Bioorganic & Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 112, P. 129923 - 129923
Published: Aug. 10, 2024
Language: Английский
Nature, Journal Year: 2025, Volume and Issue: unknown
Published: March 5, 2025
Language: Английский
Citations
1
Acta Physiologica, Journal Year: 2023, Volume and Issue: 238(4)
Published: June 27, 2023
Abstract The mitochondrial pyruvate carrier (MPC) resides in the inner membrane, where it links cytosolic and metabolism by transporting produced glycolysis into matrix. Due to its central metabolic role, has been proposed as a potential drug target for diabetes, non‐alcoholic fatty liver disease, neurodegeneration, cancers relying on metabolism. Little is known about structure mechanism of MPC, proteins involved were only identified decade ago technical difficulties concerning their purification stability have hindered progress functional structural analyses. unit MPC hetero‐dimer comprising two small homologous membrane proteins, MPC1/MPC2 humans, with alternative complex MPC1L/MPC2 forming testis, but are found throughout tree life. predicted topology each protomer consists an amphipathic helix followed three transmembrane helices. An increasing number inhibitors being identified, expanding pharmacology providing insights inhibitory mechanism. Here, we provide critical composition, structure, function summarize different classes molecule therapeutics.
Language: Английский
Citations
21
Current Obesity Reports, Journal Year: 2024, Volume and Issue: 13(3), P. 403 - 438
Published: May 4, 2024
The present study aims to review the existing literature identify pathophysiological proteins in obesity by conducting a systematic of proteomics studies. Proteomics may reveal mechanisms development and clarify links between related diseases, improving our comprehension its clinical implications.
Language: Английский
Citations
7
Disease Models & Mechanisms, Journal Year: 2023, Volume and Issue: 16(11)
Published: Nov. 1, 2023
ABSTRACT By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only uptake and efflux nutrients, but also metabolic state cell. With more than 450 members, Solute Carriers (SLCs) are largest transporter super-family, clustering into families with different substrate specificities regulatory properties. Cells types are, therefore, able to tailor their expression signatures depending on requirements, physiological importance these proteins is illustrated by mis-regulation in a number disease states. In cancer, heterogeneous, SLC family has been shown facilitate accumulation biomass, redox homeostasis, mediate crosstalk other cell within tumour microenvironment. This Review explores roles malignant settings, how can affect drug response, through either indirect modulation sensitivity or direct transport small-molecule therapeutic compounds cells.
Language: Английский
Citations
15
Advanced Science, Journal Year: 2024, Volume and Issue: 11(33)
Published: July 1, 2024
Targeting NLRP3 inflammasome has been recognized as a promising therapeutic strategy for the treatment of numerous common diseases. UK5099, long-established inhibitor mitochondrial pyruvate carrier (MPC), is previously found to inhibit macrophage inflammatory responses independent MPC expression. However, mechanisms by which UK5099 remain unclear. Here, it shown that potent in both mouse and human primary macrophages. selectively suppresses activation but not NLRC4 or AIM2 inflammasomes. Of note, retains activities on macrophages devoid expression, indicating this inhibitory effect MPC-independent. Mechanistically, abrogates mitochondria-NLRP3 interaction turn inhibits assembly inflammasome. Further, single dose persistently reduces IL-1β production an endotoxemia model. Importantly, structure modification reveals are unrelated existence activated double bond within molecule. Thus, study uncovers unknown molecular target only offers new candidate NLRP3-driven diseases also confounds its use immunometabolism studies.
Language: Английский
Citations
4
Biomolecules, Journal Year: 2025, Volume and Issue: 15(2), P. 223 - 223
Published: Feb. 3, 2025
The mitochondrial pyruvate carrier (MPC) is a transmembrane protein complex critical for cellular energy metabolism, enabling the transport of from cytosol into mitochondria, where it fuels citric acid cycle. By regulating this essential entry point carbon MPC pivotal maintaining balance and metabolic flexibility. Dysregulation activity has been implicated in several disorders, including type 2 diabetes, obesity, cancer, underscoring its potential as therapeutic target. This review provides an overview complex, examining structural components, regulatory mechanisms, biological functions. We explore current understanding transcriptional, translational, post-translational modifications that modulate function highlight clinical relevance dysfunction neurodegenerative diseases. Progress development MPC-targeting therapeutics discussed, with focus on challenges designing selective potent inhibitors. Emphasis placed modern approaches identifying novel inhibitors, particularly virtual screening computational strategies. establishes foundation further research medicinal chemistry promoting advances structure-based drug design to develop
Language: Английский
Citations
0
Molecules, Journal Year: 2025, Volume and Issue: 30(7), P. 1571 - 1571
Published: March 31, 2025
Photodynamic therapy (PDT) is a therapeutic method based on the interaction between light and photosensitizer. Supported by nanoparticles, this represents promising interdisciplinary approach for treatment of many diseases. This article reviews latest 2024 developments in design applications nanoparticles dedicated to stand-alone PDT breast cancer. Strategies improve efficacy enhancing reactive oxygen species (ROS) production, precise delivery photosensitizers their stabilization systemic circulation are discussed, among others. Results from preclinical studies indicate significant improvements efficacy, including inhibition tumor growth, reduction metastasis improvement immune microenvironment. The potential these technologies expand medicine need further clinical trials confirm safety highlighted.
Language: Английский
Citations
0
Science Advances, Journal Year: 2025, Volume and Issue: 11(16)
Published: April 18, 2025
The mitochondrial pyruvate carrier transports pyruvate, produced by glycolysis from sugar molecules, into the matrix, as a crucial transport step in eukaryotic energy metabolism. is drug target for treatment of cancers, diabetes mellitus, neurodegeneration, and metabolic dysfunction–associated steatotic liver disease. We have solved structure human MPC1L/MPC2 heterodimer inward- outward-open states cryo–electron microscopy, revealing its alternating access rocker-switch mechanism. has central binding site which contains an essential lysine histidine residue, important ΔpH-dependent also determined poses three chemically distinct inhibitor classes, exploit same state mimicking interactions using aromatic stacking interactions.
Language: Английский
Citations
0
Life Metabolism, Journal Year: 2024, Volume and Issue: 3(5)
Published: July 6, 2024
Current treatment paradigms for metabolic dysfunction-associated steatohepatitis (MASH) are based primarily on dietary restrictions and the use of existing drugs, including anti-diabetic anti-obesity medications. Given limited number approved drugs specifically MASH, recent efforts have focused promising strategies that target hepatic lipid metabolism, inflammation, fibrosis, or a combination these processes. In this review, we examined pathophysiology underlying development MASH in relation to advances effective therapy. Particularly, analyzed effects lipogenesis inhibitors, nuclear receptor agonists, glucagon-like peptide-1 (GLP-1) (GLP-1R) fibroblast growth factor mimetics, combinatorial therapeutic approaches. We summarize targets along with their preclinical clinical candidates ultimate goal optimizing prospects MASH.
Language: Английский
Citations
3
Biomolecules, Journal Year: 2024, Volume and Issue: 14(10), P. 1202 - 1202
Published: Sept. 24, 2024
Lactate accumulation and macrophage infiltration are pivotal features of both chronic inflammation cancer. Lactate, once regarded merely as an aftereffect glucose metabolism, is now gaining recognition for its burgeoning spectrum biological roles immunomodulatory significance. Recent studies have evidenced that macrophages display divergent immunophenotypes in different diseases, which play a role disease management by modulating polarization within the microenvironment. The specific patterns high-lactate environment their contribution to progression cancer remain contentious. This review presents current evidence on crosstalk lactate Additionally, we provide in-depth exploration yet enigmatic mechanisms through orchestrates pathogenesis, thereby offering novel perspectives development targeted therapeutic interventions
Language: Английский
Citations
3