The effects of cGAS-STING inhibition in liver disease, kidney disease, and cellular senescence

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Июль 24, 2024

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is one the fundamental mechanisms body's defense, which responds to abnormal presence double-stranded DNA in cytoplasm establish an effective natural immune response. In addition detecting microbial infections, cGAS may be triggered by any cytoplasmic DNA, absent from normal cytoplasm, and only conditions such as senescence mitochondrial stress can lead its leakage cause sterile inflammation. A growing body research has shown that cGAS-STING strongly associated with this study, we reviewed regulatory biological functions through involvement aseptic inflammation liver disease, kidney cellular senescence.

Язык: Английский

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NAD deficiency contributes to progressive kidney disease in HIV nephropathy mice

AJP Renal Physiology, Год журнала: 2024, Номер 327(3), С. F450 - F462

Опубликована: Сен. 1, 2024

HIV disease remains prevalent in the United States and is particularly sub-Saharan Africa. Recent investigations revealed that mitochondrial dysfunction kidney contributes to HIV-associated nephropathy (HIVAN) Tg26 transgenic mice. We hypothesized nicotinamide adenine dinucleotide (NAD) deficiency energetic progressive tubular injury. investigated metabolomic mechanisms of HIVAN tubulopathy. wild-type (WT) mice were treated with farnesoid X receptor (FXR) agonist INT-747 or riboside (NR) from 6 12 wk age. Multiomic approaches used characterize tissue transcriptomes metabolomes. Treatment NR ameliorated injury, as shown by serum creatinine, injury marker urinary neutrophil-associated lipocalin, morphometry. Integrated analysis transcriptomic measurements showed NAD levels production globally downregulated mouse kidneys, especially phosphoribosyltransferase (NAMPT), rate-limiting enzyme salvage pathway. Furthermore, NAD-dependent deacetylase sirtuin3 activity oxidative phosphorylation lower ex vivo proximal tubules kidneys compared those WT Restoration improved these abnormalities. These data suggest might be a treatable target for HIVAN.

Язык: Английский

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The multifaceted effects of mitochondria in kidney diseases

Mitochondrion, Год журнала: 2024, Номер 79, С. 101957 - 101957

Опубликована: Сен. 11, 2024

Язык: Английский

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Nicotinamide riboside activates renal metabolism and protects the kidney in a model of Alport syndrome

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Фев. 29, 2024

ABSTRACT Chronic kidney disease (CKD) is associated with renal metabolic disturbances, including impaired fatty acid oxidation (FAO). Nicotinamide adenine dinucleotide (NAD + ) a small molecule that participates in hundreds of metabolism-related reactions. NAD levels are decreased CKD, and supplementation protective. However, both the mechanism how protects from as well cell types involved, poorly understood. Using mouse model Alport syndrome, we show nicotinamide riboside (NR), an precursor, stimulates peroxisome proliferator-activated receptor alpha signaling restores FAO proximal tubules, thereby protecting CKD sexes. Bulk RNA-sequencing shows pathways mice activated by NR These transcriptional changes confirmed orthogonal imaging techniques biochemical assays. Single nuclei spatial transcriptomics, first their kind mice, tubule cells. Finally, also report, for time, sex differences at level this model. In summary, identify nephroprotective demonstrate cells substantially contribute to benefit.

Язык: Английский

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The association of TNF-alpha secretion and mtDNA copy number in CD14+ monocytes of patients with obesity and CHD

Frontiers in Molecular Biosciences, Год журнала: 2024, Номер 11

Опубликована: Март 20, 2024

Introduction Mitochondrial dysfunction may be one of the causes inflammatory activation monocytes and macrophages, which leads to excessive secretion mediators development chronic inflammation. Aims The study was aimed evaluate cytokine tumor necrosis factor-α (TNF-α) in primary culture monocytes, analyze its relationship with number mitochondrial DNA (mtDNA) copies blood patients coronary heart disease (CHD) obesity. Materials methods 108 obesity concomitant CHD a control group 25 participants were included study. CD14 + isolated by standard method ficoll-urographin gradient, followed separation using magnetic particles. mtDNA estimated qPCR. Results It demonstrated that significantly increased groups comparison group. copy positively correlated basal LPS-stimulated TNF-α secretion, most significant correlation found Conclusion Thus, change indicates presence dysfunction, confirm direct involvement mitochondria violation response revealed this as an TNF-α.

Язык: Английский

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Unraveling the nexus of NAD+ metabolism and diabetic kidney disease: insights from murine models and human data

Frontiers in Endocrinology, Год журнала: 2024, Номер 15

Опубликована: Май 21, 2024

Background Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme involved in kidney disease, yet its regulation diabetic disease (DKD) remains inadequately understood. Objective Therefore, we investigated the changes of NAD+ levels DKD and underlying mechanism. Methods Alternations biosynthesis enzymes were detected kidneys from streptozotocin-induced mouse model by real-time PCR immunoblot. The distribution de novo synthetic was explored via immunohistochemical study. metabolite measured LC-MS. Human data NephroSeq analyzed to verify our findings. Results study showed that decreased kidneys. Both mRNA protein kynurenine 3-monooxygenase (KMO) synthesis pathway decreased, while salvage consuming remained unchanged. Further analysis human suggested KMO, primarily expressed proximal tubules shown staining, consistently downregulated Conclusion Our demonstrated KMO might be responsible for reduction kidneys, offering valuable insights into complex regulatory mechanisms DKD.

Язык: Английский

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Emerging interactions between mitochondria and NAD+ metabolism in cardiometabolic diseases

Trends in Endocrinology and Metabolism, Год журнала: 2024, Номер unknown

Опубликована: Авг. 1, 2024

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NAD⁺depletion is central to placental dysfunction in an inflammatory subclass of preeclampsia

Life Science Alliance, Год журнала: 2024, Номер 7(12), С. e202302505 - e202302505

Опубликована: Окт. 10, 2024

Preeclampsia (PE) is a hypertensive disorder of pregnancy and major cause maternal/perinatal adverse health outcomes with no effective therapeutic strategies. Our group previously identified distinct subclasses PE, one which exhibits heightened placental inflammation (inflammation-driven PE). In non-pregnant populations, chronic associated decreased levels cellular NAD

Язык: Английский

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Nicotinamide Mononucleotide Restores NAD+ Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells

Antioxidants, Год журнала: 2024, Номер 14(1), С. 39 - 39

Опубликована: Дек. 31, 2024

Inflammation disrupts the normal function of granulosa cells (GCs), which leads to ovarian dysfunction and fertility decline. Inflammatory conditions such as polycystic ovary syndrome (PCOS), primary insufficiency (POI), endometriosis, age-related decline are often associated with chronic low-grade inflammation. Nicotinamide mononucleotide (NMN) is an important precursor NAD+ has gained attention for its potential modulate cellular metabolism, redox homeostasis, mitigate This study investigated protective roles NMN against lipopolysaccharide LPS-mediated inflammation in GCs. The results this experiment demonstrated that LPS had negative effects on GCs term reduced viability proliferation rates upregulated production pro-inflammatory cytokines, including interleukin-1 beta (IL-1β), interleukin-6 (IL-6), cyclooxygenase-2 (Cox-2), tumor necrosis factor-alpha (TNF-α). Notably, levels NAD+/NADH ratio were response On other hand, supplementation restored significantly expression markers at both mRNA protein levels. It also enhanced cell Furthermore, apoptosis by downregulating pro-apoptotic markers, Caspase-3, Caspase-9, Bax while upregulating anti-apoptotic marker Bcl-2. reactive oxygen species ROS improved steroidogenesis activity restoring estradiol (E2) progesterone (P4) LPS-treated Mechanistically, found suppressed activation TLR4/NF-κB/MAPK signaling pathways GCs, regulates inflammatory processes. In conclusion, findings revealed reduce changes modulating metabolism pathways. can be used a therapeutic agent related disorders.

Язык: Английский

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Randomized Crossover Clinical Trial of Nicotinamide Riboside and Coenzyme Q10 on Metabolic Health and Mitochondrial Bioenergetics in CKD

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 23, 2024

Abstract Background Mitochondria-driven oxidative/redox stress and inflammation play a major role in chronic kidney disease (CKD) pathophysiology. Compounds targeting mitochondrial metabolism may improve function, inflammation, redox stress; however, there is limited evidence of their efficacy CKD. Methods We conducted randomized, double-blind, placebo-controlled crossover trial comparing the effects 1200 mg/day coenzyme Q10 (CoQ10) or 1000 nicotinamide riboside (NR) supplementation to placebo 25 people with moderate-to-severe CKD (eGFR <60mL/min/1.73 m 2 ). assessed changes blood transcriptome using 3’-Tag-Seq gene expression profiling pre-specified secondary outcomes inflammatory oxidative biomarkers. For subsample participants (n=14), we lymphocyte monocyte bioenergetics an extracellular flux analyzer. Results The (mean±SD) age, eGFR, BMI were 61±11 years, 37±9 mL/min/1.73m , 28±5 kg/m respectively. Of participants, 16% had diabetes 40% female. Compared placebo, NR-mediated transcriptomic enriched ontology (GO) terms associated carbohydrate/lipid immune signaling while, CoQ10 immune/stress response lipid GO terms. NR increased plasma IL-2 (estimated difference, 0.32, 95% CI 0.14 0.49 pg/mL), decreased both IL-13 –0.12, –0.24 –0.01 pg/mL) CRP –0.11, –0.22 0.00 mg/dL) compared placebo. Both reduced 5 series F2-Isoprostanes –0.16 –0.11 pg/mL, respectively; P<0.05 for both). NR, but not CoQ10, bioenergetic health index (BHI) 0.29, 0.06 0.53) spare respiratory capacity 3.52, 0.04 7 pmol/min/10,000 cells) monocytes. Conclusion Six weeks improved stress, cell persons moderate severe

Язык: Английский

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