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Stem Cell Research & Therapy Jan 2024Acute kidney injury (AKI) has a complex pathophysiology and imposes serious health concerns worldwide. Extracellular vesicles (EVs) derived from induced mesenchymal stem...
BACKGROUND
Acute kidney injury (AKI) has a complex pathophysiology and imposes serious health concerns worldwide. Extracellular vesicles (EVs) derived from induced mesenchymal stem cells (iMSCs) have been recognized as novel cell-free therapeutics for various inflammatory and degenerative disorders. In this study, we investigated whether iMSCs stimulated with a pan-peroxisome proliferator-activated receptor (PPAR) agonist could enhance the therapeutic efficacy of EVs against AKI.
METHODS
Human iMSCs were primed with or without lanifibranor, a PPAR agonist for 24 h, and EVs were collected after an additional 24 h. The basic characteristics of EVs were evaluated using cryo-transmission electron microscopy imaging, immunoblot detection of EV markers, nanoparticle tracking analysis, and localization in AKI kidneys. In vitro, the potential of the EVs to promote the growth and survival of HK-2 cells undergoing cisplatin-induced apoptosis and anti-inflammatory effects in M1-polarized THP-1 was compared. Subsequently, AKI was induced in BALB/c mice using cisplatin. After 8 and 24 h of cisplatin treatment, iMSC-EVs or pan-PPAR-iMSC-EVs were injected intravascularly. At 96 h after cisplatin administration, the renoprotective effects of iMSC-EVs or pan-PPAR-iMSC-EVs in inhibiting inflammation and apoptosis were compared using serum biochemistry, histology, immunohistochemistry, and gene expression analysis by qPCR.
RESULTS
Both EV types expressed EV markers and had typical EV morphology, and their localization in the renal tissue was confirmed. The proliferation and survival of HK-2 cells were higher in pan-PPAR-iMSC-EVs than those in iMSC-EVs. In M1-polarized THP-1 cells, the reduction in the mRNA expression of inflammatory cytokines was more significant in pan-PPAR-iMSC-EVs than that in iMSC-EVs. In the mouse model of cisplatin-induced AKI, pan-PPAR-iMSC-EVs markedly enhanced renoprotective effects compared to iMSC-EVs. Specifically, pan-PPAR-iMSC-EVs reduced tissue inflammation, immune cell infiltration, and apoptosis. Pan-PPAR-iMSC-EVs also increased renal capillary density.
CONCLUSION
Priming iMSCs with a PPAR agonist significantly improved the therapeutic potential of EVs by reducing inflammation and apoptosis. The reported strategy may contribute to the development of a novel cell-free option for AKI treatment.
TRIAL REGISTRATION
Not applicable.
Topics: Animals; Humans; Mice; Acute Kidney Injury; Cisplatin; Extracellular Vesicles; Inflammation; Peroxisome Proliferator-Activated Receptors; Mesenchymal Stem Cells
PubMed: 38167146
DOI: 10.1186/s13287-023-03577-0 -
Advanced Science (Weinheim,... Mar 2024The DNA damage response is essential for preserving genome integrity and eliminating damaged cells. Although cellular metabolism plays a central role in cell fate...
The DNA damage response is essential for preserving genome integrity and eliminating damaged cells. Although cellular metabolism plays a central role in cell fate decision between proliferation, survival, or death, the metabolic response to DNA damage remains largely obscure. Here, this work shows that DNA damage induces fatty acid oxidation (FAO), which is required for DNA damage-induced cell death. Mechanistically, FAO induction increases cellular acetyl-CoA levels and promotes N-alpha-acetylation of caspase-2, leading to cell death. Whereas chemotherapy increases FAO related genes through peroxisome proliferator-activated receptor α (PPARα), accelerated hypoxia-inducible factor-1α stabilization by tumor cells in obese mice impedes the upregulation of FAO, which contributes to its chemoresistance. Finally, this work finds that improving FAO by PPARα activation ameliorates obesity-driven chemoresistance and enhances the outcomes of chemotherapy in obese mice. These findings reveal the shift toward FAO induction is an important metabolic response to DNA damage and may provide effective therapeutic strategies for cancer patients with obesity.
Topics: Mice; Animals; Humans; Oxidation-Reduction; Fatty Acids; PPAR alpha; Mice, Obese; Drug Resistance, Neoplasm; Obesity; Cell Death
PubMed: 38145969
DOI: 10.1002/advs.202304702 -
Molecules (Basel, Switzerland) Dec 2023(1) Background: Ginsenoside Rb1-PLGA nanoparticles (GRb1@PLGA@NPs) represent a novel nanotherapeutic system, yet their therapeutic efficacy and underlying mechanisms for...
(1) Background: Ginsenoside Rb1-PLGA nanoparticles (GRb1@PLGA@NPs) represent a novel nanotherapeutic system, yet their therapeutic efficacy and underlying mechanisms for treating heart failure (HF) remain unexplored. This study aims to investigate the potential mechanisms underlying the therapeutic effects of GRb1@PLGA@NPs in HF treatment; (2) Methods: The left anterior descending coronary artery ligation was employed to establish a HF model in Sprague-Dawley rats, along with an in vitro oxidative stress model using H9c2 myocardial cells. Following treatment with GRb1@PLGA@NPs, cardiac tissue pathological changes and cell proliferation were observed. Additionally, the serum levels of biomarkers such as NT-proBNP, TNF-α, and IL-1β were measured, along with the expression of the ROS/PPARα/PGC1α pathway; (3) Results: GRb1@PLGA@NPs effectively ameliorated the pathological status of cardiac tissues in HF rats, mitigated oxidative stress-induced myocardial cell damage, elevated SOD and MMP levels, and reduced LDH, MDA, ROS, NT-proBNP, TNF-α, and IL-1β levels. Furthermore, the expression of PPARα and PGC1α proteins was upregulated; (4) Conclusions: GRb1@PLGA@NPs may attenuate myocardial cell injury and treat HF through the ROS/PPARα/PGC1α pathway.
Topics: Rats; Animals; Rats, Sprague-Dawley; Reactive Oxygen Species; PPAR alpha; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Tumor Necrosis Factor-alpha; Heart Failure
PubMed: 38138606
DOI: 10.3390/molecules28248118 -
Oncogene Feb 2024Lipid droplets (LDs) are dynamic organelles with a neutral lipid core surrounded by a phospholipid monolayer. Solid tumors exhibit LD accumulation, and it is believed...
Lipid droplets (LDs) are dynamic organelles with a neutral lipid core surrounded by a phospholipid monolayer. Solid tumors exhibit LD accumulation, and it is believed that LDs promote cell survival by providing an energy source during energy deprivation. However, the precise mechanisms controlling LD accumulation and utilization in prostate cancer are not well known. Here, we show peroxisome proliferator-activated receptor α (PPARα) acts downstream of PIM1 kinase to accelerate LD accumulation and promote cell proliferation in prostate cancer. Mechanistically, PIM1 inactivates glycogen synthase kinase 3 beta (GSK3β) via serine 9 phosphorylation. GSK3β inhibition stabilizes PPARα and enhances the transcription of genes linked to peroxisomal biogenesis (PEX3 and PEX5) and LD growth (Tip47). The effects of PIM1 on LD accumulation are abrogated with GW6471, a specific inhibitor for PPARα. Notably, LD accumulation downstream of PIM1 provides a significant survival advantage for prostate cancer cells during nutrient stress, such as glucose depletion. Inhibiting PIM reduces LD accumulation in vivo alongside slow tumor growth and proliferation. Furthermore, TKO mice, lacking PIM isoforms, exhibit suppression in circulating triglycerides. Overall, our findings establish PIM1 as an important regulator of LD accumulation through GSK3β-PPARα signaling axis to promote cell proliferation and survival during nutrient stress.
Topics: Male; Humans; Animals; Mice; Glycogen Synthase Kinase 3 beta; Lipid Droplets; PPAR alpha; Prostatic Neoplasms; Cell Proliferation; Proto-Oncogene Proteins c-pim-1
PubMed: 38097734
DOI: 10.1038/s41388-023-02914-0 -
Biomedicine & Pharmacotherapy =... Jan 2024Rheumatoid arthritis (RA) is a chronic inflammatory condition known for its irreversible destructive impact on the joints. Chondrocytes play a pivotal role in the...
Rheumatoid arthritis (RA) is a chronic inflammatory condition known for its irreversible destructive impact on the joints. Chondrocytes play a pivotal role in the production and maintenance of the cartilage matrix. However, the presence of inflammatory cytokines can hinder chondrocyte proliferation and promote apoptosis. Isoliquiritigenin (ISL), a flavonoid, potentially exerts protective effects against various inflammatory diseases. However, its specific role in regulating the nuclear factor E2-associated factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in chondrocytes in RA remains unclear. To investigate this, this study used human chondrocytes and Sprague-Dawley rats to construct in vitro and in vivo RA models, respectively. The study findings reveal that cytokines markedly induced oxidative stress, the activation of matrix metalloproteinases, and apoptosis both in vitro and in vivo. Notably, ISL treatment significantly mitigated these effects. Moreover, Nrf2 or HO-1 inhibitors reversed the protective effects of ISL, attenuated the expression of Nrf2/HO-1 and peroxisome proliferator-activated receptor gamma-coactivator-1α, and promoted chondrocyte apoptosis. This finding indicates that ISL primarily targets the Nrf2/HO-1 pathway in RA chondrocytes. Moreover, ISL treatment led to improved behavior scores, reduced paw thickness, and mitigated joint damage as well as ameliorated oxidative stress in skeletal muscles in an RA rat model. In conclusion, this study highlights the pivotal role of the Nrf2/HO-1 pathway in the protective effects of ISL and demonstrates the potential of ISL as a treatment option for RA.
Topics: Rats; Humans; Animals; Heme Oxygenase-1; Chondrocytes; NF-E2-Related Factor 2; Rats, Sprague-Dawley; Oxidative Stress; Arthritis, Rheumatoid; Cytokines; Apoptosis
PubMed: 38091640
DOI: 10.1016/j.biopha.2023.116006 -
Frontiers in Immunology 2023Rates of renal cell carcinoma (RCC) occurrence and mortality are steadily rising. In an effort to address this issue, the present bioinformatics study was developed with...
BACKGROUND
Rates of renal cell carcinoma (RCC) occurrence and mortality are steadily rising. In an effort to address this issue, the present bioinformatics study was developed with the goal of identifying major lipid metabolism biomarkers and immune infiltration characteristics associated with RCC cases.
METHODS
The Cancer Genome Atlas (TCGA) and E-MTAB-1980 were used to obtain matched clinical and RNA expression data from patients diagnosed with RCC. A LASSO algorithm and multivariate Cox regression analyses were employed to design a prognostic risk model for these patients. The tumor immune microenvironment (TIME) in RCC patients was further interrogated through ESTIMATE, TIMER, and single-cell gene set enrichment analysis (ssGSEA) analyses. Gene Ontology (GO), KEGG, and GSEA enrichment approaches were further employed to gauge the mechanistic basis for the observed results. Differences in gene expression and associated functional changes were then validated through appropriate molecular biology assays.
RESULTS
Through the approach detailed above, a risk model based on 8 genes associated with RCC patient overall survival and lipid metabolism was ultimately identified that was capable of aiding in the diagnosis of this cancer type. Poorer prognostic outcomes in the analyzed RCC patients were associated with higher immune scores, lower levels of tumor purity, greater immune cell infiltration, and higher relative immune status. In GO and KEGG enrichment analyses, genes that were differentially expressed between risk groups were primarily related to the immune response and substance metabolism. GSEA analyses additionally revealed that the most enriched factors in the high-risk group included the stable internal environment, peroxisomes, and fatty acid metabolism. Subsequent experimental validation and revealed that the most significantly differentially expressed gene identified herein, ALOX5, was capable of suppressing RCC tumor cell proliferation, invasivity, and migration.
CONCLUSION
In summary, a risk model was successfully established that was significantly related to RCC patient prognosis and TIME composition, offering a robust foundation for the development of novel targeted therapeutic agents and individualized treatment regimens. In both immunoassays and functional analyses, dysregulated lipid metabolism was associated with aberrant immunological activity and the reprogramming of fatty acid metabolic activity, contributing to poorer outcomes.
Topics: Humans; Carcinoma, Renal Cell; Prognosis; Lipid Metabolism; Kidney Neoplasms; Fatty Acids; Gene Expression; Tumor Microenvironment
PubMed: 38090559
DOI: 10.3389/fimmu.2023.1324205 -
Frontiers in Pharmacology 2023Peroxisome proliferator-activated receptor gamma (PPARG), a key transcription factor involved in lipid metabolism and glucose homeostasis, has been implicated in various...
Integrated investigation and experimental validation of PPARG as an oncogenic driver: implications for prognostic assessment and therapeutic targeting in hepatocellular carcinoma.
Peroxisome proliferator-activated receptor gamma (PPARG), a key transcription factor involved in lipid metabolism and glucose homeostasis, has been implicated in various types of cancer. However, its precise role in cancer remains unclear. In this study, we conducted a comprehensive pan-cancer analysis of PPARG expression using various types of cancer obtained from public databases. We observed significant heterogeneity in PPARG expression across different types of cancer. The association between PPARG expression and patient prognosis was investigated using Cox proportional hazards regression models and survival analysis. Clinical features and protein expression levels in the cohort showed that PPARG expression was strongly associated, suggesting its potential as a therapeutic target. We also evaluated the prognostic potential of PPARG by analyzing immune infiltration and genomic stability. We experimentally validated the potential of PPARG as a therapeutic target by analyzing drug sensitivity profiles, molecular docking simulations, and cell proliferation assays associated with PPARG expression. We identified common expression patterns of PPARG with other genes involved in key carcinogenic pathways. This provides deeper insights into the molecular mechanisms underlying its carcinogenic role. Additionally, functional enrichment analysis revealed significant enrichment of genes related to drug metabolism, cell proliferation, and immune response pathways associated with PPARG. Our findings highlight the importance of PPARG in the broader biology of cancer and suggest its potential as a diagnostic and therapeutic target for specific types of cancer. The results of our study provide strong support for the potential role of PPARG as a promising prognostic biomarker and immunotherapeutic target across various types of cancer.
PubMed: 38044948
DOI: 10.3389/fphar.2023.1298341 -
PPAR Research 2023Peroxisome proliferator-activated receptor gamma (PPAR) is a key nuclear receptor transcription factor that is highly expressed in trophoblastic cells during embryonic...
Peroxisome proliferator-activated receptor gamma (PPAR) is a key nuclear receptor transcription factor that is highly expressed in trophoblastic cells during embryonic attachment and is accompanied by rapid cell proliferation and increased lipid accumulation. We previously showed that the autophagy pathway is activated in cells after activation of PPAR, accompanied by increased lipid accumulation. In this study, we used PPAR agonist rosiglitazone and inhibitor GW9662, as well as autophagy activator rapamycin and inhibitor 3-methyladenine, to unravel the probable mechanism of PPAR engaged in lipid metabolism in sheep trophoblast cells (STCs). After 12 h, 24 h, and 48 h of drug treatment, the levels of autophagy-related proteins were detected by Western blot, the triglyceride content and MDA level of cells were detected by colorimetry, and the lipid droplets and lysosomes were localized by immunofluorescence. We found that PPAR inhibited the activity of mammalian target of rapamycin (mTOR) pathway in STCs for a certain period of time, promoted the increase of autophagy and lysosome formation, and enhanced the accumulation of lipid droplets and triglycerides. Compared with cells whose PPAR function is activated, blocking autophagy before activating PPAR will hinder lipid accumulation in STCs. Pretreatment of cells with rapamycin promoted autophagy with results similar to rosiglitazone treatment, while inhibition of autophagy with 3-methyladenine reduced lysosome and lipid accumulation. Based on these observations, we conclude that PPAR can induce autophagy by blocking the mTOR pathway, thereby promoting the accumulation of lipid droplets and lysosomal degradation, providing an energy basis for the rapid proliferation of trophoblast cells during embryo implantation. In brief, this study partially revealed the molecular regulatory mechanism of PPAR, mTOR pathway, and autophagy on trophoblast cell lipid metabolism, which provides a theoretical basis for further exploring the functional regulatory network of trophoblast cells during the attachment of sheep embryos.
PubMed: 38020065
DOI: 10.1155/2023/6422804 -
International Journal of Molecular... Nov 2023Preeclampsia (PE) is one of the pregnancy complications, leading to major maternal and fetal morbidity and mortality; however, the underlying mechanisms of PE still...
Preeclampsia (PE) is one of the pregnancy complications, leading to major maternal and fetal morbidity and mortality; however, the underlying mechanisms of PE still remain unclear. We aimed to explore the role of apolipoprotein A1 (APOA1) in the pathophysiology of PE. The expression of APOA1 was elevated in both plasma and placental tissues, as detected by Western blotting, immunohistochemistry, and a qRT-PCR assay. Importantly, we detected the concentration of APOA1 using the ELISA assay in normal control women ( = 30) and women with preeclampsia ( = 29) from a prospective cohort study. The concentration of APOA1 was not significantly altered in plasma during early and mid-term gestation of the PE patients compared to the NP patients; however, it was elevated during late gestation. Additionally, the concentration of APOA1 was positively associated with systolic blood pressure during late gestation. The proliferation and invasion of trophoblast were all increased in HTR8/SVneo cells transfected with siRNA and decreased in HTR8/SVneo cells treated with the recombinant human APOA1 protein (rhAPOA1). Additionally, we used public datasets to investigate the downstream genes of APOA1 and qRT-PCR for validation. Furthermore, we explored the transcriptional activity of peroxisome proliferator-activated receptor gamma (PPARγ) in APOA1 by using a luciferase assay, which showed that the promoter was activated by PPARγ. Additionally, the inhibitory effect of rhAPOA1 on the ability of trophoblast invasion and proliferation can be rescued by the PPARγ inhibitor. Our findings suggest the crucial role of APOA1 in PE, which might provide a new strategy for the prevention and treatment of PE.
Topics: Pregnancy; Humans; Female; Placenta; Pre-Eclampsia; Apolipoprotein A-I; PPAR gamma; Prospective Studies; Trophoblasts; Cell Movement; Cell Proliferation
PubMed: 38003549
DOI: 10.3390/ijms242216363 -
Journal of Cellular and Molecular... Nov 2023Hepatocellular carcinoma (HCC), the main pathological type of liver cancer, is linked to risk factors such as viral hepatitis, alcohol intake and non-alcoholic fatty... (Review)
Review
Hepatocellular carcinoma (HCC), the main pathological type of liver cancer, is linked to risk factors such as viral hepatitis, alcohol intake and non-alcoholic fatty liver disease (NAFLD). Recent advances have greatly improved our understanding that NAFLD is playing a major risk factor for HCC. Peroxisome proliferator-activated receptors (PPARs) are a class of transcription factors divided into three subtypes: PPARα (PPARA), PPARδ/β (PPARD) and PPARγ (PPARG). As important nuclear receptors, PPARs are involved in many physiological processes, and PPARs can improve NAFLD by regulating lipid metabolism, accelerating fatty acid oxidation and inhibiting inflammation. In recent years, some studies have shown that PPARs can participate in the occurrence and development of HCC by regulating metabolic pathways. In addition, PPAR modulators have been reported to inhibit the proliferation and metastasis of HCC cells and can enhance the curative effect of conventional treatments. This article reviews the role of PPARs in the occurrence and development of HCC, as well as its value in the diagnosis, treatment and prognosis of HCC, in order to provide directions for future research.
PubMed: 37987033
DOI: 10.1111/jcmm.18042