Deficient QPRT drives trans-Golgi NAD+ hyperinflation and pathological protein secretion in rheumatoid arthritis DOI

Lucy Wanjiru Njunge,

Kaijing Liu, Chenyan Xiong

et al.

Published: Oct. 29, 2024

Abstract Aberrant protein secretion is a central driver of tissue inflammation and destruction in rheumatoid arthritis (RA). While RA fibroblast-like synoviocytes (FLSs) exhibit prominent endoplasmic reticulum (ER) Golgi, the mechanism underlying their excessive not fully understood. Here, we identified deficiency de novo NAD + synthesis enzyme, quinolinate phosphoribosyltransferase (QPRT), as significant abnormality synovium. QPRT loss counterintuitively inflates trans-Golgi network (TGN) while decreasing cytoplasm, ER cis/medial-Golgi. knockdown promoted Golgi membrane expansion epithelial-to-mesenchymal-transition (EMT)-associated secretome production FLSs by suppressing TGN-residing PARP12, resulting mTORC1-mediated translation expansion. Furthermore, gene therapy restored balance, corrected dysfunction, reduced cytokine production, improved severity mouse models. These findings underscore QPRT’s role coordinating regulatory dynamics compartmentalized , proposing targeting therapeutic strategy for inflammatory, secretory Golgi-related diseases.

Language: Английский

Crosstalk between metabolism and epigenetics during macrophage polarization DOI Creative Commons
Kangling Zhang, Chinnaswamy Jagannath

Epigenetics & Chromatin, Journal Year: 2025, Volume and Issue: 18(1)

Published: March 29, 2025

Macrophage polarization is a dynamic process driven by complex interplay of cytokine signaling, metabolism, and epigenetic modifications mediated pathogens. Upon encountering specific environmental cues, monocytes differentiate into macrophages, adopting either pro-inflammatory (M1) or anti-inflammatory (M2) phenotype, depending on the cytokines present. M1 macrophages are induced interferon-gamma (IFN-γ) characterized their reliance glycolysis role in host defense. In contrast, M2 stimulated interleukin-4 (IL-4) interleukin-13 (IL-13), favor oxidative phosphorylation participate tissue repair responses. Metabolism tightly linked to regulation, because key metabolic intermediates such as acetyl-coenzyme A (CoA), α-ketoglutarate (α-KG), S-adenosylmethionine (SAM), nicotinamide adenine dinucleotide (NAD+) serve cofactors for chromatin-modifying enzymes, which turn, directly influences histone acetylation, methylation, RNA/DNA protein arginine methylation. These control gene expression regulating chromatin accessibility, thereby modulating macrophage function polarization. Histone acetylation generally promotes more open structure conducive activation, while methylation can activate repress residue its state. Crosstalk between modifications, further fine-tunes phenotypes transcriptional networks response cues. While primarily functions epigenetics through degradation methylated proteins releases derivatives like asymmetric dimethylarginine (ADMA), contribute metabolism-a factor This review explores intricate relationships metabolism regulation during better understanding this crosstalk will likely generate novel therapeutic insights manipulating infections tuberculosis inflammatory diseases diabetes.

Language: Английский

Citations

5
New insight into arginine and tryptophan metabolism in macrophage activation during tuberculosis DOI Creative Commons
Kangling Zhang, Abhishek Mishra, Chinnaswamy Jagannath

et al.

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

Published: March 28, 2024

Arginine and tryptophan are pivotal in orchestrating cytokine-driven macrophage polarization immune activation. Specifically, interferon-gamma (IFN-γ) stimulates inducible nitric oxide synthase (iNOS) expression), leading to the conversion of arginine into citrulline (NO), while Interleukin-4 (IL4) promotes arginase activation, shifting metabolism toward ornithine. Concomitantly, IFN-γ triggers indoleamine 2,3-dioxygenase 1 (IDO1) induced (IL4i1), resulting kynurenine indole-3-pyruvic acid. These metabolic pathways tightly regulated by NAD + -dependent sirtuin proteins, with Sirt2 Sirt5 playing integral roles. In this review, we present novel insights that augment our understanding following Mycobacterium tuberculosis infection, particularly their relevance responses. Additionally, discuss methylation demethylation role regulating metabolism, potentially driving polarization.

Language: Английский

Citations

13
Precision nutrition to reset virus-induced human metabolic reprogramming and dysregulation (HMRD) in long-COVID DOI Creative Commons
A. Satyanarayan Naidu, Chin‐Kun Wang, Pingfan Rao

et al.

npj Science of Food, Journal Year: 2024, Volume and Issue: 8(1)

Published: March 30, 2024

Language: Английский

Citations

9
NAD+ precursors promote the restoration of spermatogenesis in busulfan-treated mice through inhibiting Sirt2-regulated ferroptosis DOI Creative Commons

Yanqin Feng,

Xuan Liu, Ning Zuo

et al.

Theranostics, Journal Year: 2024, Volume and Issue: 14(6), P. 2622 - 2636

Published: Jan. 1, 2024

In recent years, nicotinamide adenine dinucleotide (NAD

Language: Английский

Citations

8
Supplementing Boar Diet with Nicotinamide Mononucleotide Improves Sperm Quality Probably through the Activation of the SIRT3 Signaling Pathway DOI Creative Commons

H. Zhang,

Jiawen Chai,

Chaoyue Cao

et al.

Antioxidants, Journal Year: 2024, Volume and Issue: 13(5), P. 507 - 507

Published: April 24, 2024

Sperm quality is an important indicator to evaluate the reproduction ability of animals. Nicotinamide mononucleotide (NMN) participates in cell energy metabolism and reduces oxidative stress. However, effect regulatory mechanism NMN on porcine sperm are still unknown. Here, 32 Landrace boars were randomly assigned four groups (n = 8) fed with different levels (0, 8, 16 or mg/kg/d) for 9 weeks, then serum semen samples collected investigate function molecular quality. The results showed that dietary supplementation significantly increased volume, density motility (p < 0.05). Interestingly, apparently improved antioxidative indexes testosterone 0.05) serum. Furthermore, upregulated protein sirtuin 3 (SIRT3), antioxidation phosphorylation (OXPHOS), but downregulated apoptosis semen. Mechanically, protected from H2O2-induced stress through SIRT3 deacetylation. Importantly, SIRT3-specific inhibitor 3-TYP attenuated antiapoptosis sperm. Therefore, exerts improve boar via signaling pathway. Our findings suggest a novel potential feed additive produce high-quality

Language: Английский

Citations

7
A Multifunctional Therapeutic Strategy Using P7C3 as A Countermeasure Against Bone Loss and Fragility in An Ovariectomized Rat Model of Postmenopausal Osteoporosis DOI Creative Commons
Fei Wei, Megan Hughes,

Mahmoud Omer

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(21)

Published: March 13, 2024

Abstract By 2060, an estimated one in four Americans will be elderly. Consequently, the prevalence of osteoporosis and fragility fractures also increase. Presently, no available intervention definitively prevents or manages osteoporosis. This study explores whether Pool 7 Compound 3 (P7C3) reduces progressive bone loss following onset ovariectomy (OVX)‐induced Results confirm OVX‐induced weakened, osteoporotic together with a significant gain adipogenic body weight. Treatment P7C3 significantly reduced osteoclastic activity, marrow adiposity, whole‐body weight gain, preserved area, architecture, mechanical strength. Analyses reveal upregulated platelet derived growth factor‐BB leukemia inhibitory factor, downregulation interleukin‐1 R6, receptor activator nuclear factor kappa‐B (RANK). Together, proteomic data suggest targeting several key regulators inflammation, bone, adipose turnover, via transforming factor‐beta/SMAD, Wingless‐related integration site/be‐catenin signaling pathways. To best knowledge, this is first evidence that drives against RANK. Metatranscriptomic analyses gut microbiota show increased Porphyromonadaceae bacterium, Candidatus Melainabacteria, Ruminococcaceae bacterium abundance, potentially contributing to favorable inflammatory, adipo‐osteogenic metabolic regulation observed. The results undiscovered, multifunctional therapeutic strategy prevent pathological progression loss.

Language: Английский

Citations

5
NAD+ salvage governs the immunosuppressive capacity of mesenchymal stem cells DOI
Jiankai Fang, Pengbo Hou,

Shisong Liu

et al.

Cellular and Molecular Immunology, Journal Year: 2023, Volume and Issue: 20(10), P. 1171 - 1185

Published: Aug. 14, 2023

Language: Английский

Citations

10
Affordable mRNA Novel Proteins, Recombinant Protein Conversions, and Biosimilars—Advice to Developers and Regulatory Agencies DOI Creative Commons
Sarfaraz K. Niazi

Biomedicines, Journal Year: 2025, Volume and Issue: 13(1), P. 97 - 97

Published: Jan. 3, 2025

mRNA technology can replace the expensive recombinant for every type of protein, making biological drugs more affordable. It also expedite entry new drugs, and copies approved products be treated as generic or biosimilar due to their chemical nature. The introduction hundreds protein have been blocked high cost development. low CAPEX OPEX associated with bring it within reach developing countries that are currently deprived life-saving drugs. In this paper, we advise developers introduce novel proteins switch manufacturing delivery, further regulatory authorities allow approval less testing. We anticipate will make such natural engineered proteins, monoclonal antibodies, vaccines, accessible billions patients worldwide.

Language: Английский

Citations

0
CD38 expression by neonatal human naïve CD4+T cells shapes their distinct metabolic state and high regulatory T cell potential DOI Open Access
Laura R. Dwyer,

Sean Clancy,

Victoire Gouirand

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Abstract Neonatal life is marked by rapid antigen exposure, necessitating establishment of peripheral immune tolerance via conversion naïve CD4 + T cells into regulatory (Tregs). Here, we demonstrate that increased Treg differentiation naive from human cord blood versus adult integrally linked to their unique metabolic profile and elevated expression the NADase, CD38. Early a preference for glycolysis, which directly facilitates generation. We reveal an age-dependent gradient in CD38 levels on show high contributes both glycolytic state potential neonatal cells, effects are mediated at least part NAD-dependent deacetylase SIRT1. Thus, early window humans critically enabled immunometabolic compartment.

Language: Английский

Citations

0
Interactions between NAD+ metabolism and immune cell infiltration in ulcerative colitis: subtype identification and development of novel diagnostic models DOI Creative Commons

Linglin Tian,

Huiyang Gao,

Yao Tian

et al.

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

Published: Feb. 5, 2025

Ulcerative colitis (UC) is a chronic inflammatory disease of the colonic mucosa with increasing incidence worldwide. Growing evidence highlights pivotal role nicotinamide adenine dinucleotide (NAD+) metabolism in UC pathogenesis, prompting our investigation into subtype-specific molecular underpinnings and diagnostic potential NAD+ metabolism-related genes (NMRGs). Transcriptome data from patients healthy controls were downloaded GEO database, specifically GSE75214 GSE87466. We performed unsupervised clustering based on differentially expressed (DE-NMRGs) to classify cases distinct subtypes. GSEA GSVA identified biological pathways active within these subtypes, while CIBERSORT algorithm assessed differential immune cell infiltration. Weighted gene co-expression network analysis (WGCNA) combined expression was used pinpoint specific NMRGs UC. Robust features for subtyping diagnosis selected using two machine learning algorithms. Nomograms constructed their effectiveness evaluated receiver operating characteristic (ROC) curves. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) conducted verify lines. In study, classified subtypes DE-NMRGs levels, Cluster A exhibiting enhanced self-repair capabilities during responses B showing greater inflammation tissue damage. Through comprehensive bioinformatics analyses, we four key biomarkers (AOX1, NAMPT, NNMT, PTGS2) subtyping, (NNMT, PARP9) its diagnosis. These are closely linked various cells microenvironment, particularly NAMPT PTGS2, which strongly associated neutrophil developed demonstrated high predictive accuracy, achieving area under curve (AUC) values up 0.989 0.997 training set 0.998 0.988 validation sets. RT-qPCR showed significant upregulation NNMT PARP9 inflamed versus normal epithelia, underscoring relevance. Our study reveals UC, identifying findings could suggest therapeutic targets contribute advancing personalized treatment strategies potentially improving patient outcomes.

Language: Английский

Citations

0