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Difference Between Deoxy Ribose \u0026 Ribose Sugar- Importance of Deoxy Ribose \u0026 Ribose SugarRibose sugar and cell growth -
Another study found that 15 grams daily of the supplement enhanced the function of some of the chambers of the heart and improved quality of life in those with the same disease 5.
Overall, studies demonstrate the potential of D-ribose for improving heart metabolism and function in people with heart disease 3 , 6 , 7. Some evidence shows benefits of D-ribose supplements for those with low blood flow to the heart muscle, as seen in conditions like coronary artery disease.
This is likely due to the role of D-ribose in producing cellular energy. Due to the association between some pain disorders and problems with energy metabolism, certain studies focus on whether D-ribose supplements can reduce pain 8.
In one study in 41 people with fibromyalgia or chronic fatigue syndrome, improvements in subjective pain intensity, well-being, energy, mental clarity, and sleep were reported after receiving 15 grams of D-ribose daily for 17—35 days 8.
However, a noteworthy limitation of this study is that it did not include a placebo group and participants knew ahead of time that they were receiving D-ribose. Consequently, the improvements could have been due to a placebo effect 9.
One other case study reported similar pain-reducing benefits of D-ribose supplements in a woman with fibromyalgia, but research in this area remains limited While some results are positive, the existing research on D-ribose supplements in pain disorders is insufficient to draw any definite conclusions.
Additional high-quality research is needed. D-ribose could be beneficial for treating certain pain disorders, such as fibromyalgia.
However, research in this area is limited. Some research supports the possible benefits of D-ribose in relation to exercise and energy production in those with specific diseases 4 , 11 , Other research has demonstrated possible performance-enhancing benefits in healthy individuals but only in those with low fitness levels.
Researchers particularly saw enhanced power output and lower perceived exertion during exercise when participants with lower fitness levels took 10 grams per day of D-ribose compared to a placebo Despite these findings, the majority of research in healthy populations has not shown improvements in performance 11 , 14 , 15 , One study even showed that the group that consumed D-ribose showed less improvement than the group that consumed a different type of sugar dextrose as the placebo treatment Overall, the performance-enhancing effects of D-ribose are likely only seen in certain disease states and possibly those with low fitness levels.
Some studies have shown that D-ribose may enhance exercise performance in those with low fitness levels or specific diseases. However, research does not support these benefits in healthy individuals.
While D-ribose may help recover ATP levels in muscle tissue, this may not translate to improved performance in healthy people 1 , However, those with particular genetic conditions that affect muscle function may benefit from D-ribose supplements.
The genetic disorder myoadenylate deaminase deficiency MAD — or AMP deaminase deficiency — causes fatigue, muscle pain, or cramps after physical activity 18 , Interestingly, the prevalence of MAD varies substantially by race. Some research has examined whether D-ribose can improve function in people with this condition Moreover, several case studies have reported improvements in muscle function and well-being in people with this disorder 21 , Similarly, a small study found that people with MAD experienced less post-exercise stiffness and cramps after taking D-ribose However, other case studies have failed to find any benefit of the supplement in people with this condition Given the limited information and mixed results, people with MAD who are considering D-ribose supplements should consult with their healthcare provider.
Limited research has reported mixed results regarding the ability of D-ribose supplements to improve muscle function and well-being in people with the genetic disorder myoadenylate deaminase deficiency MAD. Many of these studies provided D-ribose multiple times per day, with total daily doses of 15—60 grams 1 , 4 , 5 , 8 , Although several of these studies did not report whether side effects occurred, those that did stated that D-ribose was well tolerated without side effects 8 , 21 , The experiment was terminated after one week.
From each mouse, blood samples were collected into EDTA BD Vacutainer K2 EDTA 3. In addition, tumours were collected, weighed and used for the extraction of TIF, as below. TIF was isolated from tumours as described In brief, tumours were rapidly dissected after euthanizing the animals.
TIF was then processed for metabolomics in a similar manner as plasma, as described below. Uridine-derived ribose carbon was traced in vivo using [ 13 C 5 ]ribose-labelled uridine Cambridge Isotope Laboratories, CLMPK. Specifically, mice bearing orthotopic or subcutaneous tumours were generated, as described above, using KPC b cell lines.
A parallel plate for protein estimation and sample normalization was also set up. After overnight incubation, the culture medium was aspirated and replaced with medium containing treatments or supplemented metabolites of interest. Thereafter, cell lysates were collected from each well and transferred into separate 1.
The samples were then centrifuged at 12, g. For each experimental condition, the volume of supernatant to collect for drying with SpeedVac Vacuum Concentrator model: SPD was determined based on the protein concentration of the parallel plate.
For tumours, the samples were flash frozen in liquid nitrogen upon collection. Samples were then centrifuged at 12, g and supernatant collected for further processing.
Data were analysed with Agilent Masshunter Workstation Quantitative Analysis for QQQ version For stable isotope tracing in cells, [ 13 C 5 ]uridine Cambridge Isotope Laboratories, CLMPK was supplemented at 0.
In brief, wild-type or UPP1-KO cells were cultured overnight in regular medium. Next day, cells were washed once followed by the introduction of medium containing the indicated amounts of glucose, dialysed FBS and supplemented with labelled uridine.
In parallel, a similar experiment was set up for unlabelled uridine. Labelled tumours were similarly collected as detailed above. Samples were prepared for time-of-flight mass spectrometry, as described in detail previously 47 , and analysed with Agilent MassHunter Workstation Profinder version For the experiments were glucose and uridine concentrations were varied 5 and 0.
Cells were scraped from the dish. Chromatograms for selected metabolites were extracted in Skyline Daily software version Natural isotope abundance correction was performed, and peak areas plotted. For quantification of uridine and glucose in TIF, quantitative metabolite profiling of fluid samples was performed as previously described Using the external standard library dilutions, we created a standard curve based on the linear relationship of the normalized peak area and the concentration of the metabolite.
This standard curve was then used to interpolate the concentration of the metabolite in the TIF sample. Patients with pancreas resections for PDA from to at the University of Michigan Health System were included in the study.
The collection of patient-derived tissues for histological analyses was approved by the Institutional Review Board at the University of Michigan IRB number: HUM All specimens are from patients with pancreas resections for pancreatitis, cystic neoplasms, or PDA from to at the University of Michigan Health System.
Corresponding areas were carefully selected and marked. The TMA was previously published In brief, paraffin wax was removed with xylene and slides were rehydrated. Samples were incubated with TSA-Cy3 fluorophore ,; Akoya Biosciences; NELAKT diluted in CoDetection Antibody Diluent.
Slides were rinsed with PBST and mounted in ProLong Gold Antifade Mountant Invitrogen, P Sections were visualized on a Leica SP5X upright confocal.
Patients tissue slides were deparaffinized and rehydrated with graded Histo-Clear National Diagnostics , ethanol, and water.
Samples underwent antigen retrieval with sodium citrate buffer 2. Slides were mounted in Permount Mounting Medium Fisher. After drying, slides were imaged using an Olympus BX53F microscope, Olympus CP80 digital camera, and CellSens standard software.
Serial sections of 4 µm thickness were cut from FFPE blocks, deparaffinized in xylene, processed in graded alcohol, and rehydrated in water. The Dako Autostainer Link 48 automated immunostaining platform was used for all the below immunostainings.
For these antibodies, EnVision FLEX Target Retrieval Solution high pH; K, Agilent and Nichirei anti-rat Histofine polymer reagent F, Nichirei Biosciences primary antibody detection kits were used. Appropriate positive and negative controls were used in all runs. The Nanozoomer-XR C Hamamatsu was used to scan whole stained sections.
Antigen expression was scored using Definiens Test Studio Software Definiens. Immunohistochemistry of UPP1 expression in human normal and PDA tissues was also accessed from the Human Protein Atlas portal Differential gene expression between PDA and non-tumours were performed in R using the limma package version 3.
Kaplan—Meier overall survival log-rank test was performed after splitting the tumour samples per dataset into UPP1 -high and UPP1 -low subsets. The iKras mice data were obtained from NCBI GEO under the accession number GSE TCGA pan-cancer datasets including bladder, colon, oesophageal, lung, head and neck, prostate cancer and glioblastoma, were downloaded from Xena Platform from University of California Santa Cruz An additional colorectal dataset GSE was also used.
For the comparisons, the normal or adjacent matched and unmatched normal samples were used. In total, 2, cancer tissue samples and non-tumoural control tissue samples were analysed. These datasets were used to compare UPP1 expression between cancer and non-cancer tissues. Gene expression data for uridine high and uridine low metabolizers were extracted from the CCLE GSE UPP1 protein expression analysis was performed in KRAS mutant and wild-type cell lines using data from DepMap Gene ontology analyses were performed with DAVID.
CiiDER 54 was used for predicting UPP1 gene transcription factor sites. As transcription factor binding sites are variable and binding sites rarely match the model perfectly, a default deficit score of 0.
Top 10 transcription factors were obtained using the predicted UPP1-binding sites with respect to sequences from the human genome GRCh Statistics were performed either with GraphPad Prism 8 GraphPad Software Inc.
or using R version 3. Data from experimental groups were compared using the two-tailed t -test or analysis of variance ANOVA with post hoc corrections where applicable, and between biological or in vitro replicates. For data analysis and visualization in R, packages with versions used include dplyr 0.
Figure 1. The assay readout, RMA, was correlated with the expression level of metabolic genes in cell lines; human PDA data were used for subsequent analyses. Nutrient-deficient medium, no glucose, 0. The experiments were performed twice with similar results.
The experiment was performed once. Figure 2. Statistical significance was measured using two-tailed unpaired t -test. Bars shown for PATUS are same as the WT bars where applicable for that cell line in the Extended Data Fig.
Tracing experiments were performed twice in these cells with similar results. g, Number of samples: sub-Q, tumours from 3 mice injected on the left and right flanks; ortho, tumours from 4 mice.
Mode of uridine injection is intratumoural for sub-Q and intraperitoneal for ortho. These samples are from the control group of the study in Fig. j,k, j shows the mass isotopologue distribution in uridine and k shows in the indicated metabolites. The metabolomics experiments b—k were performed once.
Figure 3. a, The experiment was performed once. The experiments were performed three times with similar results. Data are part of the metabolomics experiments shown in Extended Data Fig.
The metabolomics experiment was performed once. g, Representative images from patient 1 of 3 tumour tissues. PanCK, pan-cytokeratin, stain indicates tumour cells.
i, Number of samples: UPP1 -low, ; UPP1 -high, j, Number of samples: no alteration, 43; G12D, l, Vinculin is used as a loading control.
m, 3 biologically independent samples per group. n, Vinculin is used as a loading control. Figure 4. Data represent the average of quantification from three histological slides obtained per tumour. d, The cells were cultured ±1 mM uridine in glucose-free medium supplemented with 2.
KPC b, comparison of cell culture without and with 0. i, Tumour weight data are shown in j. Experiment performed once. k, Number of samples: sgV, 8; sg1, 8; sg3, 8 tumours, corresponding to four mice per group. l, Samples used for metabolomics per group: sgV, 5; sg1, 6; sg3, 6. Statistical significance was determined using the limma package version 3.
The mouse schematic a,i was drawn with Adobe Illustrator version Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. The gene microarrays were obtained from NCBI Gene Expression Omnibus. The accompanying source data are provided as supplementary tables.
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Cancer 1 , — Download references. We thank B. Bochner for providing the OmniLog instrument, helping with the data analysis, countless insightful discussions, and support; S.
Chan for support with Biolog data collection and analysis; D. DeNardo and the DeNardo laboratory for support designing the macrophage-depletion studies; N.
Guppy for processing and immunohistochemistry staining of mouse tumour samples; L. Howell for helping with the automated image analysis of immunohistochemistry staining; and members of the Sadanandam and Lyssiotis laboratories and the entire Pancreatic Disease Initiative at the Rogel Cancer Center, University of Michigan, for their insightful comments and discussions.
was supported by the Department of Veteran Affairs Career Development Award IK2BX was supported by American Cancer Society IRG , the University of Chicago Cancer Center Support Grant P30 CA , the Pancreatic Cancer Action Network Career Development Award , the Brinson Foundation, the Cancer Research Foundation and the Ludwig Center for Metastasis Research.
and C. were supported by UMCCC Core Grant P30CA The funders had no role in study design, data collection and analysis, or the content and publication of this manuscript.
These authors contributed equally: Zeribe C. Nwosu, Matthew H. Ward, Peter Sajjakulnukit, Pawan Poudel. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Zeribe C. Ward, Peter Sajjakulnukit, Steven Kasperek, Megan Radyk, Damien Sutton, Anthony Andren, Zachary Tolstyka, Ho-Joon Lee, Julia Ugras, Li Zhang, Christopher J.
For ORF screening, K cells were infected with a lentiviral-carried ORFeome v8. Cells were infected at a multiplicity of infection of 0. Barcode sequencing, mapping and read count were performed by the Genome Perturbation Platform Broad Institute.
For screen analysis, log 2 normalized read counts were used, and P values were calculated using a two-sided t -test. The presence of lentiviral recombination within the ORFeome library was not tested and as such genes that dropped out should be considered with caution, as these may represent unnatural proteins Twenty-four hours after infection, cells were selected with 0.
Protein concentration was determined from total cell lysates using a DC protein assay Bio-Rad. Gel electrophoresis was done on Novex Tris-Glycine gels Thermo Fisher Scientific before transfer using the Trans-Blot Turbo blotting system and nitrocellulose membranes Bio-Rad.
Washes were done in TBST. Specific primary antibodies were diluted at a concentration of —, in blocking buffer. Fluorescent-coupled secondary antibodies were diluted at a ratio of , in blocking buffer.
Membranes were imaged with an Odyssey CLx analyzer Li-cor with Image Studio Lite v4. The following antibodies were used: FLAG M2 Sigma, F , Actin Abcam, ab , TUBB Thermo, MA , UPP1 Sigma, SAB , MITF Sigma, HPA , TYR Santa Cruz sc , MLANA CST, , HK2 CST, , GPI CST, , ALDOA CST, , TKT CST, , RPE Proteintech, AP , PGM2 Proteintech, AP , UCK2 Proteintech, AP , TYMS Proteintech, AP , S6 ribosomal protein Santa Cruz, sc and phosphor-S6 Santa Cruz, sc Two commercially available antibodies to UPP2 were tested Sigma, SAB; Abcam, ab , but no specific band could be detected.
The medium was replaced with fresh medium on days 3 and 5. On day 6, all wells reached confluency and cells were lysed. Barcode abundance was determined from sequencing, and unexpectedly low counts for example, from sequencing noise were filtered out from individual replicates so as not to unintentionally depress cell line counts in the collapsed data.
Replicates were then mean-collapsed, and log fold change and growth rate metrics were calculated according to equations 1 and 2 :.
where n u and n g are counts from the uridine and glucose supplemented conditions, respectively, n 0 and n f are counts from the initial and final timepoints, respectively, and t is the assay length in days.
Data analysis and correlation analysis were performed by The PRISM Lab following a published workflow qPCR was performed using the TaqMan assays Thermo Fisher Scientific. Human PBMCs and mouse BMDM data were normalized to TBP , and liver mouse data were normalized to Rplp2 , both using the ΔΔCt method.
qPCR primers for ChIP are described below. Fixation was stopped by adding glycine final concentration of 0. Cells were harvested by scraping with ice-cold PBS. Samples were centrifuged to remove debris and diluted tenfold in immunoprecipitation dilution buffer DNA was purified with QIAquick PCR purification kit Qiagen.
Purified DNA was co-transfected with a GFP-expressing plasmid in the cell lines of interest using Lipofectamine Thermo Fisher Scientific. UPP1 depletion in single-cell clones was assessed by protein immunoblotting using antibodies to UPP1. The 9-bp deletion in clone 2 is expected to produce a truncated protein hypomorphic allele.
Three hours after plating, cells were further treated with 0. Human PBMCs were isolated from buffy coats of blood donors from a local transfusion centre.
On day 6, cells were detached, counted and replated at 1. PBMC polarization was performed as with BMDMs.
A secondary genome-wide CRISPR—Cas9 screening was performed using K cells expressing UPP1 -FLAG and a lentiviral-carried Brunello library Genome Perturbation Platform, Broad Institute containing 76, sgRNAs 44 , in duplicate. Cells were infected with multiplicity of infection of 0.
DNA isolation was performed as for the ORFeome screen. The log 2 fold change of each sgRNA was determined relative to the pre-swap control.
For each gene in each replicate, the mean log 2 fold change in the abundance of all four sgRNAs was calculated. log 2 fold changes were averaged by taking the mean across replicates. For each treatment, a null distribution was defined by the 3, genes with lowest expression.
To score each gene within each treatment, its mean log 2 fold change across replicates was z -score transformed, using the statistics of the null distribution defined as above. Cells were incubated for five additional hours before metabolite extraction.
All animal experiments in this paper were approved by the Massachusetts General Hospital, the University of Massachusetts Institutional Animal Care and Use Committee, or the Swiss Cantonal authorities, and all relevant ethical regulations were followed.
All cages were provided with food and water ad libitum. Food and water were monitored daily and replenished as needed, and cages were changed weekly. A standard light—dark cycle of h light exposure was used. Animals were housed at 2—5 per cage. Liver was flash frozen in liquid nitrogen before subsequent analysis, and blood was collected in EDTA plasma tubes, spun and plasma was stored for further analysis.
For each run, the total flow rate was 0. Data were acquired using Xcalibur v. Data were analysed using TraceFinder v. The flow rate was then increased to 0. Approximately 1. FBS was omitted. Data were analysed using the Seahorse Wave Desktop Software v. Data were not corrected for carbonic acid derived from respiratory CO 2.
Lactate secretion in the culture medium was determined using a glycolysis cell-based assay kit Cayman Chemical. Cells were then re-counted and seeded in fresh medium of the same formulation and incubated for three additional hours. Cells were then spun down and lactate concentration was determined on the supernatants spent media.
Gene Ontology GO analysis was performed using GOrilla with default settings and using a ranked gene list as input The complete unfiltered data can be found in Supplementary Table 1.
cDNAs of interest were custom designed Genewiz or IDT and cloned into pWPI-Neo or pLV-lenti-puro using BamHI and SpeI New England Biolabs.
All reported sample sizes n represent biological replicate plates or a different mouse. All attempts at replication were successful. Statistical tests were performed using Microsoft Excel and GraphPad Prism 9.
Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. All data generated or analysed during this study are included in the article and its Supplementary Information.
Results of the ORFeome, the CRISPR—Cas9 and the PRISM screens are available in Supplementary Table 1. Source data are provided with this paper.
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Thank Rivose for Energy-replenishing foods nature. You are using a browser Colon cleanse for optimal colon health with Timely food routine support for CSS. Andd obtain the best experience, celk recommend you use a sugsr up to date Colon cleanse for optimal colon health or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Pancreatic ductal adenocarcinoma PDA is a lethal disease notoriously resistant to therapy 12. This is mediated in part by a complex tumour microenvironment 3low vascularity 4and metabolic aberrations 56.
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