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1.
J Biol Chem ; 298(10): 102410, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36007612

RESUMEN

NAD+ is a cellular redox cofactor involved in many essential processes. The regulation of NAD+ metabolism and the signaling networks reciprocally interacting with NAD+-producing metabolic pathways are not yet fully understood. The NAD+-dependent histone deacetylase (HDAC) Hst1 has been shown to inhibit de novo NAD+ synthesis by repressing biosynthesis of nicotinic acid (BNA) gene expression. Here, we alternatively identify HDAC Rpd3 as a positive regulator of de novo NAD+ metabolism in the budding yeast Saccharomyces cerevisiae. We reveal that deletion of RPD3 causes marked decreases in the production of de novo pathway metabolites, in direct contrast to deletion of HST1. We determined the BNA expression profiles of rpd3Δ and hst1Δ cells to be similarly opposed, suggesting the two HDACs may regulate the BNA genes in an antagonistic fashion. Our chromatin immunoprecipitation analysis revealed that Rpd3 and Hst1 mutually influence each other's binding distribution at the BNA2 promoter. We demonstrate Hst1 to be the main deacetylase active at the BNA2 promoter, with hst1Δ cells displaying increased acetylation of the N-terminal tail lysine residues of histone H4, H4K5, and H4K12. Conversely, we show that deletion of RPD3 reduces the acetylation of these residues in an Hst1-dependent manner. This suggests that Rpd3 may function to oppose spreading of Hst1-dependent heterochromatin and represents a unique form of antagonism between HDACs in regulating gene expression. Moreover, we found that Rpd3 and Hst1 also coregulate additional targets involved in other branches of NAD+ metabolism. These findings help elucidate the complex interconnections involved in effecting the regulation of NAD+ metabolism.


Asunto(s)
Histona Desacetilasas , NAD , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Sirtuina 2 , Regulación Fúngica de la Expresión Génica , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , NAD/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Sirtuina 2/genética , Sirtuina 2/metabolismo
2.
Int J Mol Sci ; 24(9)2023 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-37175754

RESUMEN

Nicotinamide adenine dinucleotide (NAD+) is a critical cofactor essential for various cellular processes. Abnormalities in NAD+ metabolism have also been associated with a number of metabolic disorders. The regulation and interconnection of NAD+ metabolic pathways are not yet completely understood. By employing an NAD+ intermediate-specific genetic system established in the model organism S. cerevisiae, we show that histone deacetylases (HDACs) Hst1 and Rpd3 link the regulation of the de novo NAD+ metabolism-mediating BNA genes with certain aspects of the phosphate (Pi)-sensing PHO pathway. Our genetic and gene expression studies suggest that the Bas1-Pho2 and Pho2-Pho4 transcription activator complexes play a role in this co-regulation. Our results suggest a model in which competition for Pho2 usage between the BNA-activating Bas1-Pho2 complex and the PHO-activating Pho2-Pho4 complex helps balance de novo activity with PHO activity in response to NAD+ or phosphate depletion. Interestingly, both the Bas1-Pho2 and Pho2-Pho4 complexes appear to also regulate the expression of the salvage-mediating PNC1 gene negatively. These results suggest a mechanism for the inverse regulation between the NAD+ salvage pathways and the de novo pathway observed in our genetic models. Our findings help provide a molecular basis for the complex interplay of two different aspects of cellular metabolism.


Asunto(s)
Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Saccharomyces cerevisiae/metabolismo , NAD/metabolismo , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Fosfatos/metabolismo , Sirtuina 2/genética , Sirtuina 2/metabolismo , Transactivadores/metabolismo , Proteínas de Homeodominio/metabolismo
3.
J Biol Chem ; 295(21): 7362-7375, 2020 05 22.
Artículo en Inglés | MEDLINE | ID: mdl-32299909

RESUMEN

NAD+ is an essential metabolite participating in cellular biochemical processes and signaling. The regulation and interconnection among multiple NAD+ biosynthesis pathways are incompletely understood. Yeast (Saccharomyces cerevisiae) cells lacking the N-terminal (Nt) protein acetyltransferase complex NatB exhibit an approximate 50% reduction in NAD+ levels and aberrant metabolism of NAD+ precursors, changes that are associated with a decrease in nicotinamide mononucleotide adenylyltransferase (Nmnat) protein levels. Here, we show that this decrease in NAD+ and Nmnat protein levels is specifically due to the absence of Nt-acetylation of Nmnat (Nma1 and Nma2) proteins and not of other NatB substrates. Nt-acetylation critically regulates protein degradation by the N-end rule pathways, suggesting that the absence of Nt-acetylation may alter Nmnat protein stability. Interestingly, the rate of protein turnover (t½) of non-Nt-acetylated Nmnats did not significantly differ from those of Nt-acetylated Nmnats. Accordingly, deletion or depletion of the N-end rule pathway ubiquitin E3 ligases in NatB mutants did not restore NAD+ levels. Next, we examined whether the status of Nt-acetylation would affect the translation of Nmnats, finding that the absence of Nt-acetylation does not significantly alter the polysome formation rate on Nmnat mRNAs. However, we observed that NatB mutants have significantly reduced Nmnat protein maturation. Our findings indicate that the reduced Nmnat levels in NatB mutants are mainly due to inefficient protein maturation. Nmnat activities are essential for all NAD+ biosynthesis routes, and understanding the regulation of Nmnat protein homeostasis may improve our understanding of the molecular basis and regulation of NAD+ metabolism.


Asunto(s)
Acetiltransferasas/metabolismo , NAD/biosíntesis , Nicotinamida-Nucleótido Adenililtransferasa/metabolismo , Biosíntesis de Proteínas , Proteolisis , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Acetilación , Acetiltransferasas/genética , NAD/genética , Nicotinamida-Nucleótido Adenililtransferasa/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética
4.
Ren Fail ; 43(1): 1416-1424, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34641743

RESUMEN

Arteriovenous graft (AVG) is an important vascular access route in hemodialysis patients. The optimal waiting time between AVG creation and the first cannulation is still undetermined, therefore the current study investigated the association between ideal timing for cannulation and AVG survival. This retrospective cohort study used data from the Taiwan National Health Insurance Database, which included 6,493 hemodialysis patients with AVGs between July 1st 2008 and June 30th 2012. The waiting cannulation time was defined as the time from the date of shunt creation to the first successful cannulation. Patients were categorized according to the waiting cannulation time of their AVGs as follows: ≤30 days, between 31 and 90 days, between 91 and 180 days, and >180 days. The primary outcome was functional cumulative survival, measured as the time from the first cannulation to shunt abandonment. The AVGs which were cannulated between 31 and 90 days (reference group) after construction had significantly superior functional cumulative survival compared with those cannulated ≤30 days (adjusted HR = 1.651 with 95% CI 1.482-1.839; p < 0.0001) and >180 days (adjusted HR = 1.197 with 95% CI 1.012-1.417; p = 0.0363) after construction. An analysis of the hazard ratios in patients with different demographic characteristics, revealed that the functional cumulative survival of AVGs in most groups was better when they received cannulation >30 days after construction. Consequently, in order to achieve the best long-term survival, AVGs should be cannulated at least 1 month after construction, but you should avoid waiting for >3 months.


Asunto(s)
Derivación Arteriovenosa Quirúrgica , Cateterismo , Fallo Renal Crónico/terapia , Diálisis Renal , Anciano , Anciano de 80 o más Años , Prótesis Vascular , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Diseño de Prótesis , Estudios Retrospectivos , Factores de Riesgo , Taiwán , Factores de Tiempo
5.
J Biol Chem ; 294(14): 5562-5575, 2019 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-30760525

RESUMEN

NADH (NAD+) is an essential metabolite involved in various cellular biochemical processes. The regulation of NAD+ metabolism is incompletely understood. Here, using budding yeast (Saccharomyces cerevisiae), we established an NAD+ intermediate-specific genetic system to identify factors that regulate the de novo branch of NAD+ biosynthesis. We found that a mutant strain (mac1Δ) lacking Mac1, a copper-sensing transcription factor that activates copper transport genes during copper deprivation, exhibits increases in quinolinic acid (QA) production and NAD+ levels. Similar phenotypes were also observed in the hst1Δ strain, deficient in the NAD+-dependent histone deacetylase Hst1, which inhibits de novo NAD+ synthesis by repressing BNA gene expression when NAD+ is abundant. Interestingly, the mac1Δ and hst1Δ mutants shared a similar NAD+ metabolism-related gene expression profile, and deleting either MAC1 or HST1 de-repressed the BNA genes. ChIP experiments with the BNA2 promoter indicated that Mac1 works with Hst1-containing repressor complexes to silence BNA expression. The connection of Mac1 and BNA expression suggested that copper stress affects de novo NAD+ synthesis, and we show that copper stress induces both BNA expression and QA production. Moreover, nicotinic acid inhibited de novo NAD+ synthesis through Hst1-mediated BNA repression, hindered the reuptake of extracellular QA, and thereby reduced de novo NAD+ synthesis. In summary, we have identified and characterized novel NAD+ homeostasis factors. These findings will expand our understanding of the molecular basis and regulation of NAD+ metabolism.


Asunto(s)
NAD/biosíntesis , Niacina/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Sirtuina 2/metabolismo , Factores de Transcripción/metabolismo , Animales , Cobre/metabolismo , Ratones , NAD/genética , Niacina/genética , Proteínas Nucleares/genética , Ácido Quinolínico/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Sirtuina 2/genética , Factores de Transcripción/genética
6.
J Arthroplasty ; 35(2): 477-484.e4, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31594704

RESUMEN

BACKGROUND: The aim of this study is to compare perioperative outcomes, readmission, and mortality after hemiarthroplasty for hip fractures in diabetic patients with different renal function statuses. METHODS: In this retrospective population-based cohort study, diabetic patients who received primary hemiarthroplasty for hip fracture between January 1997 and December 2013 were identified from the Taiwan National Health Insurance Research Database. Primary outcomes were perioperative outcomes including infection and revision. Secondary outcomes were all-cause readmission and mortality. RESULTS: A total of 29,535 diabetic patients were included: 8270 patients had chronic kidney disease (CKD group), 1311 patients underwent permanent dialysis (dialysis group), and 19,954 patients did not have CKD (non-CKD group). During a mean follow-up of 4.5 years, these 3 groups had comparable risks of any infection, including superficial and deep infection. Dialysis patients had a significantly higher risk of revision than did CKD and non-CKD patients (subdistribution hazard ratio 1.65, 95% confidence interval 1.16-2.36; subdistribution hazard ratio 1.57, 95% confidence interval 1.10-2.24, respectively). Compared with the non-CKD group, the dialysis group had significantly higher risks of readmission and mortality at all time points, namely 3 months after surgery, 1 year after surgery, and the final follow-up. The CKD group also had higher risks of readmission and mortality than did the non-CKD group at all time points. CONCLUSION: CKD is associated with poor outcomes following hemiarthroplasty for fragility hip fracture. CKD patients may have higher risks of surgical complications including revision than non-CKD patients, and they have significantly elevated risks of readmission and mortality.


Asunto(s)
Diabetes Mellitus , Hemiartroplastia , Fracturas de Cadera , Insuficiencia Renal Crónica , Estudios de Cohortes , Diabetes Mellitus/epidemiología , Hemiartroplastia/efectos adversos , Fracturas de Cadera/epidemiología , Fracturas de Cadera/cirugía , Humanos , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/epidemiología , Estudios Retrospectivos , Taiwán/epidemiología
7.
J Biol Chem ; 293(8): 2927-2938, 2018 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-29317496

RESUMEN

Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite participating in cellular redox chemistry and signaling, and the complex regulation of NAD+ metabolism is not yet fully understood. To investigate this, we established a NAD+-intermediate specific reporter system to identify factors required for salvage of metabolically linked nicotinamide (NAM) and nicotinic acid (NA). Mutants lacking components of the NatB complex, NAT3 and MDM20, appeared as hits in this screen. NatB is an Nα-terminal acetyltransferase responsible for acetylation of the N terminus of specific Met-retained peptides. In NatB mutants, increased NA/NAM levels were concomitant with decreased NAD+ We identified the vacuolar pool of nicotinamide riboside (NR) as the source of this increased NA/NAM. This NR pool is increased by nitrogen starvation, suggesting NAD+ and related metabolites may be trafficked to the vacuole for recycling. Supporting this, increased NA/NAM release in NatB mutants was abolished by deleting the autophagy protein ATG14 We next examined Tpm1 (tropomyosin), whose function is regulated by NatB-mediated acetylation, and Tpm1 overexpression (TPM1-oe) was shown to restore some NatB mutant defects. Interestingly, although TPM1-oe largely suppressed NA/NAM release in NatB mutants, it did not restore NAD+ levels. We showed that decreased nicotinamide mononucleotide adenylyltransferase (Nma1/Nma2) levels probably caused the NAD+ defects, and NMA1-oe was sufficient to restore NAD+ NatB-mediated N-terminal acetylation of Nma1 and Nma2 appears essential for maintaining NAD+ levels. In summary, our results support a connection between NatB-mediated protein acetylation and NAD+ homeostasis. Our findings may contribute to understanding the molecular basis and regulation of NAD+ metabolism.


Asunto(s)
Modelos Moleculares , Acetiltransferasa B N-Terminal/metabolismo , NAD/metabolismo , Nicotinamida-Nucleótido Adenililtransferasa/metabolismo , Procesamiento Proteico-Postraduccional , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Acetilación , Acetiltransferasas/química , Acetiltransferasas/genética , Acetiltransferasas/metabolismo , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Eliminación de Gen , Genes Reporteros , Homeostasis , Inmunoprecipitación , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Mutación , Acetiltransferasa B N-Terminal/química , Acetiltransferasa B N-Terminal/genética , Nicotinamida-Nucleótido Adenililtransferasa/química , Nicotinamida-Nucleótido Adenililtransferasa/genética , Dominios y Motivos de Interacción de Proteínas , Multimerización de Proteína , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Saccharomyces cerevisiae/enzimología , Saccharomyces cerevisiae/crecimiento & desarrollo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Tropomiosina/genética , Tropomiosina/metabolismo
8.
Curr Genet ; 65(5): 1113-1119, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-30993413

RESUMEN

NAD+ (nicotinamide adenine dinucleotide) is an essential metabolite involved in a myriad of cellular processes. The NAD+ pool is maintained by three biosynthesis pathways, which are largely conserved from bacteria to human with some species-specific differences. Studying the regulation of NAD+ metabolism has been difficult due to the dynamic flexibility of NAD+ intermediates, the redundancy of biosynthesis pathways, and the complex interconnections among them. The budding yeast Saccharomyces cerevisiae provides an efficient genetic model for the isolation and study of factors that regulate specific NAD+ biosynthesis pathways. A recent study has uncovered a putative cross-regulation between the de novo NAD+ biosynthesis and copper homeostasis mediated by a copper-sensing transcription factor Mac1. Mac1 appears to work with the Hst1-Sum1-Rfm1 complex to repress the expression of de novo NAD+ biosynthesis genes. Here, we extend the discussions to include additional nutrient- and stress-sensing pathways that have been associated with the regulation of NAD+ homeostasis. NAD+ metabolism is an emerging therapeutic target for several human diseases. NAD+ preservation also helps ameliorate age-associated metabolic disorders. Recent findings in yeast contribute to the understanding of the molecular basis underlying the cross-regulation of NAD+ metabolism and other signaling pathways.


Asunto(s)
Metabolismo Energético , Redes y Vías Metabólicas , NAD/metabolismo , Saccharomyces cerevisiae/fisiología , Transducción de Señal , Regulación Fúngica de la Expresión Génica , Homeostasis , Estrés Fisiológico
9.
J Biol Chem ; 290(20): 12753-64, 2015 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-25825491

RESUMEN

Attenuated nutrient signaling extends the life span in yeast and higher eukaryotes; however, the mechanisms are not completely understood. Here we identify the Ssy1-Ptr3-Ssy5 (SPS) amino acid sensing pathway as a novel longevity factor. A null mutation of SSY5 (ssy5Δ) increases replicative life span (RLS) by ∼50%. Our results demonstrate that several NAD(+) homeostasis factors play key roles in this life span extension. First, expression of the putative malate-pyruvate NADH shuttle increases in ssy5Δ cells, and deleting components of this shuttle, MAE1 and OAC1, largely abolishes RLS extension. Next, we show that Stp1, a transcription factor of the SPS pathway, directly binds to the promoter of MAE1 and OAC1 to regulate their expression. Additionally, deletion of SSY5 increases nicotinamide riboside (NR) levels and phosphate-responsive (PHO) signaling activity, suggesting that ssy5Δ increases NR salvaging. This increase contributes to NAD(+) homeostasis, partially ameliorating the NAD(+) deficiency and rescuing the short life span of the npt1Δ mutant. Moreover, we observed that vacuolar phosphatase, Pho8, is partially required for ssy5Δ-mediated NR increase and RLS extension. Together, our studies present evidence that supports SPS signaling is a novel NAD(+) homeostasis factor and ssy5Δ-mediated life span extension is likely due to concomitantly increased mitochondrial and vacuolar function. Our findings may contribute to understanding the molecular basis of NAD(+) metabolism, cellular life span, and diseases associated with NAD(+) deficiency and aging.


Asunto(s)
Proteínas Portadoras/metabolismo , Homeostasis/fisiología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/metabolismo , NAD/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Serina Proteasas/metabolismo , Transducción de Señal/fisiología , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Proteínas Portadoras/genética , Eliminación de Gen , Regulación Fúngica de la Expresión Génica/fisiología , Péptidos y Proteínas de Señalización Intracelular/genética , Malato Deshidrogenasa/genética , Malato Deshidrogenasa/metabolismo , Proteínas de la Membrana/genética , NAD/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Serina Proteasas/genética , Vacuolas/genética , Vacuolas/metabolismo
10.
J Biol Chem ; 289(22): 15577-87, 2014 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-24759102

RESUMEN

NAD(+) is an essential metabolic cofactor involved in various cellular biochemical processes. Nicotinamide riboside (NR) is an endogenously produced key pyridine metabolite that plays important roles in the maintenance of NAD(+) pool. Using a NR-specific cell-based screen, we identified mutants that exhibit altered NR release phenotype. Yeast cells lacking the ORF YCL047C/POF1 release considerably more NR compared with wild type, suggesting that POF1 plays an important role in NR/NAD(+) metabolism. The amino acid sequence of Pof1 indicates that it is a putative nicotinamide mononucleotide adenylyltransferase (NMNAT). Unlike other yeast NMNATs, Pof1 exhibits NMN-specific adenylyltransferase activity. Deletion of POF1 significantly lowers NAD(+) levels and decreases the efficiency of NR utilization, resistance to oxidative stress, and NR-induced life span extension. We also show that NR is constantly produced by multiple nucleotidases and that the intracellular NR pools are likely to be compartmentalized, which contributes to the regulation of NAD(+) homeostasis. Our findings may contribute to the understanding of the molecular basis and regulation of NAD(+) metabolism in higher eukaryotes.


Asunto(s)
NAD/biosíntesis , Nicotinamida-Nucleótido Adenililtransferasa/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/enzimología , Secuencia de Aminoácidos , Homeostasis/fisiología , Datos de Secuencia Molecular , Niacinamida/análogos & derivados , Niacinamida/metabolismo , Nicotinamida-Nucleótido Adenililtransferasa/genética , Compuestos de Piridinio , Proteínas de Saccharomyces cerevisiae/genética
11.
FEMS Yeast Res ; 14(1): 119-35, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24205865

RESUMEN

How do cells age and die? For the past 20 years, the budding yeast, Saccharomyces cerevisiae, has been used as a model organism to uncover the genes that regulate lifespan and cell death. More recently, investigators have begun to interrogate the other yeasts, the fission yeast, Schizosaccharomyces pombe, and the human fungal pathogen, Candida albicans, to determine if similar longevity and cell death pathways exist in these organisms. After summarizing the longevity and cell death phenotypes in S. cerevisiae, this mini-review surveys the progress made in the study of both aging and programed cell death (PCD) in the yeast models, with a focus on the biology of S. pombe and C. albicans. Particular emphasis is placed on the similarities and differences between the two types of aging, replicative aging, and chronological aging, and between the three types of cell death, intrinsic apoptosis, autophagic cell death, and regulated necrosis, found in these yeasts. The development of the additional microbial models for aging and PCD in the other yeasts may help further elucidate the mechanisms of longevity and cell death regulation in eukaryotes.


Asunto(s)
Candida albicans/citología , Candida albicans/fisiología , Muerte Celular , Schizosaccharomyces/citología , Schizosaccharomyces/fisiología , Candida albicans/crecimiento & desarrollo , Modelos Biológicos , Schizosaccharomyces/crecimiento & desarrollo , Factores de Tiempo
12.
Arch Orthop Trauma Surg ; 134(1): 39-45, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24258682

RESUMEN

BACKGROUND: Chronic kidney disease (CKD) affects many physiologic systems, including bone quality, nutrition, and cardiovascular condition. Femoral neck fractures in patients on dialysis are associated with frequent complications and a high risk of mortality. However, the effect of CKD on clinical outcomes of patients with hip fractures treated with osteosynthesis remains unclear. METHODS: One hundred and thirty patients with 130 femoral neck fractures treated with internal fixation were divided into two groups and the data were then analyzed. Group 1 consisted of 98 patients (98 hip fractures) with normal renal function (estimated glomerular filtration rate, or eGFR, ≥60 ml/min/1.73 m(2)). Group 2 was composed of 32 patients (32 hip fractures) with CKD (eGFR <60 ml/min/1.73 m(2)) without dialysis. Clinical outcomes as well as early and late complications were recorded for each group. Survivorship analysis was performed, and the mortality and complication rates for the groups were then compared. RESULTS: In Group 1, 32 complications (32.6%) occurred in 98 hips, including 5 cases of nonunion and 16 cases of osteonecrosis. In Group 2, 24 complications (75%) developed in 32 hips; these included 8 cases of nonunion and 3 cases of osteonecrosis. The mean duration of follow-up was 32 months. The overall mortality rate was 11.5%. No difference was noted in early, late, or overall mortality rate between two groups. Patient with CKD had a higher nonunion rate (OR = 5.9, P = 0.023). Meanwhile, CKD and displaced fracture pattern were independent predictors for revision surgery (OR = 3.0, P = 0.032; OR = 6.9, P = 0.001, respectively). CONCLUSIONS: Osteosynthesis is a safe and effective treatment for femoral neck fractures; however, patients with femoral neck fracture and CKD have a higher risk of nonunion and subsequent surgical revision. LEVEL OF RELEVANCE: Prognostic studies, Level III.


Asunto(s)
Fracturas del Cuello Femoral/cirugía , Insuficiencia Renal Crónica/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Fracturas del Cuello Femoral/etiología , Fijación Interna de Fracturas , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Diálisis Renal , Insuficiencia Renal Crónica/complicaciones , Reoperación , Estudios Retrospectivos , Adulto Joven
14.
J Biol Chem ; 286(16): 14271-81, 2011 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-21349851

RESUMEN

Nicotinamide adenine dinucleotide (NAD(+)) is an essential cofactor involved in various cellular biochemical reactions. To date the signaling pathways that regulate NAD(+) metabolism remain unclear due to the dynamic nature and complexity of the NAD(+) metabolic pathways and the difficulty of determining the levels of the interconvertible pyridine nucleotides. Nicotinamide riboside (NmR) is a key pyridine metabolite that is excreted and re-assimilated by yeast and plays important roles in the maintenance of NAD(+) pool. In this study we establish a NmR-specific reporter system and use it to identify yeast mutants with altered NmR/NAD(+) metabolism. We show that the phosphate-responsive signaling (PHO) pathway contributes to control NAD(+) metabolism. Yeast strains with activated PHO pathway show increases in both the release rate and internal concentration of NmR. We further identify Pho8, a PHO-regulated vacuolar phosphatase, as a potential NmR production factor. We also demonstrate that Fun26, a homolog of human ENT (equilibrative nucleoside transporter), localizes to the vacuolar membrane and establishes the size of the vacuolar and cytosolic NmR pools. In addition, the PHO pathway responds to depletion of cellular nicotinic acid mononucleotide (NaMN) and mediates nicotinamide mononucleotide (NMN) catabolism, thereby contributing to both NmR salvage and phosphate acquisition. Therefore, NaMN is a putative molecular link connecting the PHO signaling and NAD(+) metabolic pathways. Our findings may contribute to the understanding of the molecular basis and regulation of NAD(+) metabolism in higher eukaryotes.


Asunto(s)
NAD/metabolismo , Fosfatos/metabolismo , Saccharomyces cerevisiae/metabolismo , Fosfatasa Alcalina/metabolismo , Transporte Biológico , Cromatografía Liquida/métodos , Tranportador Equilibrativo 1 de Nucleósido/metabolismo , Proteínas Fúngicas/metabolismo , Eliminación de Gen , Espectrometría de Masas/métodos , Proteínas de Transporte de Membrana/química , Microscopía Fluorescente/métodos , Modelos Genéticos , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Transducción de Señal , Vacuolas/metabolismo
15.
Biochim Biophys Acta ; 1804(8): 1567-75, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19818879

RESUMEN

The Sir2 family proteins (sirtuins) are evolutionally conserved NAD(+) (nicotinamide adenine dinucleotide)-dependent protein deacetylases and ADP-ribosylases, which have been shown to play important roles in the regulation of stress response, gene transcription, cellular metabolism and longevity. Recent studies have also suggested that sirtuins are downstream targets of calorie restriction (CR), which mediate CR-induced beneficial effects including life span extension in an NAD(+)-dependent manner. CR extends life span in many species and has been shown to ameliorate many age-associated disorders such as diabetes and cancers. Understanding the mechanisms of CR as well as the regulation of sirtuins will therefore provide insights into the molecular basis of these age-associated metabolic diseases. This review focuses on discussing advances in studies of sirtuins and NAD(+) metabolism in genetically tractable model system, the budding yeast Saccharomyces cerevisiae. These studies have unraveled key metabolic longevity factors in the CR signaling and NAD(+) biosynthesis pathways, which may also contribute to the regulation of sirtuin activity. Many components of the NAD(+) biosynthesis pathway and CR signaling pathway are conserved in yeast and higher eukaryotes including humans. Therefore, these findings will help elucidate the mechanisms underlying age-associated metabolic disease and perhaps human aging.


Asunto(s)
Modelos Biológicos , NAD/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas Reguladoras de Información Silente de Saccharomyces cerevisiae/metabolismo , Envejecimiento/metabolismo , Animales , Restricción Calórica , Expresión Génica , Humanos , Longevidad , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crecimiento & desarrollo , Proteínas Reguladoras de Información Silente de Saccharomyces cerevisiae/química , Sirtuina 2/química , Sirtuina 2/metabolismo , Estrés Fisiológico , Telómero/genética , Telómero/metabolismo
16.
Curr Opin Cell Biol ; 15(2): 241-6, 2003 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-12648681

RESUMEN

Nicotinamide adenine dinucleotide (NAD) is a ubiquitous biological molecule that participates in many metabolic reactions. Recent studies show that NAD also plays important roles in transcriptional regulation, longevity, calorie-restriction-mediated life-span extension and age-associated diseases. It has been shown that NAD affects longevity and transcriptional silencing through the regulation of the Sir2p family, which are NAD-dependent deacetylases. Many human diseases are associated with changes in NAD level and/or the NAD : NADH ratio, raising the possibility that the Sir2p family might play a role in these diseases.


Asunto(s)
Envejecimiento/genética , Células Eucariotas/metabolismo , Genes Reguladores/fisiología , Longevidad/genética , NAD/metabolismo , Envejecimiento/metabolismo , Animales , Humanos , Enfermedades Metabólicas/genética , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/fisiopatología , Sirtuinas/genética , Sirtuinas/metabolismo
17.
Front Mol Biosci ; 8: 686412, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34095234

RESUMEN

Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite with wide-ranging and significant roles in the cell. Defects in NAD+ metabolism have been associated with many human disorders; it is therefore an emerging therapeutic target. Moreover, NAD+ metabolism is perturbed during colonization by a variety of pathogens, either due to the molecular mechanisms employed by these infectious agents or by the host immune response they trigger. Three main biosynthetic pathways, including the de novo and salvage pathways, contribute to the production of NAD+ with a high degree of conservation from bacteria to humans. De novo biosynthesis, which begins with l-tryptophan in eukaryotes, is also known as the kynurenine pathway. Intermediates of this pathway have various beneficial and deleterious effects on cellular health in different contexts. For example, dysregulation of this pathway is linked to neurotoxicity and oxidative stress. Activation of the de novo pathway is also implicated in various infections and inflammatory signaling. Given the dynamic flexibility and multiple roles of NAD+ intermediates, it is important to understand the interconnections and cross-regulations of NAD+ precursors and associated signaling pathways to understand how cells regulate NAD+ homeostasis in response to various growth conditions. Although regulation of NAD+ homeostasis remains incompletely understood, studies in the genetically tractable budding yeast Saccharomyces cerevisiae may help provide some molecular basis for how NAD+ homeostasis factors contribute to the maintenance and regulation of cellular function and how they are regulated by various nutritional and stress signals. Here we present a brief overview of recent insights and discoveries made with respect to the relationship between NAD+ metabolism and selected human disorders and infections, with a particular focus on the de novo pathway. We also discuss how studies in budding yeast may help elucidate the regulation of NAD+ homeostasis.

18.
Ther Adv Musculoskelet Dis ; 13: 1759720X211011374, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33995605

RESUMEN

BACKGROUND: The incidence of osteoporotic fracture increases with age, particularly in elderly populations with atrial fibrillation (AF). However, direct oral anticoagulants (DOACs) have less effect on osteoporotic fracture than vitamin K antagonists, it is unclear whether the risk of osteoporotic fracture is affected by different types and doses of DOACs in AF patients. METHODS: This nationwide population-based cohort study included AF patients prescribed DOACs between 2011 and 2016 taken from the Taiwan National Health Insurance database. Adjusted hazard ratios (aHRs) for the risk of osteoporotic, hip, and spine fractures between DOAC users were compared using the Fine and Gray subdistribution hazard model to adjust for possible confounders. RESULTS: A total of 56,795 patients who were prescribed DOACs were included in the present study. Among them, 24,597 patients received dabigatran, 26,968 received rivaroxaban, and 5230 received apixaban. After 2 years' follow up, there was no significant difference in the incidence of osteoporotic, spine, or hip fracture among those receiving dabigatran, rivaroxaban, or apixaban. Subgroup analysis showed that patients taking dabigatran had a higher incidence of osteoporotic and hip fracture than those taking rivaroxaban and apixaban in cases with concomitant peripheral artery disease (PAD) or a history of hip fracture (p for interaction: 0.004 and 0.030, respectively). However, dabigatran users had a lower incidence of osteoporotic fracture and spine fracture in those receiving standard-dose DOACs compared with rivaroxaban and apixaban; whereas, they had a higher incidence of hip fractures when administered at low dose. CONCLUSION: AF patients with different DOACs did not have different risks of osteoporotic fracture overall. However, additional concomitant morbidities, such as PAD or a history of hip fracture, and standard/low doses might be associated with different risks for different DOACs. These findings should be taken into consideration in the clinic when the DOAC is being chosen. PLAIN LANGUAGE SUMMARY: Different direct oral anticoagulants had different impact on osteoporotic fracture Anticoagulation therapy is an essential therapy in atrial fibrillation (AF) patients, but osteoporotic fracture is another important issue in these patients prescribed with anticoagulants. However, no study has been conducted to evaluate the impact of different DOACs on different types of osteoporotic fractures. In our findings, although different DOACs had no significantly different impact on osteoporotic fractures, dabigatran users had a slightly higher incidence of osteoporotic and hip fractures among different DOACs, particularly in those have simultaneously had peripheral artery disease, a history of hip fracture. In addition, when AF patients taking low-dose DOACs, dabigatran users also have higher incidence of hip fracture than those taking other DOACs.

19.
Diagnostics (Basel) ; 11(5)2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-34062879

RESUMEN

The number of diabetic patients with chronic kidney disease (CKD) undergoing shoulder arthroplasty is growing. This study aims to compare perioperative outcomes of shoulder arthroplasty in diabetic patients at different renal function stages. Between 1998 and 2013, a total of 4443 diabetic patients with shoulder arthroplasty were enrolled: 1174 (26%) had CKD without dialysis (CKD group), 427 (9%) underwent dialysis (dialysis group), and 3042 (68%) had no CKD (non-CKD group). Compared with the non-CKD group, the CKD (odds ratio [OR], 4.69; 95% confidence interval [CI], 2.02-10.89) and dialysis (OR, 6.71; 95% CI, 1.63-27.73) groups had a high risk of in-hospital death. The dialysis group had a high risk of infection after shoulder arthroplasty compared with the CKD (subdistribution hazard ratio [SHR], 1.69; 95% CI, 1.07-2.69) and non-CKD (SHR, 1.76; 95% CI, 1.14-2.73) groups. The dialysis group showed higher risks of all-cause readmission and mortality than the CKD and non-CKD groups after a 3-month follow-up. In conclusion, CKD was associated with worse outcomes after shoulder arthroplasty. Compared with those without CKD, CKD patients had significantly increased readmission and mortality risks but did not have an increased risk of surgical complications, including superficial infection or implant removal.

20.
PLoS One ; 16(10): e0258393, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34624055

RESUMEN

BACKGROUND: The proximal humerus fracture (PHF) is the third most common fragility fracture. Diabetes mellitus (DM) and chronic kidney disease (CKD) are both risks for fragility fractures; however, the interplay of DM and CKD makes treatment outcomes unpredictable. This study aimed to investigate and compare early and late outcomes following proximal humerus fracture fixation surgery in diabetic patients with different renal function conditions. METHODS: DM patients receiving PHF fixation surgery during 1998-2013 were recruited from Taiwan's National Health Insurance Research Database. According to their renal function, patients were divided into three study groups: non-chronic kidney disease (CKD), non-dialysis CKD, and dialysis. Outcomes of interest were early and late perioperative outcomes. Early outcomes included in-hospital newly-onset morbidities. Late outcomes included infection, revision, readmission, and all-cause mortality. RESULTS: This study included a total of 10,850 diabetic patients: 2152 had CKD (non-dialysis CKD group), 196 underwent permanent dialysis (dialysis group), and the remaining 8502 did not have CKD (non-CKD group). During a mean follow-up of 5.56 years, the dialysis group showed the highest risk of overall infection, all-cause revision, readmission, and mortality compared to the non-dialysis CKD group and non-CKD group. Furthermore, subgroup analysis showed that CKD patients had a higher risk of surgical infection following PHF surgery than non-CKD patients in cases with a traffic accident or fewer comorbidities (Charlson Comorbidity Index, CCI <3) (P for interaction: 0.086 and 0.096, respectively). Also, CKD patients had an even higher mortality risk after PHF surgery than non-CKD patients, in females, those living in higher urbanization areas, or with more comorbidities (CCI ≥3) (P for interaction: 0.011, 0.057, and 0.069, respectively). CONCLUSION: CKD was associated with elevated risks for infection, revision, readmission, and mortality after PHF fixation surgery in diabetic patients. These findings should be taken into consideration when caring for diabetic patients.


Asunto(s)
Insuficiencia Renal Crónica , Anciano , Estudios de Cohortes , Comorbilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Diálisis Renal
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