In addition, the emergence of novel risk factors such as hyperglycemia will lead to increased understanding of the pathogenesis of worse lung function and hence new possibilities for intervention. In view of the public health importance of lung function in health and the increasing prevalence of diabetes, this is a subject that warrants further investigation.

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MATERIALS AND METHODS. Journal Article. Lung Function and Glucose Metabolism: An Analysis of Data from the Third National Health and Nutrition Examination Survey. McKeever , Tricia M. Correspondence to Dr. Tricia McKeever, Division of Respiratory Medicine, Clinical Science Building, City Hospital, Hucknall Road, Nottingham NG5 1PB, United Kingdom e-mail: Tricia.

McKeever Nottingham. Oxford Academic. Google Scholar. Philip J. Richard Hubbard. Andrew Fogarty. PDF Split View Views. Cite Cite Tricia M. Select Format Select format. ris Mendeley, Papers, Zotero. enw EndNote. bibtex BibTex. txt Medlars, RefWorks Download citation. Permissions Icon Permissions.

Close Navbar Search Filter American Journal of Epidemiology This issue Public Health and Epidemiology Books Journals Oxford Academic Enter search term Search. Abstract Although people with diabetes have decreased lung function, the dose-response relation between measures of glucose control and lung function in nondiabetic people is not known.

glucose , hemoglobin A, glycosylated , insulin , lung , respiratory function tests. E,; Sue, D. Y; Stringer, W. Pages These teachings are incorporated by reference. There exists a deficiency spectrum in ventilatory efficiency.

Patients may present with reduced VE even before the diagnosis of a medical condition. These patients may include those with primary lung dysfunction because of emphysema, whether due to smoking or to genetic causes, pulmonary hypertension, asthma, chronic bronchitis and chronic obstructive pulmonary disorders.

Patients with automimmune diseases such as rheumatoid arthritis often develop "rheumatoid lung. Often, persons who consider themselves to be in good health with a good nutritional status are actually somewhat suboptimal in both parameters, rendering them at risk for developing medical conditions or predisposing them to fatigue.

Those who would benefit from exercise are disinclined to do so. An advanced approach to treat and prevent pulmonary dysfunction is to recommend supplementation of key nutrients that will aid healing and enhance the physiological state.

Such nutritional formulations may be termed "dietary supplements," "functional foods" or "medical foods. Once a well-grounded recommendation toward dietary modification is made, it may have a powerful influence on delay of onset of a medical condition, slowing of progression of the illness, hastening the recovery and continued maintenance of improved health in the individual afflicted with the medical condition.

It would be especially useful to develop a method to identify pulmonary dysfunction from a functional standpoint during the course of disease, even before the patient is aware of his pulmonary dysfunction. The method comprises the treatment with a medical food, D-ribose.

Since both arms of the axis are compromised, it is unclear which or both arms are benefitted. No such supplement has been identified to improve the pulmonary arm of the cardiac-pulmonary axis.

The need remains to provide a supplement to improve the pulmonary condition of persons suffering from reduced pulmonary function. The need also remains for a therapy to improve the homeostasis of the cardiac-pulmonary axis and to limit the progression of pulmonary dysfunction, whether congenital, primary or acquired.

The present invention relates to a method for supplementing the diet of subjects having reduced pulmonary function, or who are at risk of pulmonary dysfunction, which has not yet progressed to cardiac involvement. According to the methods of this invention, an effective amount of a pentose is administered to a patient with reduced pulmonary function.

The pentose may be D-ribose, ribulose, xylulose or the pentose-related alcohol xylitol all of which are meant to be included in the term "ribose". The effective amount of pentose is 0. The most beneficial regimen is the daily dose administered in at least two to four portions.

Any dose of D-ribose will show beneficial effect, but the lower doses must be administered more times per day for maximal effect.

Higher daily doses must be divided into several doses, each not exceeding eight grams, in order to avoid gastrointestinal side effects.

It has been found that patient compliance is best with a dose of three to eight, preferably five, grams of D-ribose given three times a day. It is most convenient to administer ribose at meals, for example, sprinkled on cereal or salad or added to any cold liquid. The unit dosage may be dissolved in a suitable amount of liquid or may be ingested as a powder.

The above regimen is designed for human subjects. The effective dose for other mammals is dependent on the size of the animal. For a horse, a unit dosage of 50 to grams of ribose is effective. For a dog, an effective dose is mg to three grams of ribose.

Figure 1 shows respiratory rate RR versus tidal volume VT before IA and after IB eight weeks of ribose supplementation. Figure 2 shows VT versus VE before and after eight weeks of ribose supplementation. Figure 3 shows energy expenditure before and after eight weeks of ribose supplementation.

The invention comprises a method for the administration of pentose to a mammal suffering from suboptimal function of the cardiac-pulmonary axis wherein the nidus of the dysfunction resides in the pulmonary circuit or arm.

A preferred mammal is one suffering from pulmonary dysfunction, whether congenital or acquired. The pulmonary dysfunction may be mild or severe to life-threatening, sporadic or chronic.

A chosen exemplar is a mammal suffering from chronic obstructive pulmonary disease that does not yet involve the cardiac arm. Humans, horses and racing dogs are examples of mammals presenting with suboptimal function of the cardiac-pulmonary axis.

Humans generally represent chronic dysfunction while horses and dogs experience sporadic dysfunction following a strenuous race or workout. Race horses often have "hemorrhagic lung" due to extreme exertion, which leads to pulmonary dysfunction and often right ventricular hypertrophy.

When the mammal experiencing pulmonary dysfunction is a horse, suitable adjustments must be made in the effective dosage. The preferred effective amount of ribose for a horse is 30 to grams of ribose per day.

A tolerable single dosage for horses is 30 to 80 grams of ribose. Racing dogs range in size from the whippet at 35 pounds to the greyhound at 65 pounds.

The preferred effective dose for a dog is 0. A single tolerable dosage for a dog is 0. D-ribose is a natural 5-carbon sugar found in every cell of the body. It has been found in other studies that the pentoses ribulose, xylulose and the pentose- related alcohol xylitol have effects similar to those of D-ribose; therefore, the subsequent use of the term "ribose" in this application is meant to include D- ribose and these other pentoses.

Ribose is the key ingredient in the compositions described in this invention. Other energy enhancers might be included that may augment the effect of ribose. Supplements that act by other mechanisms can be energy enhancers that would optimize the nutritional composition. For example, increasing a vessel's diameter by a vasodilator such as adenosine or nitrate would increase blood flow to hibernating muscle tissue beds and thus improve the transport of ribose and nutrients to that tissue with subsequent positive enhancement of its physiological function.

The effective amount of ribose is 0. The following examples are provided for illustrative purposes only and do not limit the scope of the appended claims. Ventilatory efficiency has been critically shown to be the most powerful, independent predictor of CHF patient survival.

The steeper the slope, the worse the ventilation efficiency of the patient. Ventilation efficiency represents the degree of sympatho-excitation in the heart disease patient that reflects increased dead space in the lungs and augmented mechanoreceptor "drive" from the skeletal muscles.

CHF patients with a VE slope greater than Ventilation efficiency correlates with the level of cardiac preload or filling pressures to the heart. Higher filling pressures adversely affect pulmonary venous flow and cause pulmonary ventilation- to-perfusion mismatching, thus increasing the ventilatory efficiency slope.

Ventilatory efficiency slope has also been shown to correlate inversely with heart rate variability HRV , a known predictor of sudden cardiac death in CHF patients. As an exemplar cohort of patients with reduced ventilatory efficiency, patients suffering from CHF were recruited.

Patients having CHF were selected according to the following criteria:. The test group was administered D-ribose, 15 grams tid for eight weeks; the controls received 15 grams Dextrose tid.

All patients in this group underwent repeated cardiopulmonary exercise using a four-minute sub-maximal step protocol. Patients were tested on a step apparatus. Others in the study were tested on a treadmill with varied grade or on drug-driven exercise simulation for those patients unable to use the other two devices.

Upper extremity blood pressure was obtained at every two minutes and also at peak exercise. Patients were tested on a treadmill with varying grade, on a step apparatus or with simulated drug-driven exercise simulation for those patients unable to exercise physically.

V CO2 and V 02max before and after exercise was measured and VE calculated. The methodology is described in Circulation: www. org Ponikowski et al. Ventilation in Chronic Heart Failure, February 20, , the teachings of which are incorporated by reference.

Ventilatory efficiency, VO 2 and O 2 pulse were assessed up to the anaerobic threshold at baseline and again at eight weeks.

Weber function class was also determined based on VO 2 at the anaerobic threshold AT. The results for the first group of test patients 2 females and 13 males are summarized in Table I.

Each patient acted as his or her control, that is, results after ribose administration were compared to baseline results. VO 2 efficiency is the O 2 uptake per unit time. O 2 pulse is a measurement of the heart stroke volume.

It was also found that several of the patients were reclassified into a higher, that is, less severe, Wever functional class. A 59 year old male, normal weight, was diagnosed with blockage of the coronary arteries with stable angina, not yet progressing to congestive heart failure.

A CAT scan showed no myocardial infarction. Using a treadmill, with incremental increase in grade, his V 02 max and V CO2 were determined.

Following eight weeks of ribose administration of five grams four times a day, he was retested under the same conditions. Plotting a regression analysis of V 02 versus log V, the VE slope decreased from It is considered that a slope of Therefore, while this patient was not in the normal range of ventilatory efficiency, improvement was marked.

A second patient, a 77 year old male of normal weight, self administered five grams of ribose four times a day for eight weeks. At the beginning of the study, his VE slope was At the end of the study, his VE slope had decreased to This patient also was tested on the step test.

The initial test was rated as "good" and the second test was subjectively considered to be "great. A third patient, a 72 year old obese woman, was on nasal oxygen and was tested with drug-driven simulated exercise.

After administration of five grams of ribose four times daily for eight weeks, her VE slope decreased from She was able to discontinue the oxygen. Although her VE was now in the normal range, the test results, although improved were not subjectively rated as "good". Little is known of the effect of ribose on the pulmonary arm of patients who are not suffering from cardiac complications.

Example 2. Ventilatory efficiency in rheumatoid lung. Autoimmune diseases such as rheumatoid arthritis and sarcoidosis eventually result in poor pulmonary function..

Exposure to toxins may cause similar deficits in breathing ability. These conditions are chronic and patients are advised to exercise as much as possible, but many are not willing to do so-because of fatigue, shortness of breath and wheezing.

A year old woman developed rheumatoid arthritis in the 's. By , she began to show symptoms of rheumatoid lung, began the use of rescue inhalers such as Albuterol® inhaler and was hospitalized for respiratory distress three times in the next five years.

At that point, she was prescribed Advair® steroid inhaler, which relieved her symptoms considerably, although she still required a rescue inhaler several times per week. In , she began the administration of ribose, approximately five grams two to three times a day.

Within a month, she was able to discontinue the use of the rescue inhaler and to exercise more without breathlessness symptoms. Example 3.

Improvement of ventilatory efficiency in COPD. Although CHF patients represent a major fraction of the group of patients showing a deficit in ventilatory efficiency as a late sequela of their disease, many patients with normal heart function may also show a deficit in ventilatory efficiency.

While the benefit of ribose administration in CHF is disclosed in Example 1, and the improvement of ventilatory efficiency by administration of ribose in patients with pulmonary dysfunction, not suffering from advanced CHF, as shown in Example 2, more information on the effect of ribose on diagnosed primary lung disease was needed before ribose could be recommended for improvement of pulmonary function in those suffering from primary lung dysfunction.

It would be most desirable to determine whether progression of the disease can be slowed before involvement of the cardiac arm of the cardiac- pulmonary axis. A major category of lung disease is chronic obstructive pulmonary disease COPD.

This condition is commonly caused by smoking, however, recurring bouts of bacterial bronchitis in which the pulmonary tissue is attacked by bacteria with inflammation seems to be due to the response to the infection.

Among these patients may be smokers, asthmatics, persons with a genetic absence of alpha- 1 antitrypsinogen, industrial or environmental exposure to organic solvents or toxins, or cystic fibrosis.

In order to prevent pulmonary dysfunction at the earliest phase before involvement of the cardiac arm, it is important to identify patterns of measurements, preferably during submaximal exercise see: Principles of Exercise Testing, supra that are predictive of the status of the pulmonary arm.

The following experiments were designed to identify the useful patterns. Four patients presenting with chronic obstructive pulmonary disease were tested for various parameters of pulmonary function as described in Example 1. Baseline measurements of pulmonary function were taken during moderate, sub-maximum step exercise.

Patients were instructed to self- administer five grams of ribose four times a day. After eight weeks, pulmonary function was again measured during moderate exercise.

The results are shown in Table II. This ratio is taken at the nadir of sub-maximal exercise is a measure of lung function.. Patient 5 was included to show that the early- identified patient at risk for COPD could benefit from ribose administration.

by Franca Davenport , Ryan O'Hare 05 January People with the lung disease COPD have higher levels of glucose in their airways, researchers have shown for the first time. An estimated 1.

Many of these people are prone to suffering from bacterial lung infections. In the latest study , published in the Journal of Allergy and Clinical Immunology, researchers found that the concentration of glucose in the airways of people with COPD was almost twice as high as in people without the condition.

According to the authors, when subjects with COPD contracted a virus, glucose levels in their airways further increased, alongside increases in airway inflammation and increases in bacteria. Results suggest that reducing glucose levels in the airways could provide an alternative approach to antibiotics in reducing bacterial infection of the lungs.

Healthy lungs are continually pumping out glucose and it is likely we have developed this as a protective mechanism to starve bacteria and stop infections. The research analysed existing sputum samples from people with COPD.

The analysis of the existing samples found that the average concentration of glucose in sputum samples of COPD subjects was micromoles compared to Analysis also demonstrated a negative relationship between glucose concentration and forced expiratory volume FEV , which is a measure of lung function, suggesting that glucose levels increase with the severity of COPD.

To investigate how glucose levels vary when COPD symptoms worsen, the research team also analysed samples from volunteers with COPD who had contracted a respiratory virus either naturally, or after being deliberately infected with the virus that brings on symptoms of a common cold rhinovirus.

Results indicated that when subjects caught a respiratory virus by either means there was a further increase in levels of glucose in their airways. The analysis also showed a relationship between levels of glucose and levels of bacteria in their airways following the virus infection.

Many patients who get a viral infection, such as from rhinovirus pictured suffer from secondary bacterial infections. This indicates that treatments that reduce airway glucose may have the potential to reduce bacterial infections in people with COPD, without the use of antibiotics. However there is a growing concern that widespread antibiotic use is leading to increasing antibiotic resistance.

Professor Johnston added: "Reducing levels of glucose in the lung could provide an alternative approach that could reduce bacterial infections, and thus help patients with lung disease, while also reducing antibiotic use, and thereby reducing development of antibiotic resistance.

The researchers pointed out that the analysis included only small numbers of subjects with more severe COPD and focussed only on glucose levels in the airways, although other substances in the lung may also influence bacterial growth.

Nonetheless, given the importance of PPP enzymes and the dispensability of upper glycolysis, we reinvestigated this possibility and measured lactate secretion in uridine-grown cells. Strikingly, we found that UPP1 -expressing cells grown in uridine secreted high amounts of lactate Fig.

Accordingly, we found using liquid chromatography—mass spectrometry LC—MS that uridine restored steady-state abundance of most central carbon metabolism detected in the absence of glucose, strongly suggesting some degree of lower glycolysis activity from uridine Extended Data Fig. To directly test if uridine-derived ribose could serve as a substrate for glycolysis, we designed a tracer experiment using isotopically labelled uridine with five ribose carbons 13 C 5 -uridine and LC—MS Fig.

UPP1 -expressing cells avidly incorporated 13 C 5 -uridine, as seen by the presence of 13 C in all the intracellular intermediates of the PPP and glycolysis analysed, including ribose-phosphate, upper and lower glycolytic intermediates and lactate, while control cells showed very little label incorporation.

As in cell lines, we found 13 C incorporation in ribose-phosphate and glycolysis in 13 C 5 -uridine-treated animals Fig. Incorporation efficiency was smaller than in cell culture, as expected from low-dose 13 C 5 -uridine injection, shorter treatment time and competition with other endogenous substrates in vivo, including unlabelled uridine.

We also found modest but significant incorporation of uridine-derived 13 C in glucose, indicating gluconeogenesis from uridine-derived carbons Fig. Together, our results indicate that in cell lines and in animals in vivo, uridine catabolism provides ribose for the PPP, and that the non-oxPPP and the glycolytic pathway communicate via F6P and G3P to replenish glycolysis thus entirely bypassing the requirement for glucose in supporting lower glycolysis, biosynthesis and energy production in sugar-free medium Fig.

We next sought to determine whether any human cell lines exhibit a latent ability to use uridine-derived ribose to grow on uridine when glucose is absent without the need for over-expression. Cells from the melanoma and the glioma lineages grew remarkably well in uridine as compared to the other lineages, whereas Ewing sarcoma cells grew significantly less well Fig.

Cell lines from the PRISM collection have been extensively characterized at a molecular level 14 , so we searched for genomic factors that correlate with the ability to grow on uridine Supplementary Table 1. Genome wide, the top-scoring transcript, protein and genomic copy number variant was UPP1 Fig.

Expression of UPP1 across the CCLE collection was the highest in cell lines of skin origin Extended Data Fig. In agreement with these results, we confirmed significant, UPP1 -dependent, proliferation and uridine catabolism in melanoma cells grown in sugar-free medium supplemented with uridine or RNA Fig.

We conclude that the endogenous expression of UPP1 is necessary and sufficient to support the growth of cancer cells on uridine. False discovery rates FDRs were calculated using a Benjamini—Hochberg algorithm correcting for multiple comparisons UPP1 is encoded on Chr7p MDA, MDA-MBS.

with two-sided t -test relative to untreated cells. We next investigated the factors that promote UPP1 expression and growth on uridine by integrating our results with CCLE data to prioritize transcription factors, which highlighted MITF as a strong candidate in melanoma cells, both at the protein and the transcript level Fig.

We found that MITF over-expression promoted UPP1 expression and uridine growth Extended Data Fig. Accordingly, siRNA-mediated depletion of MITF decreased UPP1 expression in melanoma cells Extended Data Fig.

Our solid tumour PRISM cancer cells collection did not include cells of the immune lineage, where UPP1 is expressed at high levels 17 , 18 , so we asked whether immune cells exhibit the capacity to metabolize ribose from uridine either at baseline or in a transcriptionally regulated manner.

Among the immunostimulatory molecules, RNA enhanced UPP1 expression, suggesting the existence of a feed-forward loop, where RNA and conceivably RNA-containing pathogens and debris may trigger UPP1 expression and uridine salvage for building blocks and energy production.

Label incorporation from uridine ribose was also strongly increased in citrate and lactate after differentiation of THP1 and after BMDM stimulation with R, while it wasn't further increased in M-CSF-matured PBMCs, possibly due to high baseline capacity for uridine catabolism in these cells Fig.

Together, our results indicate that macrophages have the capacity to use uridine-derived ribose for glycolysis, and that UPP1 expression and uridine catabolism can sharply increase during cellular differentiation and in response to immunostimulating molecules, with cell type and species differences.

We next sought to determine whether glycolysis from uridine is under acute regulation in the same way as from glucose.

Active OXPHOS tends to keep glucose uptake and glycolysis at lower levels, while acute inhibition of OXPHOS leads to an immediate and strong increase in glucose-supported glycolysis, as evidenced by a robust increase in the extracellular acidification rate ECAR following oligomycin treatment Fig.

Strikingly, we found no ECAR stimulation by OXPHOS inhibitors, no difference in 13 C 5 -uridine incorporation following antimycin blockage of the electron transport chain, and no increase in uridine import in OXPHOS-inhibited UPP1 -expressing cells grown on uridine Fig.

Because glycolysis from both uridine and glucose share a common pathway from G3P Fig. Consistent with this notion, we observed no stimulation of ECAR in mannose-grown cells, a sugar connected to glycolysis by F6P Extended Data Fig. We conclude that substrates such as uridine can enter glycolysis in a constitutive way, in contrast to glucose, by bypassing regulatory steps of upper glycolysis such as glucose transport and initial phosphorylation.

a , Schematic of glycolysis inhibition by OXPHOS. G6P, glucosephosphate. O, oligomycin; C, CCCP; A, antimycin A. In line with this, we next performed a competition experiment to evaluate if the presence of glucose affects the incorporation of uridine in cells.

Incorporation of uridine in lactate was notably not affected by competition with glucose in our experimental conditions, despite the presence of a large molar excess of glucose Fig. Therefore, and in agreement with a bypass of regulatory steps of upper glycolysis, uridine can be incorporated into cells even when lactate production from glucose is saturated, suggesting constitutive import and catabolism.

Cells with severe OXPHOS dysfunction classically have to be grown on glucose, and uridine must be supplemented 1. The traditional explanation has been that glucose is required to support glycolytic ATP production as OXPHOS is debilitated, and that uridine supplementation is required for pyrimidine salvage given that de novo pyrimidine synthesis via DHODH requires coupling to a functional electron transport chain 1 , 3 Extended Data Fig.

Having observed energy harvesting from uridine, we finally tested whether uridine-derived ribose could also benefit OXPHOS-inhibited cells in the absence of glucose. We found a significant UPP1 -dependent rescue of viability in galactose-grown cells treated with antimycin A Fig. For decades it has been known that cells with mitochondrial deficiencies are dependent on uridine to support pyrimidine synthesis given the dependence of de novo pyrimidine synthesis on DHODH, whose activity is coupled to the electron transport chain 1.

Although it has been documented, it is less appreciated that uridine supplementation can support cell growth in the absence of glucose 4 , 5 , 6 , 7 , 8 , 9 , Here, we show that, in addition to nucleotide synthesis, uridine can serve as a substrate for energy production, biosynthesis and gluconeogenesis.

By comparing uridine to other nucleosides and using similar tracer experiments to ours, Wice et al. However, they did not detect pyruvate and lactate in uridine, and concluded that uridine does not participate in glycolysis, but rather is required for nucleotide synthesis, and proposed that energy is derived exclusively from glutamine in the absence of glucose 6 , 7.

Loffler et al. and Linker et al. reached the same conclusion 4 , 8. Our observations based on a genome-wide CRISPR—Cas9 screening and metabolic tracers Fig.

It has previously been reported that uridine protects cortical neurons and immunostimulated astrocytes from glucose deprivation-induced cell death, in a way related to ATP, and it was hypothesized that uridine could serve as an ATP source 9.

Our genetic perturbation and tracer studies are consistent with this hypothesis. The capacity to harvest energy and building blocks from uridine appears to be widespread.

Here, we report very high capacity for uridine-derived ribose catabolism in melanoma and glioma cell lines Fig. Based on gene expression atlases 18 , 19 , we predict uridine may be a meaningful source of energy in blood cells, lung, brain and kidney, as well as in certain cancers. Uridine is the most abundant and soluble nucleoside in circulation 20 and it is possible that uridine may serve as an alternative energy source in these tissues, or for immune and cancer metabolism, similar to what has been proposed for other sugars and nucleosides 21 , 22 , It is notable that the strongest human metabolic quantitative trait loci for circulating uridine corresponds to UPP1 ref.

A fascinating aspect of glycolysis from uridine is its apparent absence of regulation, at least at shorter timescales. The ability of uridine to serve as a constitutive input into glycolysis might have clinical implications for human diseases, as uridine is present at high levels in foods such as milk and beer 26 , 27 , and previous in vivo studies have shown that a uridine-rich diet leads to glycogen accumulation, gluconeogenesis, fatty liver and pre-diabetes in mice 28 , We now report that glycolysis from uridine lacks at least two checkpoints as 1 it is not controlled by OXPHOS Fig.

Although glycolysis from uridine appears to occur at a slower pace than from glucose, we speculate that constitutive fuelling of glycolysis and gluconeogenesis from a uridine-rich diet may contribute to human conditions such as fatty liver disease and diabetes.

This ability of uridine to bypass upper glycolysis may be beneficial in certain cases. At longer timescales, UPP1 expression and capacity for ribose catabolism from uridine appear to be determined by cellular differentiation and further activation by extracellular signals.

Here we focused on the monocytic lineage and found that 1 in THP1 cells, UPP1 expression and activity sharply increased during differentiation and polarization, 2 high baseline rates of glycolysis from uridine are observed in M-CSF-matured PBMCs and 3 treatment with immunostimulating molecules acutely promote both UPP1 expression and uridine catabolism in BMDMs Fig.

It is thus likely that NF-κB may serve as a transcription factor for UPP1. Supporting this assertion, we found that blocking NF-κB signalling with upstream IKK inhibitors abolished Rinduced Upp1 expression Extended Data Fig.

Uridine phosphorylase and ribose salvage by UPP1 appears to lie downstream of a number of signalling pathways with potential relevance to disease. We have demonstrated that uridine breakdown is promoted by MITF, a transcription factor associated with melanoma progression, which we show binds upstream of UPP1 to promote its expression Extended Data Fig.

In an accompanying study, Nwosu, Ward et al. It is notable that both MITF and NF-kB can act downstream of KRAS—MAPK 34 , 35 , 36 , 37 , 38 and that some pancreatic cell lines with high uridine phosphorylase activity highlighted by Nwosu, Ward et al.

Finally, we found that RNA in the medium can replace glucose to promote cellular proliferation Fig. Recycling of ribosomes through ribophagy, for example, plays an important role in supporting viability during starvation Cells of our immune system also ingest large quantities of RNA during phagocytosis, and we experimentally showed that the expression of UPP1 increases with macrophage activation Fig.

Uridine seems to be the only constituent of RNA that can be efficiently used for energy production, at least in K cells Fig. Whereas the salvage of RNA to provide building blocks during starvation has long been appreciated for nucleotide synthesis, to our knowledge, its contribution to energy metabolism has not been considered in the past, except for some fungi that can grow on minimum media with RNA as their sole carbon source We speculate that, similar to glycogen and starch, RNA itself may constitute as large stock of energy in the form of a polymer, and that it may be used for energy storage and to support cellular function during starvation, or during processes associated with high energy costs such as the immune response.

K CCL , T CRL , HeLa CCL-2 , A CRL , A CRL , SH4 CRL , MDA-MBS HTB , SK-MEL-5 HTB , SK-MEL HTB and THP1 TIB cell lines were obtained from the American Type Culture Collection ATCC. UACC, UACC and LOX-IMVI cells were obtained from the Frederick Cancer Division of Cancer Treatment and Diagnosis DCTD Tumor Cell Line Repository.

All cell lines were re-authenticated by STR profiling at ATCC before submission of the manuscript and compared to ATCC and Cellosaurus ExPASy STR profiles in , with the exception of THP1 TIB and U CRL Cells lines from the PRISM collection were obtained from The PRISM Lab Broad Institute and were not further re-authenticated.

MDA-MBS cells were previously assumed to be ductal carcinoma cells and recent gene expression analysis assigned them to the melanoma lineage ATCC. All growth assays, metabolomics, screens and bioenergetics experiments were performed in medium containing dialysed FBS.

For RNA and other nucleoside complementation assays, 0. Cell viability in glucose and galactose was determined using the same Vi-Cell Counter assay. Measurements were taken from distinct samples. 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.

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Humans generally represent chronic dysfunction while horses and dogs experience sporadic dysfunction following a strenuous race or workout. Race horses often have "hemorrhagic lung" due to extreme exertion, which leads to pulmonary dysfunction and often right ventricular hypertrophy.

When the mammal experiencing pulmonary dysfunction is a horse, suitable adjustments must be made in the effective dosage. The preferred effective amount of ribose for a horse is 30 to grams of ribose per day.

A tolerable single dosage for horses is 30 to 80 grams of ribose. Racing dogs range in size from the whippet at 35 pounds to the greyhound at 65 pounds. The preferred effective dose for a dog is 0. A single tolerable dosage for a dog is 0. D-ribose is a natural 5-carbon sugar found in every cell of the body.

It has been found in other studies that the pentoses ribulose, xylulose and the pentose- related alcohol xylitol have effects similar to those of D-ribose; therefore, the subsequent use of the term "ribose" in this application is meant to include D- ribose and these other pentoses.

Ribose is the key ingredient in the compositions described in this invention. Other energy enhancers might be included that may augment the effect of ribose.

Supplements that act by other mechanisms can be energy enhancers that would optimize the nutritional composition. For example, increasing a vessel's diameter by a vasodilator such as adenosine or nitrate would increase blood flow to hibernating muscle tissue beds and thus improve the transport of ribose and nutrients to that tissue with subsequent positive enhancement of its physiological function.

The effective amount of ribose is 0. The following examples are provided for illustrative purposes only and do not limit the scope of the appended claims. Ventilatory efficiency has been critically shown to be the most powerful, independent predictor of CHF patient survival.

The steeper the slope, the worse the ventilation efficiency of the patient. Ventilation efficiency represents the degree of sympatho-excitation in the heart disease patient that reflects increased dead space in the lungs and augmented mechanoreceptor "drive" from the skeletal muscles.

CHF patients with a VE slope greater than Ventilation efficiency correlates with the level of cardiac preload or filling pressures to the heart. Higher filling pressures adversely affect pulmonary venous flow and cause pulmonary ventilation- to-perfusion mismatching, thus increasing the ventilatory efficiency slope.

Ventilatory efficiency slope has also been shown to correlate inversely with heart rate variability HRV , a known predictor of sudden cardiac death in CHF patients. As an exemplar cohort of patients with reduced ventilatory efficiency, patients suffering from CHF were recruited.

Patients having CHF were selected according to the following criteria:. The test group was administered D-ribose, 15 grams tid for eight weeks; the controls received 15 grams Dextrose tid. All patients in this group underwent repeated cardiopulmonary exercise using a four-minute sub-maximal step protocol.

Patients were tested on a step apparatus. Others in the study were tested on a treadmill with varied grade or on drug-driven exercise simulation for those patients unable to use the other two devices.

Upper extremity blood pressure was obtained at every two minutes and also at peak exercise. Patients were tested on a treadmill with varying grade, on a step apparatus or with simulated drug-driven exercise simulation for those patients unable to exercise physically.

V CO2 and V 02max before and after exercise was measured and VE calculated. The methodology is described in Circulation: www. org Ponikowski et al. Ventilation in Chronic Heart Failure, February 20, , the teachings of which are incorporated by reference.

Ventilatory efficiency, VO 2 and O 2 pulse were assessed up to the anaerobic threshold at baseline and again at eight weeks. Weber function class was also determined based on VO 2 at the anaerobic threshold AT.

The results for the first group of test patients 2 females and 13 males are summarized in Table I. Each patient acted as his or her control, that is, results after ribose administration were compared to baseline results. VO 2 efficiency is the O 2 uptake per unit time.

O 2 pulse is a measurement of the heart stroke volume. It was also found that several of the patients were reclassified into a higher, that is, less severe, Wever functional class.

A 59 year old male, normal weight, was diagnosed with blockage of the coronary arteries with stable angina, not yet progressing to congestive heart failure.

A CAT scan showed no myocardial infarction. Using a treadmill, with incremental increase in grade, his V 02 max and V CO2 were determined. Following eight weeks of ribose administration of five grams four times a day, he was retested under the same conditions.

Plotting a regression analysis of V 02 versus log V, the VE slope decreased from It is considered that a slope of Therefore, while this patient was not in the normal range of ventilatory efficiency, improvement was marked. A second patient, a 77 year old male of normal weight, self administered five grams of ribose four times a day for eight weeks.

At the beginning of the study, his VE slope was At the end of the study, his VE slope had decreased to This patient also was tested on the step test. The initial test was rated as "good" and the second test was subjectively considered to be "great.

A third patient, a 72 year old obese woman, was on nasal oxygen and was tested with drug-driven simulated exercise. After administration of five grams of ribose four times daily for eight weeks, her VE slope decreased from She was able to discontinue the oxygen.

Although her VE was now in the normal range, the test results, although improved were not subjectively rated as "good". Little is known of the effect of ribose on the pulmonary arm of patients who are not suffering from cardiac complications.

Example 2. Ventilatory efficiency in rheumatoid lung. Autoimmune diseases such as rheumatoid arthritis and sarcoidosis eventually result in poor pulmonary function.. Exposure to toxins may cause similar deficits in breathing ability.

These conditions are chronic and patients are advised to exercise as much as possible, but many are not willing to do so-because of fatigue, shortness of breath and wheezing. A year old woman developed rheumatoid arthritis in the 's.

By , she began to show symptoms of rheumatoid lung, began the use of rescue inhalers such as Albuterol® inhaler and was hospitalized for respiratory distress three times in the next five years. At that point, she was prescribed Advair® steroid inhaler, which relieved her symptoms considerably, although she still required a rescue inhaler several times per week.

In , she began the administration of ribose, approximately five grams two to three times a day. Within a month, she was able to discontinue the use of the rescue inhaler and to exercise more without breathlessness symptoms.

Example 3. Improvement of ventilatory efficiency in COPD. Although CHF patients represent a major fraction of the group of patients showing a deficit in ventilatory efficiency as a late sequela of their disease, many patients with normal heart function may also show a deficit in ventilatory efficiency.

While the benefit of ribose administration in CHF is disclosed in Example 1, and the improvement of ventilatory efficiency by administration of ribose in patients with pulmonary dysfunction, not suffering from advanced CHF, as shown in Example 2, more information on the effect of ribose on diagnosed primary lung disease was needed before ribose could be recommended for improvement of pulmonary function in those suffering from primary lung dysfunction.

It would be most desirable to determine whether progression of the disease can be slowed before involvement of the cardiac arm of the cardiac- pulmonary axis. A major category of lung disease is chronic obstructive pulmonary disease COPD.

This condition is commonly caused by smoking, however, recurring bouts of bacterial bronchitis in which the pulmonary tissue is attacked by bacteria with inflammation seems to be due to the response to the infection.

Among these patients may be smokers, asthmatics, persons with a genetic absence of alpha- 1 antitrypsinogen, industrial or environmental exposure to organic solvents or toxins, or cystic fibrosis. In order to prevent pulmonary dysfunction at the earliest phase before involvement of the cardiac arm, it is important to identify patterns of measurements, preferably during submaximal exercise see: Principles of Exercise Testing, supra that are predictive of the status of the pulmonary arm.

The following experiments were designed to identify the useful patterns. Four patients presenting with chronic obstructive pulmonary disease were tested for various parameters of pulmonary function as described in Example 1. Baseline measurements of pulmonary function were taken during moderate, sub-maximum step exercise.

Patients were instructed to self- administer five grams of ribose four times a day. After eight weeks, pulmonary function was again measured during moderate exercise. The results are shown in Table II. This ratio is taken at the nadir of sub-maximal exercise is a measure of lung function..

Patient 5 was included to show that the early- identified patient at risk for COPD could benefit from ribose administration. One goal of this study was to determine whether the progression of pulmonary dysfunction in such a patient could be slowed or halted over time.

These patterns may be understood better when plotted on a graph. Each figure is based on a single patient and is representative of the various ratios.

Figure 1 shows that when respiratory rate is plotted against tidal volume, ribose administration results in a decreased slope, that is, more efficient breathing. Figure 3 shows the energy expenditure during exercise, pre- and post- ribose. Overall, review of these pulmonary graph patterns shows that patients with reduced function of the pulmonary arm of the cardiac-pulmonary axis show significantly improved pulmonary performance during exercise by facilitating a reduced dead-space and improving ventilation-to-perfusion matching.

In addition, an improvement observed in RR to VT slope may be an indirect measurement of improvement in pulmonary compliance, as well as the observed increase of VT to VE slope figure 4.

Energy expenditure is actually able to increase at the point of optimal lung performance figure 3. In addition CO 2 production and elimination are shown to increase with ribose administration to patients with reduced pulmonary function, with or without COPD.

Regardless of the proposed mechanisms of ribose in patients with reduced pulmonary function, ribose appears to augment lung function, a key component to improving functional capacity. These patients and others should be followed longterm for years to determine whether progression to more serious lung dysfunction and involvement of the cardiac arm of the cardiac-pulmonary axis can be slowed or halted.

All references cited within are hereby incorporated by reference. It will be understood by those skilled in the art that variations and substitutions may be made in the invention without departing from the spirit and scope of this invention as defined in the following claims. We claim: 1. A method of treating suboptimal pulmonary function comprising the chronic administration of two to ten grams of D-ribose one to four times daily to a subject having suboptimal pulmonary function but who is not suffering from cardiac complications.

The method of claim 1 wherein three to five grams of D-ribose is administered three or four times daily to the subject. The method of claim 2 wherein D-ribose is administered one to four times daily to the subject for at least one month. The method of claim 1 wherein the subject having suboptimal pulmonary function suffers from chronic obstructive pulmonary disease.

The method of claim 1 wherein the subject having suboptimal pulmonary function is at risk for chronic obstructive pulmonary disease due to bronchitis, smoking, asthma, genetic absence of alpha- 1 antitrypsinogen, industrial or environmental exposure to organic solvents or toxins, or cystic fibrosis.

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