Cell Reports Medicine
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2025
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IF 10.6
Liming Gui,Kaiwen Chen,Jingjing Yan,Ping Chen,Wei-Qiang Gao,Bin Ma
The induction of immunogenic cell death (ICD) impedes tumor progression via both tumor cell-intrinsic and -extrinsic mechanisms, representing a robust therapeutic strategy. However, ICD-targeted therapy remains to be explored and optimized. Through kinome-wide CRISPR-Cas9 screen, NUAK family SNF1-like kinase 1 (NUAK1) is identified as a potential target. The ICD-provoking effect of NUAK1 inhibition depends on the production of reactive oxygen species (ROS), consequent to the downregulation of nuclear factor erythroid 2-related factor 2 (NRF2)-mediated antioxidant gene expression. Moreover, the mevalonate pathway/cholesterol biosynthesis, activated by spliced form of X-box binding protein 1 (XBP1s) downstream of ICD-induced endoplasmic reticulum (ER) stress, functions as a negative feedback mechanism. Targeting the mevalonate pathway with CRISPR knockout or the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor simvastatin amplifies NUAK1 inhibition-mediated ICD and antitumor activity, while cholesterol dampens ROS and ICD, and therefore also dampens tumor suppression. The combination of NUAK1 inhibitor and statin enhances the efficacy of anti-PD-1 therapy. Collectively, our study unveils the promise of blocking the mevalonate-cholesterol pathway in conjunction with ICD-targeted immunotherapy.
研究领域:
癌症研究
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免疫学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Journal of Animal Science and Biotechnology
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2022
·Vol. 13
·期 1
·1-13
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IF 6.175
Zhou Xiaoge,Mo Zhaoyi,Li Yankun,Huang Liang,Yu Sihai,Ge Lan,Hu Yamei,Shi Shengjie,Zhang Lutong,Wang Liguang,Gao Lei,Yang Gongshe,Chu Guiyan
Background Oleic acid is an abundant free fatty acid present in livestock that are in a negative energy-balance state, and it may have detrimental effects on female reproduction and fertility. Oleic acid induces lipid accumulation in bovine granulosa cells, which leads to a foam cell-like morphology and reduced steroidogenesis. However, why oleic acid increases lipid accumulation but decreases steroidogenesis remains unclear. This study focused on oleic acid’s effects on lipid type and steroidogenesis. Results Oleic acid increased the lipid accumulation in a concentration-dependent manner and mainly increased the triglyceride level and decreased the cholesterol ester level. Oleic acid also led to a decline in estradiol and progesterone production in porcine granulosa cells in vitro. In addition, oleic acid up-regulated the expression of CD36 and diacylglycerol acyltransferase 2, but down-regulated the expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, scavenger receptor class B member 1 and acetyl-Coenzyme A acetyltransferase 2, as well as steroidogenesis-related genes, including cytochrome P450 family 11 subfamily A member 1, cytochrome P450 family 19 subfamily A member 1 and 3 as well as steroidogenic acute regulatory protein at the mRNA and protein levels. An oleic acid-rich diet also enhanced the triglyceride levels and reduced the cholesterol levels in ovarian tissues of female mice, which resulted in lower estradiol levels than in control-fed mice. Compared with the control, decreases in estrus days and the numbers of antral follicles and corpora lutea, as well as an increase in the numbers of the atretic follicles, were found in the oleic acid-fed female mice. Conclusions Oleic acid changed the lipid type stored in lipid droplets of ovarian granulosa cells, and led to a decrease in steroidogenesis. These results improve our understanding of fertility decline in livestock that are in a negative energy-balance state.
研究领域:
生殖生物学
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内分泌学
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动物科学
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DOI
PubMed
高影响因子
ENVIRONMENTAL RESEARCH
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2023
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IF 8.3
Wei Peng,Yufeng Qian,Xuchen Qi
Glioma is the most common primary malignant tumor of the nervous system that starts in the glial cells. Its high invasiveness and recurrence pose major challenges to its effective treatment. Ferroptosis is a new type of programmed cell death characterized by intracellular iron overload and accumulation of lipid peroxides. Existing studies have demonstrated the efficacy of targeted ferroptosis therapy in the treatment of glioma. In this study, folic acid (FA)-modified layered double hydroxide loaded with simvastatin (SIM), a ferroptosis drug, was used to prepare a novel ferroptosis nanodrug (FA-LDH@SIM). The prepared nanodrug improved the therapeutic effect of SIM on glioma. Compared with free SIM, FA-LDH@SIM showed greater cytotoxicity, significantly inhibited glioma cell proliferation, and significantly inhibited glioma invasion and migration ability. Furthermore, SIM could induce changes in certain ferroptosis indicators, including increased intracellular LPO, ROS and MDA level, decreased GSH production, increased divalent iron level, and changes in mitochondrial morphology. Further experiments revealed that SIM induced ferroptosis in tumor cells by down-regulating HMGCR expression and inhibiting the mevalonate pathway to down-regulate GPX4 expression. In addition, the FA-LDH@SIM group significantly inhibited tumor growth after treatment in the animal glioma model. These results indicate that the FA-LDH@SIM nanodrug delivery system exhibits excellent anti-tumor effects both in vitro and in vivo , and is an effective method for the treatment of glioma.
研究领域:
肿瘤学
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药理学
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纳米技术
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF DAIRY SCIENCE
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2023
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IF 3.5
Shendong Zhou,Mengru Chen,Meijuan Meng,Nana Ma,Wan Xie,Xiangzhen Shen,Zhixin Li,Guangjun Chang
ABSTRACT Ketosis is a metabolic disease that often occurs in dairy cows postpartum and results from disordered lipid metabolism. Acetyl-coenzyme A (CoA) acetyltransferase 2 ( ACAT2 ) is important for balancing cholesterol and triglyceride ( TG ) metabolism; however, its role in subclinical ketotic dairy cows is unclear. This study aimed to explore the potential correlation between ACAT2 and lipid metabolism disorders in subclinical ketotic cows through in vitro and in vivo experiments. In the in vivo experiment, liver tissue and blood samples were collected from healthy cows ( CON , n = 6, β-hydroxybutyric acid [ BHBA ] concentration < 1.0 mM) and subclinical ketotic cows (subclinical ketosis [ SCK] , n = 6, BHBA concentration = 1.2–3.0 mM) to explore the effect of ACAT2 on lipid metabolism disorders in SCK cows. For the in vitro experiment, bovine hepatocytes ( BHEC ) were used as the model. The effects of BHBA on ACAT2 and lipid metabolism were investigated via BHBA concentration gradient experiments. Subsequently, the relation between ACAT2 and lipid metabolism disorder was explored by transfection with siRNA of ACAT2. Transcriptomics showed an upregulation of differentially expression genes ( DEGs ) during lipid metabolism and significantly lower ACAT2 mRNA levels in the SCK group. Compared with the CON group in vivo, the SCK group showed significantly higher expression levels of peroxisome proliferator–activated receptor γ ( PPARγ ) and sterol regulator element binding protein 1c ( SREBP1c ) and significantly lower expression levels of peroxisome proliferator-activated receptor α ( PPARα ), carnitine palmitoyl-transferase 1A ( CPT1A ), sterol regulatory element binding transcription factor 2 ( SREBP2 ), and 3-hydroxy-3-methylglutaryl-CoA reductase ( HMGCR ). Moreover, the SCK group had a significantly higher liver TG content and significantly lower plasma total cholesterol ( TC ) and free cholesterol ( FC ) content. These results were indicative of TG and cholesterol metabolism disorders in the liver of dairy cows with SCK. Additionally, the SCK group showed an increased expression of Perilipin-2 ( PLIN2 ), decreased expression of apolipoprotein B ( APOB ), and decreased plasma concentration of very low-density lipoproteins ( VLDL ) and low-density lipoproteins-cholesterol ( LDL-C ) by downregulating ACAT2, which indicated an accumulation of TG in liver. I n vitro experiments showed that BHBA induced an increase in the TG content of BHEC, decreased content TC, increased expression of PPARγ and SREBP1c, and decreased expression of PPARα, CPT1A, SREBP2, and HMGCR. Additionally, BHBA increased the expression of PLIN2 in BHEC, decreased the expression and fluorescence intensity of ACAT2, and decreased the VLDL and LDL-C contents. Furthermore, silencing ACAT2 expression increased the TG content; decreased the TC, VLDL, and LDL-C contents; decreased the expression of HMGCR and SREBP2; and increased the expression of SREBP1c; but had no effect on the expression of PLIN2. These results suggest that ACAT2 downregulation in BHEC promotes TG accumulation and inhibits cholesterol synthesis, leading to TG and cholesterol metabolic disorders. In conclusion, ACAT2 downregulation in the SCK group inhibited cholesterol synthesis, increased TG synthesis, and reduced the contents of VLDL and LDL-C, eventually leading to disordered TG and cholesterol metabolism.
研究领域:
兽医学
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分子生物学
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生物化学
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动物生理学
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产品关联
DOI
PubMed
高影响因子
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