in vitro decidualization. A high concentration of testosterone inhibits human endometrial stromal cells (HESCs) decidualization. RNA-Seq analysis demonstrated that pyruvate dehydrogenase kinase 4 (PDK4) expression was significantly lower in the endometrium of PCOS patients with hyperandrogenism compared to those without hyperandrogenism. We also characterized that the expression of PDK4 is elevated in the endometrium stroma at the mid-secretory phase. Artificial decidualization could enhance PDK4 expression, while downregulation of PDK4 leads to abnormal decidualization both in vivo and in vitro. Mechanistically, testosterone excess inhibits IGFBP1 and PRL expression, followed by phosphorylating of AMPK that stimulates PDK4 expression. Based on co-immunoprecipitation analysis, we observed an interaction between SIRT1 and PDK4, promoting glycolysis to facilitate decidualization. Restrain of AR activation resumes the AMPK/SIRT1/PDK4 pathway suppressed by testosterone excess, indicating that testosterone primarily acts on decidualization through AR stimulation. Androgen excess in the endometrium inhibits decidualization by disrupting the AMPK/SIRT1/PDK4 signaling pathway. These data demonstrate the critical roles of endometrial PDK4 in regulating decidualization and provide valuable information for understanding the underlying mechanism during decidualization.
研究领域:
生殖内分泌学
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分子生物学
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细胞生物学
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内分泌学
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产品关联
DOI
PubMed
高影响因子
Theranostics
·
2024
·Vol. 14
·期 19
·7534
·
IF 12.4
Wenfang He,Chenguang Ding,Ting Lin,Binqi Wang,Wenjing Wang,Zhichao Deng,Taian Jin,Yiwei Shang,Danna Zheng,Ting Bai,Mingzhen Zhang,Runqing Li,Juan Jin,Qiang He
Rationale : Ischemia-reperfusion-induced acute kidney injury (IR-AKI), characterized by the abrupt decline in renal function, is distinguished by the intricate interplay between oxidative stress and inflammation. In this study, a reactive oxygen species (ROS) scavenger-CF@PDA was developed to effectively target antioxidant and anti-inflammatory pathways to disrupt the oxidative stress-inflammation cycle in IR-AKI. Methods : UV-vis absorption spectra, FTIR spectra, and TEM were employed to determine the successful construction of CF@P. ABTS, TMB, and NBT analyses were performed to detect the antioxidant ability and enzyme-mimicking ability of CF@P. In vitro and in vitro , the antioxidant/anti-inflammatory effect of CF@P was detected by MTT, qPCR, fluorescence, and flow cytometry. Multi-omics revealed the mechanism of CF@P in IR-AKI therapy, and molecular docking was further used to determine the mechanism. MRI and photoacoustic imaging were employed to explore the dual-mode imaging capacity of CF@P in IR-AKI management. Results : CF@P could disrupt the oxidative stress-inflammatory cascade by scavenging ROS, reducing pro-inflammatory cytokines, and modulation of macrophage polarization. Subsequent multi-omics indicated that the renal protective effects may be attributed to the inhibition of pyruvate dehydrogenase kinase 4 (PDK4). Metabolomics demonstrated that CF@P could improve the production of antioxidant compounds and reduce nephrotoxicity. Additionally, CF@P exhibited promising capabilities in T1-MRI and photoacoustic imaging for AKI management. Conclusions : Collectively, CF@P, possessing antioxidant/anti-inflammatory properties by inhibiting PDK4, as well as imaging capabilities and superior biocompatibility, holds promise as a therapeutic strategy for IR-AKI.
研究领域:
医学
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药理学
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生物化学
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产品关联
DOI
PubMed
高影响因子
CURRENT MEDICINAL CHEMISTRY
·
2023
·Vol. 30
·期 29
·3368-3381
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IF 4.1
Dai Xiaoyu,Chen Ke,Xie Yangyang
Background: The role of WT1-associated protein (WTAP) in mediating the N6-methyladenosine (m6A) modification of pyruvate dehydrogenase kinase 4 (PDK4) in colorectal cancer (CRC) has been previously reported. Objective: This research manages to unveil the function and mechanism
of WTAP mediating the m6A modification in CRC. Methods: Expressions of PDK4 and WTAP in CRC were assessed by bioinformatics analysis and verified by Western blot. After the transfection with short hairpin RNAs (shRNAs) for WTAP (shWTAP) and PDK4 (shPDK4) to manipulate the expressions
of PDK4 and WTAP, the viability, proliferation, migration, invasion, and levels of m6A, PDK4 and WTAP in CRC cells were determined by cell counting kit-8 (CCK-8), colony formation, transwell, Western blot, or M6A-RNA immunoprecipitation (MeRIP)-qPCR assays. M6A binding sites in PDK4 were additionally
predicted through bioinformatics analysis, and the interaction of PDK4 and WTAP was confirmed using an RNA pull-down assay. Tumor volume and weight in the constructed xenograft-tumor mouse model were recorded. Results: PDK4 expression was low, yet WTAP and m6A expressions were high in
CRC cells. WTAP bound with the m6A binding sites in PDK4. PDK4 silencing facilitated the viability, proliferation, migration and invasion, inhibited the expression of PDK4 in CRC cells, and accelerated the growth of xenografts in vivo. However, the depletion of WTAP4 exerted the opposite effects
and further offset the impact of PDK4 silencing. Conclusion: WTAP mediates the m6A modification of PDK4 to regulate the malignant behaviors of CRC cells in vitro and in vivo.
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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癌症研究
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DOI
PubMed
高影响因子
MICROBIAL PATHOGENESIS
·
2024
·
IF 3.3
Xiaoye Cheng,Yijin Jiang,Xu Zhao,Nana Ma,Xiangzhen Shen
Lactate has been increasingly recognized for its role in diseases progression, necessitating a deeper understanding of its metabolic processes and regulatory mechanisms. This study aimed to evaluate the impact of lipopolysaccharide (LPS) on lactate accumulation in bovine mammary epithelial cells (BMECs) and to elucidate the underlying regulatory mechanisms. Further optimization of LPS treatment points was achieved by assessing the content of key glycolytic enzymes-hexokinases (HK), pyruvate kinase (PK) and pyruvate dehydrogenase (PDH)-as well as the expression levels of HK2, pyruvate dehydrogenase kinase4 (PDK4) and lactate dehydrogenase (LDHA). Our results indicate that LPS can promote intracellular glycolysis and inhibits pyruvate synthesis, thereby increasing lactate content. BMECs were cultured and divided into a control group (CON) and an LPS-stimulated group (10 μg/mL for 6 h, LPS group). LPS was found to upregulate expression levels of HIF-1α and MCT1, suggesting a role for HIF-1α and MCT1 in cellular glucose metabolism. To explore the effect of HIF-1α on lactate accumulation, BMECs were stimulated with a HIF-1α inducer (COCL 2 ) and HIF-1α inhibitor (DMBPA). COCL 2 was observed to promote lactate accumulation, while DMBPA inhibited it. Additionally, modulation of HIF-1α expression influenced the expression of MCT1, which is a crucial transporter for extracellular lactate influx. To investigate the specific impact of MCT1 on intracellular lactate, we utilized overexpression plasmids and small interfering RNA to modulate MCT1 expression. The findings indicate that while MCT1 expression alone does not affect intracellular lactate levels, it does modulate the changes induced by LPS. In conclusion, our study suggests that LPS regulates lactate accumulation in BMECs through the HIF-1α/MCT1 pathway, providing insights into the metabolic dysregulation associated with LPS-induced stress in dairy cattle.
研究领域:
动物科学
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细胞生物学
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代谢学
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乳品科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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