FASEB JOURNAL
·
2020
·Vol. 34
·期 6
·8671-8685
·
IF 4.966
Jie Cai,Diming Wang,Shulin Liang,Jinrong Peng,Fengqi Zhao,Jianxin Liu
During lactation, an improper glucose supply often threatens mammary gland (MG) health. However, information is limited on the metabolic trajectories and molecules that regulate lactating MGs with an excessive glucose supply. Based on the network analysis of transcriptome and microRNAs, we found that the oversupply of glucose-induced severe glucose metabolic disorders in MGs of lactating goats, shifting lactose synthesis to acute fermentative glycolysis which caused increased flux of glucose metabolism into lactate. Moreover, NF-κB2 played a key role in regulating glycolysis, exhibiting a metabolic shift when MGs had an excessive supply of glucose. In primary mammary epithelial cells, fermentative glycolysis, and intracellular concentration of reactive oxygen species (ROS) were reduced by ganoderic acid A through blocking NF-κB2, while activation of NF-κB2 with phorbol myristate acetate (PMA) upregulated fermentative glycolysis and increased cellular ROS accumulation under excessive glucose. Thus, we established an NF-κB2-targeting method to reform the metabolic shift toward glycolysis caused by glucose oversupply by integrating NF-κB2 blockade and intracellular ROS scavenging.
研究领域:
动物生理学
·
分子生物学
·
营养学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2022
·Vol. 10
·期 22
·4306-4320
·
IF 7.571
Jie Zhou,Qianwen Yin,Shengnan Li,Ruhe Yang,Rui Lou,Yiwen Sun,Bin Du
The poor penetration into deep tumor tissues of nanomedicines could not inhibit the production of lactic acid by deep tumor glycolysis, which leads to the accumulation of lactic acid and promotes tumor metastasis. In order to increase tumor penetration, it remains challenging to avoid tumor metastasis by the direct degradation of the extracellular matrix (ECM). Herein, in order to increase tumor penetration, a nano-platform, which can reduce extracellular matrix (ECM) production, and inhibit the glycolysis of deep tumors by releasing ethylenediaminetetraacetic acid (EDTA) is reported. In this design, EDTA and indocyanine green (ICG) are encapsulated in the liposome by a thin-film hydration method, and folic acid (FA) and the polyethyleneimine polymer (FA-PEI) are applied to coat the surface of liposomes through electrostatic interactions, and the FA-EDTA/ICG-Lip nanoparticles are obtained. FA-EDTA/ICG-Lip NPs can release EDTA and ICG in lysosomes (pH 4.5) to reduce ECM production by down-regulating transforming growth factor β (TGF-β) and activating an immune response by inducing tumor cell immunogenic cell death (ICD), respectively. Simultaneously, EDTA inhibits glycolysis of deep tumors by chelating Mg2+. By avoiding tumor metastasis, the strategy of indirectly reducing ECM production is demonstrated to enhance tumor penetration and inhibit deep tumor glycolysis.
研究领域:
肿瘤学
·
纳米医学
·
免疫学
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DOI
PubMed
高影响因子
ANALYTICA CHIMICA ACTA
·
2024
·
IF 5.7
Zhirong Geng,Miaomiao Zhang,Binghuan Huang,Xiaohong Zhang,Zhilin Wang
Background Adenosine 5′-triphosphate (ATP) plays an important role in cell metabolism and has been regarded as an indicator of cell survival and damage. Golgi apparatus participates in the signal transduction processes of substance transport, ion homeostasis and stress when extracellular substances enter cells. Till now, there is no fluorescent probe for monitoring Golgi ATP level fluctuation and visualizing the configuration change of the Golgi apparatus during the inhibition of glycolysis. Results Herein, we report the synthesis of a novel water-soluble cationic polythiophene derivative ( PEMTEA) that can be employed as a fluorescent sensor for measuring ATP in the Golgi apparatus. PEMTEA self-assembles into PT-NP nanoparticles in aqueous solution with a diameter of approximately 2 nm. PT-NP displays high sensitivity and superb selectivity towards ATP with a detection limit of 90 nM and a linear detection range from 0 to 3.0 μM. The nanoparticles show low toxicity to HepG2 cells and good photostability in the Golgi apparatus. With the stimulation of Ca 2+ , PT-NP was practically applied to real-time monitor of endogenous ATP levels in the Golgi apparatus through fluorescence microscopy. Finally, we studied the relationship between the concentration of ATP and configuration of the Golgi apparatus during the inhibition of glycolysis using PT-NP . Significance We have demonstrated that PT-NP can not only indicate the fluctuation and distribution of ATP in the Golgi apparatus, but also give the information of the configuration change of the Golgi apparatus at the single-cell level during the inhibition of glycolysis.
研究领域:
细胞生物学
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生物化学
·
医学
✓ 已验证
DOI
PubMed
高影响因子
CURRENT MEDICINAL CHEMISTRY
·
2024
·
IF 3.5
Liu Guangyi,Wang Huan,Ran Rui,Wang Yicheng,Li Yang
Background: Chemotherapy resistance is one of the main causes of clinical
chemotherapy failure. Current cancer research explores the drug resistance mechanism
and new therapeutic targets. This work aims to elucidate the mechanism of thyroid hormone
receptor interactor 13 (TRIP13) affecting doxorubicin (DOX) resistance in colorectal
cancer (CRC).
Methods: Bioinformatics analyses were employed to clarify TRIP13 expression in CRC
tissues and predict the correlation of the TRIP13 enrichment pathway with glycolysis-related
genes and stemness index mRNAsi. Quantitative real-time polymerase chain reaction
and western blot were adopted to analyze the expression of TRIP13 and glycolysis-
related genes. Cell Counting Kit-8 was utilized to determine the cell viability and
IC50 value. Western blot was employed to measure the expression of stemness-related
factors. Cell function assays were performed to detect cells' sphere-forming ability and
glycolysis level. Animal models were constructed to determine the effects of TRIP13 expression
on CRC tumor growth.
Results: TRIP13 was significantly overexpressed in CRC, concentrated in the glycolysis
signaling pathway, and positively correlated with stemness index mRNAsi. High expression
of TRIP13 facilitated DOX resistance in CRC. Further mechanistic studies revealed
that overexpression of TRIP13 could promote cell stemness through glycolysis, which
was also confirmed in animal experiments.
Conclusion: TRIP13 was highly expressed in CRC, which enhanced the DOX resistance
of CRC cells by activating glycolysis to promote cell stemness. These findings offer
new insights into the pathogenesis of DOX resistance in CRC and suggest that
TRIP13 may be a new target for reversing DOX resistance in CRC.
研究领域:
肿瘤学
·
分子生物学
·
癌症研究
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
BIOLOGICAL TRACE ELEMENT RESEARCH
·
2023
·Vol. 202
·期 7
·3180-3192
·
IF 3.9
Nong Weihua,Wei Gaomeng,Wang Junli,Lei Xiaocan,Wang Jinyuan,Wei Yanhong,Dong Mingyou,He Liqiao
This study aimed to investigate the protective effect of nicotinamide mononucleotide (NMN) on testicular spermatogenesis in aluminum chloride (AlCl 3 )-exposed rats and to elucidate the potential underlying mechanism. The results indicated that AlCl 3 -induced testicular damage, leading to reduced sperm quality, increased apoptosis, decreased cell proliferation, and impaired Sertoli cell function in rats. Additionally, glycolytic metabolism was observed to be hindered. However, after NMN treatment, there was a noticeable improvement in testicular damage among the rats, marked by increased sperm quality, reduced apoptosis, enhanced cell proliferation, improved Sertoli cell function, and an activated glycolytic metabolism. The findings of this study suggest that NMN alleviates testicular spermatogenesis impairment induced by AlCl 3 exposure through the inhibition of spermatogenic cell apoptosis, promotion of spermatogenic cell proliferation, and activation of glycolytic pathways. The study contributes an experimental foundation for potential future clinical applications of NMN in cases of AlCl 3 -exposed spermatogenic dysfunction.
研究领域:
生殖生物学
·
毒理学
·
代谢生物学
✓ 已验证
DOI
高影响因子
Food & Function
·
2019
·Vol. 10
·期 2
·1123-1131
·
IF 3.241
Dongmei Li,Xiaokang Na,Wanru Zhou,Congcong Wang,Yuliang Li,Bei-Wei Zhu,Mingqian Tan
The effect of endogenous carbon nanoparticles from food sources is one of the hot topics in the current food research field. The relationship between the foodborne nanoparticle properties and the cytotoxic mechanism has been insufficiently studied. In this work, carbon dots (CDs) with strong fluorescence were found and purified from canned yellow croaker, and their cytotoxicity was investigated for the first time. The canned yellow croaker CDs are nearly spherical with a particle size distribution in the range of 1.8–5.8 nm. The fluorescence quantum yield of the isolated CDs is 9.7% and the maximum excitation wavelength is 340 nm, with a significant redshift phenomenon in fluorescence spectra. The surface elemental analysis showed that the composition of the canned yellow croaker CDs was C (76.42%), N (6.49%), and O (16.7%), and various functional groups are on the surface. The CDs have good stability in sodium chloride solution and the fluorescence intensity was stable within the pH value of 4 to 10. A strong fluorescence quenching effect was found upon the addition of Cu2+ and Fe3+ to the CD aqueous solution. The CDs can easily enter the interior of the live cells. Moreover, a concentration-dependent behavior of HepG2 cell viability was found when the cells were incubated with the canned yellow croaker CDs. Glycolysis and mitochondrial function analysis of HepG2 cells revealed that both the extracellular acidification rate and oxygen consumption rate significantly decreased in contrast to the normal level prior to the addition of CDs. In addition, the CDs significantly inhibited the glycolytic pathway by reducing the activity of key enzymes hexokinase and pyruvate kinase in the glycolytic pathway.
研究领域:
食品科学
·
毒理学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
BRITISH JOURNAL OF DERMATOLOGY
·
2017
·Vol. 176
·期 3
·713-722
·
IF 4.706
Kang H.,Li X.,Zhou Q.,Quan C.,Xue F.,Zheng J.,Yu Y.
BackgroundRecent studies have shown that dysregulated metabolic pathways are linked to psoriasis pathogenesis. However, an extensive, unbiased metabolic analysis in patients with psoriasis has not been completely explored. The metabolome represents the end products of proteomics or cellular processes that may be closely associated with the pathogenesis of psoriasis.ObjectivesTo determine the differences in serum metabolomic profiles among patients with psoriasis and healthy controls with the goal of identifying potential biomarkers in patients with psoriasis.Materials and methodsSerum metabolomic profiles from 29 subjects (14 patients with psoriasis and 15 sex‐ and age‐matched healthy controls). The serum metabolites were analysed by gas chromatography‐mass spectrometry based on a combined full scan and selected‐ion monitoring mode.ResultsMultivariate statistical analysis of metabolomics data revealed altered serum metabolites between the patients with psoriasis and healthy individuals. Compared with healthy individuals, patients with psoriasis had higher levels of amino acids including asparagine, aspartic acid, isoleucine, phenylalanine, ornithine and proline; higher levels of lactic acid and urea; and lower levels of crotonic acid, azelaic acid, ethanolamine and cholesterol.ConclusionsIt appears that the glycolysis pathway and amino acid metabolic activity are increased in patients with psoriasis. These metabolic perturbations may stem from increased demand for protein biosynthesis and keratinocyte hyperproliferation. Our findings may help to elucidate the pathogenesis of psoriasis and provide insights into early diagnosis and therapeutic intervention.
研究领域:
皮肤病学
·
代谢组学
·
医学
✓ 已验证
DOI
PubMed
高影响因子
iScience
·
2022
·
IF 6.107
Dawei Yang,Jie Yin,Liuqun Shan,Xingling Yi,Wei Zhang,Yongbin Ding
Summary Cancer cells tend to utilize aerobic glycolysis to generate energy and metabolites; the end product of aerobic glycolysis is lactate, which promotes lysine lactylation (Kla). Kla is a newly discovered histone post-translational modification (PTM) that plays important roles in regulating gene expression. However, Kla in non-histone mammalian proteins is unclear. Here, a comprehensive analysis of lactylated proteins in gastric cancer AGS cells was conducted. There were 2375 Kla sites found in 1014 proteins. Interestingly, KEGG pathway analysis showed that these proteins were significantly enriched in spliceosome function. In addition, Kla was more abundant in gastric tumors than in adjacent tissues, and high levels of Kla in gastric tumors were associated with poor prognosis. These results suggest that Kla could be a prognostic marker in gastric cancer. This lysine lactylome analysis in gastric cancer cells, the first of its kind, provides a valuable foundation for further studies of Kla.
研究领域:
癌症生物学
·
蛋白质组学
·
分子生物学
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Cancer
·
2019
·
IF 3.182
Mingtong Ye,Nengzhi Pang,Ting Wan,Yuanling Huang,Tianyi Wei,Xuye Jiang,Yujia Zhou,Yufeng Huang,Hainan Yang,Zhenfeng Zhang,Lili Yang
Switching aerobic respiration to anaerobic glycolysis of cancer cells plays an important role in development and progression of acquired resistance. Since vitamin C enabled the inhibition of glycolysis of cancer cells, and erlotinib-resistant sub-line of HCC827 (ER6 cells) switched its metabolic features to higher glycolysis for survival, we hypothesize that vitamin C is able to inhibit glycolysis of ER6 cells. In this study, we found that both reduced vitamin C and oxidized vitamin C (DHA) could selectively suppress the viability of ER6 cells. DHA was efficient in inhibiting glycolysis and leading to energy crisis, which could be one mechanism for overcoming drug resistance to erlotinib of ER6 cells. Our data suggest that applying DHA could be a novel treatment strategy for NSCLC with acquired resistance to targeted therapy.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2018
·Vol. 5
·期 3
·1700392
·
IF 12.441
Yang Wang,Xingyun Liao,Jianguo Sun,Bin Yi,Shenglin Luo,Tao Liu,Xu Tan,Dengqun Liu,Zelin Chen,Xin Wang,Chunmeng Shi
The characterization of cancer stem-like cells (CSCs) has profound implications for elucidating cancer biology and developing treatment strategies. Although surface markers are already used to identify CSCs, the expression of these markers is controversially linked to the phenotypes in different types of tumors and does not represent all functionally relevant of CSCs. Very recently, hyperactive HIF-1α/glycolysis metabolic pathway is recognized as a master regulator of CSCs. In this study, a near-infrared fluorescent small-molecule, IR-780, is identified for the exclusive characterization of human CSCs through the HIF-1α/glycolysis dependent mitochondrial transporter ABCB10's activity. The results identified for the first time that ABCB10 is involved in the preferential uptake of IR-780 in CSCs, which is regulated by HIF-1α via the direct interaction with the binding site of ABCB10 gene promoter region. In addition, IR-780 is demonstrated to conjugate with anticancer drug 5-fluorouracil to act as a potential drug delivery carrier for CSC-targeted therapy. Thus, the studies provide a new rational approach independent of surface markers to characterize CSCs via small-molecule-based imaging of HIF-1α/glycolysis hyperactive metabolic pathway dependent mitochondrial transporter's activity, which holds promise for the further development of CSCs targeted diagnostic and therapeutic strategies.
研究领域:
肿瘤学
·
分子生物学
·
癌症代谢
·
药物递送系统
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 7.3
Wenyan She,Tingting Liu,Haimei Li,Zichen Wang,Zhibin Guo,Yi Liu,Yujiao Liu
In many types of cancers, pyruvate dehydrogenase kinase (PDK) is abnormally overexpressed and has become a promising target for cancer therapy. However, few highly effective inhibitors of PDK have been reported to date. Herein, we designed and synthesized a series of PDK inhibitors based on dichloroacetate (DCA) and arsenicals. Of the 27 compounds, 1f demonstrated PDK inhibition with high efficiency at a cellular level (IC50 = 2.0 μM) and an enzyme level (EC50 = 68 nM), far more effective than that of DCA. In silico, in vitro, and in vivo studies demonstrated that 1f inhibited PDK, shifted the energy metabolism from aerobic glycolysis to oxidative phosphorylation, and induced cell apoptosis. Moreover, new 1f-loaded nanoparticles were developed, and the administration of high-drug-loading nanoparticles (0.15 mg/kg) caused up to 90% tumor shrinkage without any apparent toxicity. Hence, this study provided a novel metabolic therapy for cancer treatment.
研究领域:
肿瘤学
·
药理学
·
生物技术
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2024
·
IF 6.9
Xia Rui-xue,Zou Pei-chen,Xie Jun-ting,Tang Ya-bin,Gong Miao-miao,Fan Fu,Aihemaiti Ayinazhaer,Liu Yu-qing,Shen Ying,Zhou Bin-bing S.,Zhu Liang,Lei Hui-min
RAS is the most frequently mutated oncoprotein for cancer driving. Understanding of RAS biology and discovery of druggable lynchpins in RAS pathway is a prerequisite for targeted therapy of RAS-mutant cancers. The recent identification of KRAS G12C inhibitor breaks the “undruggable” curse on RAS and has changed the therapy paradigm of KRAS-mutant cancers. However, KRAS mutations, let alone KRAS G12C mutation, account for only part of RAS-mutated cancers. Targeted therapies for cancers harboring other RAS mutations remain the urgent need. In this study we explored the pivotal regulatory molecules that allow for broad inhibition of RAS mutants. By comparing the expression levels of nucleotide pyrophosphatase (NPPS) in a panel of cell lines and the functional consequence of increased NPPS expression in RAS-mutant cells, we demonstrated that cancer cells with various kinds of RAS mutations depended on NPPS for growth and survival, and that this dependence conferred a vulnerability of RAS-mutant cancer to treatment of NPPS inhibition. RAS-mutant cells, compared with RAS-wildtype cells, bored and required an upregulation of NPPS. Transcriptomics and metabolomics analyses revealed a NPPS-dependent hyperglycolysis in RAS-mutant cells. We demonstrated that NPPS promoted glucose-derived glycolytic intermediates in RAS-mutant cells by enhancing its interaction with hexokinase 1 (HK1), the enzyme catalyzing the first committed step of glycolysis. Pharmacological inhibition of NPPS-HK1 axis using NPPS inhibitor Enpp-1-IN-1 or HK1 inhibitor 2-deoxyglucose (2-DG), or genetic interfere with NPPS suppressed RAS-mutant cancers in vitro and in vivo. In conclusion, this study reveals an unrecognized mechanism and druggable lynchpin for modulation of pan-mutant-RAS pathway, proposing a new potential therapeutic approach for treating RAS-mutant cancers.
研究领域:
肿瘤学
·
分子生物学
·
癌症治疗
✓ 已验证
DOI
高影响因子
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