Peroxisome proliferator-activated receptors: A key link between lipid metabolism and cancer progression

Clinical Nutrition, Journal Year: 2023, Volume and Issue: 43(2), P. 332 - 345

Published: Dec. 9, 2023

Lipids represent the essential components of membranes, serve as fuels for high-energy processes, and play crucial roles in signaling cellular function. One key hallmarks cancer is reprogramming metabolic pathways, especially abnormal lipid metabolism. Alterations uptake, desaturation, de novo lipogenesis, droplets, fatty acid oxidation cells all contribute to cell survival a changing microenvironment by regulating feedforward oncogenic signals, functions, oxidative other stresses, immune responses, or intercellular communication. Peroxisome proliferator-activated receptors (PPARs) are transcription factors activated acids act core sensors involved regulation homeostasis fate. In addition whole-body energy physiological states, PPARs role metabolism cancer, which receiving increasing research attention, fundamental molecular mechanisms therapies targeting PPARs. this review, we discuss how alter patterns regulate promote their own progression through Finally, potential therapeutic strategies based on recent studies from last five years.

Language: Английский

---

Functional and Structural Insights into the Human PPARα/δ/γ Targeting Preferences of Anti-NASH Investigational Drugs, Lanifibranor, Seladelpar, and Elafibranor

Antioxidants, Journal Year: 2023, Volume and Issue: 12(8), P. 1523 - 1523

Published: July 29, 2023

No therapeutic drugs are currently available for nonalcoholic steatohepatitis (NASH) that progresses from fatty liver via oxidative stress-involved pathways. Three cognate peroxisome proliferator-activated receptor (PPAR) subtypes (PPARα/δ/γ) considered as attractive targets. Although lanifibranor (PPARα/δ/γ pan agonist) and saroglitazar (PPARα/γ dual under investigation in clinical trials NASH, the development of seladelpar (PPARδ-selective agonist), elafibranor (PPARα/δ many other dual/pan agonists has been discontinued due to serious side effects or little/no efficacies. This study aimed obtain functional structural insights into potency, efficacy, selectivity against PPARα/δ/γ three current past anti-NASH investigational drugs: lanifibranor, seladelpar, elafibranor. Ligand activities were evaluated by assays detect different facets PPAR activation: transactivation assay, coactivator recruitment thermal stability assay. Seven high-resolution cocrystal structures (namely, those PPARα/δ/γ-ligand-binding domain (LBD)-lanifibranor, PPARα/δ/γ-LBD-seladelpar, PPARα-LBD-elafibranor) obtained through X-ray diffraction analyses, six which represent first deposit Protein Data Bank. Lanifibranor found bind regions pockets activated all with potencies efficacies assays. In contrast, induced (not stability) subtypes, but PPARδ/γ-LBD-elafibranor cocrystals not obtained. These results illustrate highly variable activation profiles binding modes these ligands define their pharmacological actions.

Language: Английский

---

PPARs in atherosclerosis: The spatial and temporal features from mechanism to druggable targets

Journal of Advanced Research, Journal Year: 2024, Volume and Issue: unknown

Published: March 1, 2024

Atherosclerosis is a chronic and complex disease caused by lipid disorder, inflammation, other factors. It closely related to cardiovascular diseases, the chief cause of death globally. Peroxisome proliferator-activated receptors (PPARs) are valuable anti-atherosclerosis targets that showcase multiple roles at different pathological stages atherosclerosis for cell types tissue sites. Aim Review: Considering spatial temporal characteristics evolution atherosclerosis, pharmacological clinical studies PPARs were summarized systematically updated under in vascular cells atherosclerosis. Moreover, selective PPAR modulators PPAR-pan agonists can exert their synergistic effects meanwhile reducing side effects, thereby providing novel insight into future drug development precise spatial–temporal therapeutic strategy targeting PPARs. Key Scientific Concepts Based on we have proposed importance stage- type-dependent precision therapy. Initially, improve endothelial cells' dysfunction inhibiting inflammation oxidative stress then regulate macrophages' metabolism polarization fatty streak. Finally, reduce fibrous cap formation suppressing proliferation migration smooth muscle (VSMCs). Therefore, research type-specific mechanisms provide foundation space–time treatment. demonstrated several drugs or compounds activation Selective (that specifically activate gene subsets PPARs) cell-specific effects. Furthermore, dual- pan-PPAR agonist could perform better role balancing efficacy cells/tissue-specific basis therapy

Language: Английский

---

Natural products in atherosclerosis therapy by targeting PPARs: a review focusing on lipid metabolism and inflammation

Frontiers in Cardiovascular Medicine, Journal Year: 2024, Volume and Issue: 11

Published: April 18, 2024

Inflammation and dyslipidemia are critical inducing factors of atherosclerosis. Peroxisome proliferator-activated receptors (PPARs) ligand-activated transcription control the expression multiple genes that involved in lipid metabolism inflammatory responses. However, synthesized PPAR agonists exhibit contrary therapeutic effects various side atherosclerosis therapy. Natural products structural diversity have a good safety. Recent studies find natural herbs compounds attractive on by alleviating hyperlipidemia inflammation through modulation PPARs. Importantly, preparation generally causes significantly lower environmental pollution compared to chemical compounds. Therefore, it is interesting discover novel modulator develop alternative strategies for therapy based This article reviews recent findings, mainly from year 2020 present, about roles regulation PPARs their provides theoretical basis using targeting PPARs, offers valuable information researchers interested developing modulators.

Language: Английский

---

Overview of Panax ginseng and its active ingredients protective mechanism on cardiovascular diseases

Journal of Ethnopharmacology, Journal Year: 2024, Volume and Issue: 334, P. 118506 - 118506

Published: July 2, 2024

Language: Английский

---

M6A plays a potential role in carotid atherosclerosis by modulating immune cell modification and regulating aging-related genes

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Jan. 2, 2024

Abstract RNA N6-methyladenosine (m6A) regulators play essential roles in diverse biological processes, including immune responses. Mounting evidence suggests that their dysregulation is intricately linked to numerous diseases. However, the role of m6A-associated genes carotid atherosclerosis and relationship with aging cells remain unclear. Analyze expression profiles m6A-related atherosclerosis-related datasets. Based on patterns genes, perform consistent clustering analysis samples investigate associated cell infiltration characteristics. Develop an m6A prediction model specific analyze relationships between features. The methylation modification level exhibited a substantial decrease early-stage compared late-stage samples. Subsequently, two distinct subtypes were defined through consensus analysis, lower group showing associations heightened increased aging-related genes. A composed five was formulated, results indicated this possesses effective predictive therapeutic capabilities for atherosclerosis. Furthermore, downregulation YTHDC1 resulted elevated inflammatory factors gene RGN. Single-cell data reduced may degradation inflammation-related macrophages, leading highly state artery wall. sustained release increase RGN vascular smooth muscle cells, further exacerbating progression could enhance inflammation expedite cellular aging, thereby contributing development

Language: Английский

---

Thermal-crosslinked acellular dermal matrix combined with adipose-derived stem cells to regenerate vascularized adipose tissue

Biomedical Materials, Journal Year: 2025, Volume and Issue: 20(2), P. 025020 - 025020

Published: Jan. 29, 2025

The reconstruction of large-sized soft tissue defects remains a substantial clinical challenge, with adipose engineering emerging as promising solution. acellular dermal matrix (ADM), known for its intricate spatial arrangement and active cytokine involvement, is widely employed scaffold in engineering. Since ADM shares high similarity decellularized matrix, it holds potential substitute tissue. This study explores the adipogenic ability spongy material derived from via vacuum-thermal crosslinking (T-ADM), characterized by porosity, adjustable thickness, suitable mechanical strength. Adipose-derived stem cells (ADSCs) are considered ideal seed Nevertheless, whether pre-adipogenic induction necessary before their incorporation debatable. In this context, ADSCs, both without induction, were seeded into T-ADM to regenerate vascularized A comparative analysis two constructs was performed evaluate angiogenesis adipogenesisin vitro, regeneration efficacyin vivo. Additionally, RNA-seq utilized investigate mechanisms. results showed that exhibited good performance terms volume retention maintenance adipocyte phenotype, confirming suitability engineering.In-vitrooutcomes demonstrated enhanced level but reduced promote vascularization. Furthermore, utilizing pre-induced ADSCs an insignificant superiority inin-vivofat formation, neovascularization compared those non-induced which may be attributed similar macrophage regulation, balanced modulation proliferator-activated receptor-γand hypoxia-inducible factor 1αpathways. Consequently, direct use advocated streamline process reduce associated costs. combined strategy proves feasible, convenient effective, offering addressing deficits facilitating applications.

Language: Английский

---

Conditional knockdown of hepatic PCSK9 ameliorates high-fat diet-induced liver inflammation in mice

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 3, 2025

Instruction Accumulating evidence has shown that proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with inflammation in the vascular system. However, roles of PCSK9 hepatic remain unclear. Because mainly expressed liver and modulates lipid uptake through low-density lipoprotein receptor family members, present study aimed to elucidate effect conditional knockdown on hyperlipidemia-induced underlying mechanisms action. Methods PCSK9flox/flox mice were bred ALB-Cre + obtain (−/−) , (+/−) (+/+) mice. These fed a high-fat diet for weeks induce inflammation. The effects investigated by molecular biological techniques. Moreover, findings verified vitro using HepG2 cells. Results Discussion Conditional remarkably decreased plasma levels total cholesterol alleviated injury. Mechanistically, significantly reduced pro-inflammatory factors downregulating expression Toll-like receptors, mitogen-activated protein kinase (MAPK), phosphoinositide-3 kinase/protein B, which subsequently attenuated downstream molecules, namely nuclear factor kappa-B activator protein-1. related confirmed lipid-loaded cells together siRNA, alirocumab (anti-PCSK9 antibody), and/or p38-MAPK inhibitor. attenuates following hyperlipidemia induction modulating multiple signaling pathways; this suggests targeting knockdown/inhibition appropriate agents useful not only treating but also ameliorating

Language: Английский

---

Integrative analysis of genes provides insights into the molecular and immune characteristics of mitochondria-related genes in atherosclerosis

Genomics, Journal Year: 2025, Volume and Issue: 117(2), P. 111013 - 111013

Published: Feb. 4, 2025

Language: Английский

---

Huoxue Tongluo Tablet Enhances Atherosclerosis Efferocytosis by Promoting the Differentiation of Trem2+ Macrophages via PPARγ Signaling Pathway

Phytomedicine, Journal Year: 2025, Volume and Issue: 140, P. 156579 - 156579

Published: Feb. 27, 2025

Language: Английский

---