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Annals of the Rheumatic Diseases Jan 2024To investigate the effect of the L-arginine metabolism on arthritis and inflammation-mediated bone loss.
OBJECTIVES
To investigate the effect of the L-arginine metabolism on arthritis and inflammation-mediated bone loss.
METHODS
L-arginine was applied to three arthritis models (collagen-induced arthritis, serum-induced arthritis and human TNF transgenic mice). Inflammation was assessed clinically and histologically, while bone changes were quantified by μCT and histomorphometry. In vitro, effects of L-arginine on osteoclast differentiation were analysed by RNA-seq and mass spectrometry (MS). Seahorse, Single Cell ENergetIc metabolism by profilIng Translation inHibition and transmission electron microscopy were used for detecting metabolic changes in osteoclasts. Moreover, arginine-associated metabolites were measured in the serum of rheumatoid arthritis (RA) and pre-RA patients.
RESULTS
L-arginine inhibited arthritis and bone loss in all three models and directly blocked TNFα-induced murine and human osteoclastogenesis. RNA-seq and MS analyses indicated that L-arginine switched glycolysis to oxidative phosphorylation in inflammatory osteoclasts leading to increased ATP production, purine metabolism and elevated inosine and hypoxanthine levels. Adenosine deaminase inhibitors blocking inosine and hypoxanthine production abolished the inhibition of L-arginine on osteoclastogenesis in vitro and in vivo. Altered arginine levels were also found in RA and pre-RA patients.
CONCLUSION
Our study demonstrated that L-arginine ameliorates arthritis and bone erosion through metabolic reprogramming and perturbation of purine metabolism in osteoclasts.
Topics: Humans; Mice; Animals; Osteoclasts; Arthritis, Rheumatoid; Arthritis, Experimental; Inflammation; Mice, Transgenic; Arginine; Inosine; Hypoxanthines; Purines; Bone Resorption
PubMed: 37775153
DOI: 10.1136/ard-2022-223626 -
The New England Journal of Medicine Mar 2024Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear.
METHODS
In this international, open-label, randomized, phase 3 trial, we randomly assigned patients with HR-positive, HER2-negative early breast cancer in a 1:1 ratio to receive ribociclib (at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI; letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for ≥5 years) or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer. Here we report the results of a prespecified interim analysis of invasive disease-free survival, the primary end point; other efficacy and safety results are also reported. Invasive disease-free survival was evaluated with the use of the Kaplan-Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided P-value threshold of 0.0128 for superior efficacy.
RESULTS
As of the data-cutoff date for this prespecified interim analysis (January 11, 2023), a total of 426 patients had had invasive disease, recurrence, or death. A significant invasive disease-free survival benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, invasive disease-free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P = 0.003). Secondary end points - distant disease-free survival and recurrence-free survival - also favored ribociclib plus an NSAI. The 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals.
CONCLUSIONS
Ribociclib plus an NSAI significantly improved invasive disease-free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer. (Funded by Novartis; NATALEE ClinicalTrials.gov number, NCT03701334.).
Topics: Female; Humans; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Letrozole; Purines; Receptor, ErbB-2; Aromatase Inhibitors; Receptors, Estrogen; Receptors, Progesterone; Goserelin; Antineoplastic Agents, Hormonal; Male
PubMed: 38507751
DOI: 10.1056/NEJMoa2305488 -
Nature Aug 2023Uncoupling protein 1 (UCP1) conducts protons through the inner mitochondrial membrane to uncouple mitochondrial respiration from ATP production, thereby converting the...
Uncoupling protein 1 (UCP1) conducts protons through the inner mitochondrial membrane to uncouple mitochondrial respiration from ATP production, thereby converting the electrochemical gradient of protons into heat. The activity of UCP1 is activated by endogenous fatty acids and synthetic small molecules, such as 2,4-dinitrophenol (DNP), and is inhibited by purine nucleotides, such as ATP. However, the mechanism by which UCP1 binds to these ligands remains unknown. Here we present the structures of human UCP1 in the nucleotide-free state, the DNP-bound state and the ATP-bound state. The structures show that the central cavity of UCP1 is open to the cytosolic side. DNP binds inside the cavity, making contact with transmembrane helix 2 (TM2) and TM6. ATP binds in the same cavity and induces conformational changes in TM2, together with the inward bending of TM1, TM4, TM5 and TM6 of UCP1, resulting in a more compact structure of UCP1. The binding site of ATP overlaps with that of DNP, suggesting that ATP competitively blocks the functional engagement of DNP, resulting in the inhibition of the proton-conducting activity of UCP1.
Topics: Humans; Adenosine Triphosphate; Protons; Uncoupling Protein 1; Fatty Acids; 2,4-Dinitrophenol; Protein Conformation; Cell Membrane; Cytosol
PubMed: 37336486
DOI: 10.1038/s41586-023-06332-w -
Biomolecules Oct 2023The prevalence of patients with hyperuricemia or gout is increasing worldwide. Hyperuricemia and gout are primarily attributed to genetic factors, along with lifestyle... (Review)
Review
The prevalence of patients with hyperuricemia or gout is increasing worldwide. Hyperuricemia and gout are primarily attributed to genetic factors, along with lifestyle factors like consuming a purine-rich diet, alcohol and/or fructose intake, and physical activity. While numerous studies have reported various comorbidities linked to hyperuricemia or gout, the range of these associations is extensive. This review article focuses on the relationship between uric acid and thirteen specific domains: transporters, genetic factors, diet, lifestyle, gout, diabetes mellitus, metabolic syndrome, atherosclerosis, hypertension, kidney diseases, cardiovascular diseases, neurological diseases, and malignancies. The present article provides a comprehensive review of recent developments in these areas, compiled by experts from the Young Committee of the Japanese Society of Gout and Uric and Nucleic Acids. The consolidated summary serves to enhance the global comprehension of uric acid-related matters.
Topics: Humans; Hyperuricemia; Uric Acid; Gout; Metabolic Syndrome; Diet
PubMed: 37892201
DOI: 10.3390/biom13101519 -
Science Immunology Jul 2023The extracellular nucleoside adenosine reduces tissue inflammation and is generated by irreversible dephosphorylation of adenosine monophosphate (AMP) mediated by the... (Review)
Review
The extracellular nucleoside adenosine reduces tissue inflammation and is generated by irreversible dephosphorylation of adenosine monophosphate (AMP) mediated by the ectonucleotidase CD73. The pro-inflammatory nucleotides adenosine triphosphate, nicotinamide adenine dinucleotide, and cyclic guanosine -monophosphate-AMP (cGAMP), which are produced in the tumor microenvironment (TME) during therapy-induced immunogenic cell death and activation of innate immune signaling, can be converted into AMP by ectonucleotidases CD39, CD38, and CD203a/ENPP1. Thus, ectonucleotidases shape the TME by converting immune-activating signals into an immunosuppressive one. Ectonucleotidases also hinder the ability of therapies including radiation therapy, which enhance the release of pro-inflammatory nucleotides in the extracellular milieu, to induce immune-mediated tumor rejection. Here, we review the immunosuppressive effects of adenosine and the role of different ectonucleotidases in modulating antitumor immune responses. We discuss emerging opportunities to target adenosine generation and/or its ability to signal via adenosine receptors expressed by immune and cancer cells in the context of combination immunotherapy and radiotherapy.
Topics: Humans; Neoplasms; Adenosine; Adenosine Triphosphate; Adenosine Monophosphate; DNA Damage; Tumor Microenvironment
PubMed: 37418547
DOI: 10.1126/sciimmunol.abq3015 -
Cancer Discovery Sep 2023Fumarate accumulation due to loss of fumarate hydratase (FH) drives cellular transformation. Germline FH alterations lead to hereditary leiomyomatosis and renal cell...
UNLABELLED
Fumarate accumulation due to loss of fumarate hydratase (FH) drives cellular transformation. Germline FH alterations lead to hereditary leiomyomatosis and renal cell cancer (HLRCC) where patients are predisposed to an aggressive form of kidney cancer. There is an unmet need to classify FH variants by cancer-associated risk. We quantified catalytic efficiencies of 74 variants of uncertain significance. Over half were enzymatically inactive, which is strong evidence of pathogenicity. We next generated a panel of HLRCC cell lines expressing FH variants with a range of catalytic activities, then correlated fumarate levels with metabolic features. We found that fumarate accumulation blocks de novo purine biosynthesis, rendering FH-deficient cells reliant on purine salvage for proliferation. Genetic or pharmacologic inhibition of the purine salvage pathway reduced HLRCC tumor growth in vivo. These findings suggest the pathogenicity of patient-associated FH variants and reveal purine salvage as a targetable vulnerability in FH-deficient tumors.
SIGNIFICANCE
This study functionally characterizes patient-associated FH variants with unknown significance for pathogenicity. This study also reveals nucleotide salvage pathways as a targetable feature of FH-deficient cancers, which are shown to be sensitive to the purine salvage pathway inhibitor 6-mercaptopurine. This presents a new rapidly translatable treatment strategy for FH-deficient cancers. This article is featured in Selected Articles from This Issue, p. 1949.
Topics: Humans; Fumarate Hydratase; Virulence; Carcinoma, Renal Cell; Kidney Neoplasms; Skin Neoplasms; Purines
PubMed: 37255402
DOI: 10.1158/2159-8290.CD-22-0874 -
Nature Cell Biology Dec 2023The intricate orchestration of enzymatic activities involving nicotinamide adenine dinucleotide (NAD) is essential for maintaining metabolic homeostasis and preserving...
The intricate orchestration of enzymatic activities involving nicotinamide adenine dinucleotide (NAD) is essential for maintaining metabolic homeostasis and preserving genomic integrity. As a co-enzyme, NAD plays a key role in regulating metabolic pathways, such as glycolysis and Kreb's cycle. ADP-ribosyltransferases (PARPs) and sirtuins rely on NAD to mediate post-translational modifications of target proteins. The activation of PARP1 in response to DNA breaks leads to rapid depletion of cellular NAD compromising cell viability. Therefore, the levels of NAD must be tightly regulated. Here we show that exogenous NAD, but not its precursors, has a direct effect on mitochondrial activity. Short-term incubation with NAD boosts Kreb's cycle and the electron transport chain and enhances pyrimidine biosynthesis. Extended incubation with NAD results in depletion of pyrimidines, accumulation of purines, activation of the replication stress response and cell cycle arrest. Moreover, a combination of NAD and 5-fluorouridine selectively kills cancer cells that rely on de novo pyrimidine synthesis. We propose an integrated model of how NAD regulates nucleotide metabolism, with relevance to healthspan, ageing and cancer therapy.
Topics: NAD; Glycolysis; Metabolic Networks and Pathways; Genomics; DNA Replication
PubMed: 37957325
DOI: 10.1038/s41556-023-01280-z -
Journal of the American College of... Jan 2024Gout is characterized by increased production of purines (through the pentose phosphate pathway), which is coupled with reduced renal or intestinal excretion of urate.... (Review)
Review
Gout is characterized by increased production of purines (through the pentose phosphate pathway), which is coupled with reduced renal or intestinal excretion of urate. Concurrent upregulation of nutrient surplus signaling (mammalian target of rapamycin and hypoxia-inducible factor-1a) and downregulation of nutrient deprivation signaling (sirtuin-1 and adenosine monophosphate-activated protein kinase) redirects glucose toward anabolic pathways (rather than adenosine triphosphate production), thus promoting heightened oxidative stress and cardiomyocyte and proximal tubular dysfunction, leading to cardiomyopathy and kidney disease. Hyperuricemia is a marker (rather than a driver) of these cellular stresses. By inducing a state of starvation mimicry in a state of nutrient surplus, sodium-glucose cotransporter-2 inhibitors decrease flux through the pentose phosphate pathway (thereby attenuating purine and urate synthesis) while promoting renal urate excretion. These convergent actions exert a meaningful effect to lower serum uric acid by ≈0.6 to 1.5 mg/dL and to reduce the risk of gout by 30% to 50% in large-scale clinical trials.
Topics: Humans; Hyperuricemia; Sodium-Glucose Transporter 2 Inhibitors; Uric Acid; Gout; Heart Failure; Diabetes Mellitus; Glucose
PubMed: 38199714
DOI: 10.1016/j.jacc.2023.10.030 -
International Journal of Molecular... Aug 2023Numerous basic studies have reported on the neuroprotective properties of several purine derivatives such as caffeine and uric acid (UA). Epidemiological studies have... (Review)
Review
Numerous basic studies have reported on the neuroprotective properties of several purine derivatives such as caffeine and uric acid (UA). Epidemiological studies have also shown the inverse association of appropriate caffeine intake or serum urate levels with neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson's disease (PD). The well-established neuroprotective mechanisms of caffeine and UA involve adenosine A receptor antagonism and antioxidant activity, respectively. Our recent study found that another purine derivative, paraxanthine, has neuroprotective effects similar to those of caffeine and UA. These purine derivatives can promote neuronal cysteine uptake through excitatory amino acid carrier protein 1 (EAAC1) to increase neuronal glutathione (GSH) levels in the brain. This review summarizes the GSH-mediated neuroprotective effects of purine derivatives. Considering the fact that GSH depletion is a manifestation in the brains of AD and PD patients, administration of purine derivatives may be a new therapeutic approach to prevent or delay the onset of these neurodegenerative diseases.
Topics: Humans; Adenosine A2 Receptor Antagonists; Alzheimer Disease; Brain; Cysteine; Excitatory Amino Acid Transporter 3; Glutathione; Neuroprotection; Neuroprotective Agents; Parkinson Disease; Purines; Receptor, Adenosine A2A; Theophylline; Uric Acid; Caffeine
PubMed: 37685879
DOI: 10.3390/ijms241713067 -
Molecules (Basel, Switzerland) Dec 2023In addition to comprising monomers of nucleic acids, nucleotides have signaling functions and act as second messengers in both prokaryotic and eukaryotic cells. The most... (Review)
Review
In addition to comprising monomers of nucleic acids, nucleotides have signaling functions and act as second messengers in both prokaryotic and eukaryotic cells. The most common example is cyclic AMP (cAMP). Nucleotide signaling is a focus of great interest in bacteria. Cyclic di-AMP (c-di-AMP), cAMP, and cyclic di-GMP (c-di-GMP) participate in biological events such as bacterial growth, biofilm formation, sporulation, cell differentiation, motility, and virulence. Moreover, the cyclic-di-nucleotides (c-di-nucleotides) produced in pathogenic intracellular bacteria can affect eukaryotic host cells to allow for infection. On the other hand, non-cyclic nucleotide molecules pppGpp and ppGpp are alarmones involved in regulating the bacterial response to nutritional stress; they are also considered second messengers. These second messengers can potentially be used as therapeutic agents because of their immunological functions on eukaryotic cells. In this review, the role of c-di-nucleotides and cAMP as second messengers in different bacterial processes is addressed.
Topics: Second Messenger Systems; Cyclic GMP; Signal Transduction; Bacteria; Cyclic AMP; Nucleotides, Cyclic; Bacterial Proteins
PubMed: 38138485
DOI: 10.3390/molecules28247996