Project description:The study aims to explore the effect of PPARγ signaling on ferroptosis and preeclampsia (PE) development. Serum and placental tissue are collected from healthy subjects and PE patients. The PPARγ and Nrf2 decreases in the PE. Rosiglitazone intervention reverses hypoxia-induced trophoblast ferroptosis and decreases lipid synthesis by regulating Nfr2 and SREBP1. Compared to the Hypoxia group, the migratory and invasive abilities enhance after rosiglitazone and ferr1 treatment. Rosiglitazone reduces the effect of hypoxia and erastin. The si-Nrf2 treatment attenuats the effects of rosiglitazone on proliferation, migration, and invasion. The si-Nrf2 does not affect SREBP1 expression. PPARγ agonists alleviates ferroptosis in the placenta of the PE rats. The study confirms that PPARγ signaling and ferroptosis-related indicators were dysregulated in PE. PPARγ/Nrf2 signaling affects ferroptosis by regulating lipid oxidation rather than SREBP1-mediated lipid synthesis. In conclusion, our study find that PPARγ can alleviate PE development by regulating lipid oxidation and ferroptosis.
Project description:Altered lipid metabolism is an emerging hallmark of cancers. Mirabilite has a therapeutic effect on colorectal cancer (CRC); however, its metabolic mechanism remains unclear. This study aims to explore the potential therapeutic targets of mirabilite protection against colorectal cancer in APCmin/+ mice model. Oral administration of mirabilite was started from the ninth month, while the same dosage of distilled water was given to both the control group and the model group. Based on lipidomics, we collected serum samples of all mice at the 20th week and used a non-targeted method to identify the lipid biomarkers of CRC. Compared with C57BL/6J mice, the metabolic profile of CRC model mice was significantly disturbed, and we identified that 25 lipid-related biomarkers, including linoleic acid, 2-hydroxybutyric acid, 6-deoxocastasterone, hypoxanthine, PC(16:1), PC(18:4), and retinyl acetate, were associated with CRC. According to the abovementioned results, there were six lipid molecules with significant differences that can be used as new targets for handling of CRC through six metabolic pathways, namely, linoleic acid metabolism, retinol metabolism, propanoate metabolism, arachidonic acid metabolism, biosynthesis of unsaturated fatty acids and purine metabolism. Compared with the model group, the metabolic profiles of these disorders tend to recover after treatment. These results indicated that the lipid molecules associated with CRC were regulated by mirabilite. In addition, we identified seven key lipid molecules, of which four had statistical significance. After administration of mirabilite, all disordered metabolic pathways showed different degrees of regulation. In conclusion, high-throughput lipidomics approach revealed mirabilite regulating the altered lipid metabolism as anticancer therapeutics.
Project description:This study is aimed at evaluating the regulatory mechanism of quercetin on lipid metabolism in the ileum of broilers to better understand these pathways decreasing abdominal fat. 480 chickens were randomly divided into 4 groups (control, 0.02% quercetin, 0.04% quercetin, and 0.06% quercetin). Breast muscle, thigh muscle, and abdominal fat pad were removed and weighed at 42 d of age. Serum was obtained by centrifuging blood samples from the jugular vein (10 ml) to determine high-density lipoprotein (HDL), total cholesterol (TC), low-density lipoprotein (LDL), triglyceride (TG), leptin, and adiponectin using ELISA. About 5 g of the ileum was harvested and immediately frozen in liquid nitrogen for RNA-seq. Then, the confirmation of RNA-seq results by the Real-Time Quantitative PCR (RT-qPCR) method was evaluated using Pearson's correlation. Compared with control, abdominal fat percentage was significantly decreased with increasing quercetin supplementation, and the best result was obtained at 0.06% dietary quercetin supplementation (P < 0.01). Breast muscle percentage was significantly decreased at 0.02% quercetin (P < 0.01), and thigh muscle percentage tended to increase (P = 0.078). Meanwhile, 0.04% and 0.06% quercetin significantly decreased TG (P < 0.01), TC (P < 0.01), and LDL content (P < 0.05) in serum. Serum leptin and adiponectin contents were significantly increased by 0.04% and 0.06% dietary quercetin supplementation, compared with the control (P < 0.01). Analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) database were used to identify differently expressed genes and lipid metabolism pathways. Quercetin decreased abdominal fat percentage through regulating fat digestion and absorption, glycerophospholipid metabolism, AMPK signaling pathway, fatty acid degradation, and cholesterol metabolism.
Project description:Stigmasterol is a sterol compound found in various traditional Chinese medicines; however, its effects on glioma remain unclear. The present study aimed to investigate the effects of stigmasterol on the biological behaviors of glioblastoma (GBM) cells and to explore the underlying mechanisms. In vitro experiments assessed its effects on GBM cell proliferation, apoptosis, cell cycle progression, invasion, migration and vasculogenic mimicry (VM). The potential targets for stigmasterol in treating GBM were identified using databases and Venn diagram analysis, followed by enrichment analysis using R language. A prognostic model related to the target genes of stigmasterol was developed through univariate Cox regression and least absolute shrinkage and selection operator analyses. Stigmasterol was found to suppress the proliferation of GBM cells in a dose‑ and time‑dependent manner, to induce apoptosis, and to inhibit invasion, migration and VM formation. Additionally, 31 potential targets of stigmasterol were identified, linked to lipid metabolism and the G protein‑coupled receptor signaling pathway. Lipid metabolism assays revealed that stigmasterol significantly reduced free fatty acids and total cholesterol levels. Furthermore, two prognosis‑related target genes, fatty acid binding protein 5 and α‑1B adrenergic receptor, were selected, and the prognostic model effectively predicted GBM outcomes. Moreover, molecular docking revealed strong binding affinities between stigmasterol and the target proteins. Overall, these findings suggested that stigmasterol may exert anti‑glioma effects, which could be potentially mediated through the regulation of lipid metabolism.
Project description:Glioma is a common and destructive brain tumor, which is highly heterogeneous with poor prognosis. Developing diagnostic and prognostic markers to identify and treat glioma early would significantly improve the therapeutic outcomes. Here, we conducted RNA next-generation sequencing with 33 glioma samples and 15 normal brain samples. We found Perilipin 1 (PLIN1) downregulated in glioma and correlated with poorer outcome. Subsequent experiments revealed that up regulation of PLIN1 led to repressed cell growth and invasion in glioma. Moreover, overexpression of PLIN1 increased lipid accumulation in glioma cells, with increasing expression of lipid biosynthesis related genes and decreasing expression of lipolysis related genes. Mechanically, we revealed that the PI3K/AKT axis could regulate PLIN1 levels in glioma, that inhibition of the activity of PI3K/AKT axis could increase PLIN1 levels in glioma. In conclusion, the dysregulation PI3K/AKT axis led to PLIN1 downregulation and the following tumor proliferation, invasion and lipid metabolism reprogramming in glioma.
Project description:Triple-negative breast cancer (TNBC) has limited therapeutic options, is highly metastatic and characterized by early recurrence. Lipid metabolism is generally deregulated in TNBC and might reveal vulnerabilities to be targeted or used as biomarkers with clinical value. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation which is facilitated by the presence of polyunsaturated fatty acids (PUFA). Here we identify fatty acid desaturases 1 and 2 (FADS1/2), which are responsible for PUFA biosynthesis, to be highly expressed in a subset of TNBC with a poorer prognosis. Lipidomic analysis, coupled with functional metabolic assays, showed that FADS1/2 high-expressing TNBC are susceptible to ferroptosis-inducing agents and that targeting FADS1/2 by both genetic interference and pharmacological approach renders those tumors ferroptosis-resistant while unbalancing PUFA/MUFA ratio by the supplementation of exogenous PUFA sensitizes resistant tumors to ferroptosis induction. Last, inhibiting lipid droplet (LD) formation and turnover suppresses the buffering capacity of LD and potentiates iron-dependent cell death. These findings have been validated in vitro and in vivo in mouse and human-derived clinically relevant models and in a retrospective cohort of TNBC patients.
Project description:An essential function of the epidermis is to provide a physical barrier that prevents the loss of water. Essential mediators of this barrier function include ceramides, cholesterol, and very long chain fatty acids, and their alteration causes human pathologies, including psoriasis and atopic dermatitis. A frameshift mutation in the human ZNF750 gene, which encodes a zinc finger transcription factor, has been shown to cause a seborrhea-like dermatitis. Here, we show that genetic deletion of the mouse homolog ZFP750 results in loss of epidermal barrier function, which is associated with a substantial reduction of ceramides, nonpolar lipids. The alteration of epidermal lipid homeostasis is directly linked to the transcriptional activity of ZFP750. ZFP750 directly and/or indirectly regulates the expression of crucial enzymes primarily involved in the biosynthesis of ceramides. Overall, our study identifies the transcription factor ZFP750 as a master regulator epidermal homeostasis through lipid biosynthesis and thus contributing to our understanding of the pathogenesis of several human skin diseases.
Project description:Various clinical studies have determined that aspirin shows anticancer effects in many human malignant cancers, including human epidermal growth factor receptor-2 (HER-2)-positive breast cancer. However, the anti-tumor mechanism of aspirin has not been fully defined. The aim of this study was to determine the role of Compound C in enhancing the anticancer effect of aspirin. HER-2-positive breast cancer cell lines were treated with aspirin with or without Compound C pre-treatment; their phenotypes and mechanisms were then analyzed in vitro and in vivo. Aspirin exhibited anticancer effects in HER-2-positive breast cancer by inhibiting cell growth and inducing apoptosis through the activation of AMP-activated protein kinase (AMPK). Unexpectedly, pre-treatment with Compound C, a widely used AMPK inhibitor, induced robust anticancer effects in cells compared to aspirin monotherapy. This anticancer effect was not distinct in HER-2 negative breast cancer MDA-MB-231 cells and may be due to the inhibition of lipid metabolism mediated by c-myc. Besides, c-myc re-expression or palmitic acid supply could partially restored cell proliferation. Aspirin exhibits anticancer effects in HER-2-positive breast cancer by regulating lipid metabolism mediated by c-myc, and Compound C strengthens these effects in an AMPK-independent manner. Our results potentially provide a novel therapeutic strategy exploiting combined aspirin and Compound C therapy for HER-2-positive breast cancer, which acts by reducing de novo lipid synthesis.
Project description:Triple-negative breast cancer (TNBC) has limited therapeutic options, is highly metastatic and characterized by early recurrence. Lipid metabolism is generally deregulated in TNBC and might reveal vulnerabilities to be targeted or used as biomarkers with clinical value. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation which is facilitated by the presence of polyunsaturated fatty acids (PUFA). Here we identify fatty acid desaturases 1 and 2 (FADS1/2), which are responsible for PUFA biosynthesis, to be highly expressed in a subset of TNBC with a poorer prognosis. Lipidomic analysis, coupled with functional metabolic assays, showed that FADS1/2 high-expressing TNBC are susceptible to ferroptosis-inducing agents and that targeting FADS1/2 by both genetic interference and pharmacological approach renders those tumors ferroptosis-resistant while unbalancing PUFA/MUFA ratio by the supplementation of exogenous PUFA sensitizes resistant tumors to ferroptosis induction. Last, inhibiting lipid droplet (LD) formation and turnover suppresses the buffering capacity of LD and potentiates iron-dependent cell death. These findings have been validated in vitro and in vivo in mouse- and human-derived clinically relevant models and in a retrospective cohort of TNBC patients.
Project description:Melatonin (Mel), a classical antioxidant, has the potential to mediate ferroptosis. Cadmium (Cd) poses a substantial threat to the male reproductive system, as it can induce testicular injury by triggering ferroptosis. The study aimed to explore the protective role and mechanism of Mel in Cd-induced ferroptosis in spermatogonia (spg). Our results demonstrated that Cd disrupted the mitochondrial ultrastructure and induced more autophagosomes in spg. Exposure to Cd resulted in a reduction of the mitochondrial membrane potential of the cells. The transcriptomics analysis revealed significant differences in gene expression associated with ferroptosis and autophagy. Mel could reverse the changes caused by Cd in the genes mentioned above. Furthermore, Cd increased cellular iron content and elevated reactive oxygen species levels, which induced oxidative stress in spg. Mel pretreatment reduced iron accumulation and oxidative damage caused by Cd exposure. Additional studies demonstrated that Cd exposure activated NCOA4-mediated ferritinophagy in spg. Mel pretreatment, as anticipated, inhibited the increased the mRNA and protein expression of ATG5, LC3B, and NCOA4 caused by Cd, ameliorated Cd-caused iron overload and oxidative stress, and protected spg from ferroptosis. Our study provides a therapeutic basis for the use of Mel to treat Cd-induced testicular injury.