G-Protein-Coupled Receptor 91-Dependent Signalling Does Not Influence Vascular Inflammation and Atherosclerosis in Hyperlipidaemic Mice DOI Creative Commons

Silke Griepke,

Mette Trauelsen, Michelle Duen Nilsson

et al.

Cells, Journal Year: 2023, Volume and Issue: 12(21), P. 2580 - 2580

Published: Nov. 6, 2023

The TCA cycle intermediate metabolite ‘succinate’ has been proposed as an inflammatory mediator, influencing autoimmunity and allergic reactions, through ligation to its sensing receptor SUCNR1/GPR91. Whether GPR91-mediated signalling influences the chronic process of atherosclerosis never investigated. examination publicly available datasets revealed that SUCNR1 gene is expressed in human atherosclerotic plaques, especially vascular smooth muscle cells. Using GPR91 knockout (Gpr91−/−) wildtype (WT) littermates, made hyperlipidaemic with overexpression gain-of-function mutated Pcsk9 Western diet feeding, we showed full ablation did not accelerate atherosclerosis—lesions aortic arch 2.18 ± 0.48% vs. 1.64 0.31%, roots 10.06 0.91% 10.67 1.53% for Gpr91−/− WT mice, respectively. In line this, no differences between groups were observed macrophage T-cell infiltration plaque, well polarization towards M1- or M2-like macrophages aorta, spleen liver control mice. conclusion, our study indicates global does influence inflammation atherogenesis.

Language: Английский

Cellular succinate metabolism and signaling in inflammation: implications for therapeutic intervention DOI Creative Commons
Hong Huang,

Gejing Li,

Yini He

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: June 11, 2024

Succinate, traditionally viewed as a mere intermediate of the tricarboxylic acid (TCA) cycle, has emerged critical mediator in inflammation. Disruptions within TCA cycle lead to an accumulation succinate mitochondrial matrix. This excess subsequently diffuses into cytosol and is released extracellular space. Elevated cytosolic levels stabilize hypoxia-inducible factor-1α by inhibiting prolyl hydroxylases, which enhances inflammatory responses. Notably, also acts extracellularly signaling molecule engaging receptor 1 on immune cells, thus modulating their pro-inflammatory or anti-inflammatory activities. Alterations have been associated with various disorders, including rheumatoid arthritis, bowel disease, obesity, atherosclerosis. These associations are primarily due exaggerated cell Given its central role inflammation, targeting pathways offers promising therapeutic avenues for these diseases. paper provides extensive review succinate's involvement processes highlights potential targets future research possibilities development.

Language: Английский

Citations

17
Type 2 diabetes and succinate: unmasking an age-old molecule DOI Creative Commons
Sonia Fernández‐Veledo, Anna Marsal-Beltran, Joan Vendrell

et al.

Diabetologia, Journal Year: 2024, Volume and Issue: 67(3), P. 430 - 442

Published: Jan. 5, 2024

Beyond their conventional roles in intracellular energy production, some traditional metabolites also function as extracellular messengers that activate cell-surface G-protein-coupled receptors (GPCRs) akin to hormones and neurotransmitters. These signalling metabolites, often derived from nutrients, the gut microbiota or host's intermediary metabolism, are now acknowledged key regulators of various metabolic immune responses. This review delves into multi-dimensional aspects succinate, a dual metabolite with roots both mitochondria microbiome. It connects dots between succinate's role Krebs cycle, mitochondrial respiration, its double-edge transmitter within outside cell. We aim provide an overview succinate-succinate receptor 1 (SUCNR1) axis diabetes, discussing potential use succinate biomarker novel prospect targeting SUCNR1 manage complications associated diabetes. further propose strategies manipulate succinate-SUCNR1 for better diabetes management; this includes pharmacological modulation innovative approaches concentrations, such administration indirect strategies, like modulation. The nature terms origins roles, offers rich landscape understanding intricate connections diseases, indicates promising pathways developing new therapeutic strategies.

Language: Английский

Citations

8
Novel insights into macrophage immunometabolism in nonalcoholic steatohepatitis DOI

Yali Yuan,

Ye Zhang, Xinyu Lu

et al.

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 131, P. 111833 - 111833

Published: March 18, 2024

Language: Английский

Citations

4
A comparative immunological assessment of multiple clinical-stage adjuvants for the R21 malaria vaccine in nonhuman primates DOI
Prabhu S. Arunachalam, Na‐Young Ha,

S. Moses Dennison

et al.

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(758)

Published: July 31, 2024

Authorization of the Matrix-M (MM)–adjuvanted R21 vaccine by three countries and its subsequent endorsement World Health Organization for malaria prevention in children are a milestone fight against malaria. Yet, our understanding innate adaptive immune responses elicited this remains limited. Here, we compared clinically relevant adjuvants [3M-052 + aluminum hydroxide (Alum) (3M), TLR7/8 agonist formulated Alum; GLA-LSQ, TLR4 liposomes with QS-21; MM, now-approved adjuvant R21] their capacity to induce durable macaques. adjuvanted 3M on 0, 8, 23–week schedule anti-circumsporozoite antibody comparable magnitude R21/MM administered using 0-4-8–week regimen persisted up 72 weeks half-life 337 days. A booster dose at induced recall response similar vaccination. In contrast, R21/GLA-LSQ immunization lower, short-lived used. Consistent serum responses, MM long-lived plasma cells bone marrow other tissues, including spleen. Furthermore, whereas stimulated potent persistent antiviral transcriptional cytokine signatures after primary immunizations, enhanced expression interferon- T H 2-related more highly Collectively, these findings provide resource highlight promise as another malarial vaccines.

Language: Английский

Citations

4
SUCNR1 Deficiency Alleviates Liver Ischemia–Reperfusion Injury by Regulating Kupffer Cell Activation and Polarization Through the ERK/NF-κB Pathway in Mice DOI Creative Commons
Huan Yang, Wei An,

Xinting Zhou

et al.

Inflammation, Journal Year: 2025, Volume and Issue: unknown

Published: March 19, 2025

Succinate regulates inflammation through its receptor, succinate receptor 1 (SUCNR1). However, the effects of this interaction on Kupffer cell (KC)-driven during liver ischemia–reperfusion injury (IRI) remain unclear. Herein, we investigated succinate/SUCNR1 axis in progression IRI. In study, levels and SUCNR1 expression were analyzed mice underwent segmental Sucnr1 deficiency (Sucnr1−/−) Wild-type treated with or without clodronate before IRI modeling, a co-culture system was established to assess impact KCs hepatocyte viability apoptosis. KC activation status polarization determined, vivo vitro. Furthermore, downstream pathways regulating investigated. We observed significant increase serum liver, after deletion alleviated apoptosis either aforementioned hepatoprotective abolished by depletion clodronate. inhibited M1 polarization, dampened proinflammatory cytokine release addition, knockout reversed increasing phosphorylation ERK NF-κB p65 following The ERK/NF-κB also antagonist Compound 4C inhibitor SCH772984. Together, these findings suggest that protects against modulating probably pathway.

Language: Английский

Citations

0
Supplementing Limosilactobacillus reuteri FN041 alleviates hypercholesterolemia by promoting indole-3-carboxaldehyde production by gut microbiota in high-fat diet mice DOI
Wenhao Wang,

Qingcui Li,

Xin Geng

et al.

Food Bioscience, Journal Year: 2025, Volume and Issue: unknown, P. 106393 - 106393

Published: March 1, 2025

Language: Английский

Citations

0
Impaired angiogenesis in gestational diabetes is linked to succinate/SUCNR1 axis dysregulation in late gestation DOI Open Access
Sergiy Klid, Francisco Algaba‐Chueca, Elsa Maymó‐Masip

et al.

The Journal of Physiology, Journal Year: 2025, Volume and Issue: unknown

Published: March 31, 2025

Abstract Recent research has highlighted the significance of succinate and its receptor in gestational diabetes (GDM) pathogenesis. However, a clear interconnection between placenta metabolism, levels, SUCNR1 signalling pregnancy pathologies remains elusive. Here, we set out to investigate potential role on labour placental mechanisms by combining clinical functional experimental data at same time as exploring specific SUCNR1‐mediated effects vascularization, addressing agonist actions. According our data, levels vary throughout postpartum, with natural increase during peripartum period. We also show that activation umbilical cord endothelium promotes angiogenesis under normal conditions. GDM, excessive impaired function may weaken this angiogenic response. In conclusion, present study underlines an emerging molecule placenta, regulating processes. The reduced sensitivity succinate/SUCNR1 pathway GDM environment serve protective physiological mechanism or could have pathogenic effect. image Key points Succinate delivery maternal fetal circulation. Gestational induces accumulation downregulation cords. compromises gene profile modulation endothelium. stimulates sprouting tube‐forming capacity human vein endothelial cells from healthy, but not pregnancies.

Language: Английский

Citations

0
Targeted Redox Regulation α-Ketoglutarate Dehydrogenase Complex for the Treatment of Human Diseases DOI Creative Commons
Ryan J. Mailloux

Cells, Journal Year: 2025, Volume and Issue: 14(9), P. 653 - 653

Published: April 29, 2025

α-ketoglutarate dehydrogenase complex (KGDHc) is a crucial enzyme in the tricarboxylic acid (TCA) cycle that intersects monosaccharides, amino acids, and fatty catabolism with oxidative phosphorylation (OxPhos). A key feature of KGDHc its ability to sense changes redox environment through reversible oxidation vicinal lipoic thiols dihydrolipoamide succinyltransferase (DLST; E2) subunit, which controls activity and, by extension, OxPhos. This characteristic inculcates regulatory properties for modulation metabolism mediating intra- intercellular signals. The innate capacity participate regulation cell homeodynamics also occurs production mitochondrial hydrogen peroxide (mtH2O2), generated (DLD; E3) downstream from E2 subunit. Reversible covalent modification subunit this mtH2O2 KGDHc, not only protects distress but modulates eustress pathways. importance modulating underscored pathogenesis neurological metabolic disorders occur due hyper-generation complex. implies targeted could be potential therapeutic strategy limiting triggered hyper-generation. In short article, I will discuss recent findings demonstrating potent source can trigger manifestation several diseases, including non-alcoholic liver disease (NAFLD), inflammation, cancer, alleviate these syndromes.

Language: Английский

Citations

0
Pulmonary succinate receptor 1 elevation in high-fat diet mice exacerbates lipopolysaccharides-induced acute lung injury via sensing succinate DOI
Ling Liu, Wenjing Tang, Siqi Wu

et al.

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2024, Volume and Issue: 1870(5), P. 167119 - 167119

Published: March 12, 2024

Language: Английский

Citations

3
Mechanism Study of Coreopsis tinctoria Nutt. on Diabetes Retinopathy Based on Liver–Eye Axis by UHPLC‐MS DOI Creative Commons

Hongxia Yang,

Yuan Zhang, Song Hou

et al.

Separation Science Plus, Journal Year: 2025, Volume and Issue: 8(2)

Published: Feb. 1, 2025

ABSTRACT Coreopsis tinctoria Nutt. (CT) has the effects of clearing heat and detoxifying, which can be used to treat red‐eye swelling. At present, there are studies on CT treatment diabetic retinopathy (DR). Diabetes affect function eyes, is closely related liver. The connection between liver eyes valued as liver–eye axis. There no reports mechanism action in DR. This study analyzed differences DR rats before after administration using network pharmacology, LC‐MS‐based non‐targeted metabolomics, energy substances metabolism. Then, a joint analysis hepatomics, plasma metabolism, pharmacology results was conducted discover overall biological axis pattern. Non‐targeted metabolomics revealed pentose phosphate pathway (PPP) riboflavin main enriched metabolic pathways, Energy substance metabolism regulates tricarboxylic acid cycle pathway. Integrated PPP upstream key research reveals for based provides reference studying

Language: Английский

Citations

0