Activin B promotes the initiation and progression of liver fibrosis.

The role of activin B, a transforming growth factor ß (TGFß) superfamily cytokine, in liver health and disease is largely unknown. We aimed to investigate whether activin B modulates liver fibrogenesis. Liver and serum activin B, along with its analog activin A, were analyzed in patients with liver fibrosis from different etiologies and in mouse acute and chronic liver injury models. Activin B, activin A, or both was immunologically neutralized in mice with progressive or established carbon tetrachloride (CCl4 )-induced liver fibrosis. Hepatic and circulating activin B was increased in human patients with liver fibrosis caused by several liver diseases. In mice, hepatic and circulating activin B exhibited persistent elevation following the onset of several types of liver injury, whereas activin A displayed transient increases. The results revealed a close correlation of activin B with liver injury regardless of etiology and species. Injured hepatocytes produced excessive activin B. Neutralizing activin B largely prevented, as well as improved, CCl4 -induced liver fibrosis, which was augmented by co-neutralizing activin A. Mechanistically, activin B mediated the activation of c-Jun-N-terminal kinase (JNK), the induction of inducible nitric oxide synthase (iNOS) expression, and the maintenance of poly (ADP-ribose) polymerase 1 (PARP1) expression in injured livers. Moreover, activin B directly induced a profibrotic expression profile in hepatic stellate cells (HSCs) and stimulated these cells to form a septa structure. Conclusions: We demonstrate that activin B, cooperating with activin A, mediates the activation or expression of JNK, iNOS, and PARP1 and the activation of HSCs, driving the initiation and progression of liver fibrosis.

Study protocol, randomized controlled trial: reducing symptom burden in patients with heart failure with preserved ejection fraction using ubiquinol and/or D-ribose.

BACKGROUND: Heart failure (HF), the leading cause of morbidity and mortality in the US, affects 6.6 million adults with an estimated additional 3 million people by 2030. More than 50% of HF patients have heart failure with preserved left ventricular ejection fraction (HFpEF). These patients have impaired cardiac muscle relaxation and diastolic filling, which investigators have associated with cellular energetic impairment. Patients with HFpEF experience symptoms of: (1) fatigue; (2) shortness of breath; and (3) swelling (edema) of the lower extremities. However, current HF guidelines offer no effective treatment to address these underlying pathophysiologic mechanisms. Thus, we propose a biobehavioral symptom science study using ubiquinol and D-ribose (therapeutic interventions) to target mitochondrial bioenergetics to reduce the complex symptoms experienced by patients with HFpEF. METHODS: Using a randomized, double-blind, placebo-controlled design, the overall objective is to determine if administering ubiquinol and/or D-ribose to HFpEF patients for 12 weeks would decrease the severity of their complex symptoms and improve their cardiac function. The measures used to assess patients' perceptions of their health status and level of vigor (energy) will be the Kansas City Cardiomyopathy Questionnaire (KCCQ) and Vigor subscale of the Profile of Mood States. The 6-min walk test will be used to test exercise tolerance. Left ventricular diastolic function will be assessed using innovative advanced echocardiography software called speckle tracking. We will measure B-type natriuretic peptides (secreted from ventricles in HF) and lactate/ATP ratio (measure of cellular energetics). DISCUSSIONS: Ubiquinol (active form of Coenzyme Q10) and D-ribose are two potential treatments that can positively affect cellular energetic impairment, the major underlying mechanism of HFpEF. Ubiquinol, the reduced form of CoQ10, is more effective in adults over the age of 50. In patients with HFpEF, mitochondrial deficiency of ubiquinol results in decreased adenosine triphosphate (ATP) synthesis and reduced scavenging of reactive oxygen species. D-ribose is a substrate required for ATP synthesis and when administered has been shown to improve impaired myocardial bioenergetics. Therefore, if the biological underpinning of deficient mitochondrial ATP in HFpEF is not addressed, patients will suffer major symptoms including lack of energy, fatigue, exertional dyspnea, and exercise intolerance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03133793 ; Data of Registration: April 28, 2017.

Gavage of D-Ribose induces Aß-like deposits, Tau hyperphosphorylation as well as memory loss and anxiety-like behavior in mice.

In addition to D-Glucose, D-Ribose is also abnormally elevated in the urine of type 2 diabetic patients, establishing a positive correlation between the concentration of uric D-Ribose and the severity of diabetes. Intraperitoneal injection of D-Ribose causes memory loss and brain inflammation in mice. To simulate a chronic progression of age-related cognitive impairment, we orally administered D-Ribose by gavage at both a low and high dose to 8 week-old male C57BL/6J mice daily for a total of 6 months, followed by behavioral, histological and biochemical analysis. We found that long-term oral administration of D-Ribose impairs spatial learning and memory, accompanied by anxiety-like behavior. Tau was hyperphosphorylated at AT8, S396, S214 and T181 in the brain. Aß-like deposition was also found in the hippocampus for the high dose group. D-Glucose-gavaged mice did not show significant memory loss and anxiety-like behavior under the same experimental conditions. These results demonstrate that a long-term oral administration of D-Ribose not only induces memory loss with anxiety-like behavior, but also elevates Aß-like deposition and Tau hyperphosphorylation, presenting D-Ribose-gavaged mouse as a model for age-related cognitive impairment and diabetic encephalopathy.

(D)-Ribose supplementation in the equine: lack of effect on glycated plasma proteins suggesting safety in humans.

BACKGROUND: d-Ribose is a popular dietary supplement for humans and the equine because of its crucial role in cellular bioenergetics. However, as a reducing sugar, it has been suggested that ingestion of d-ribose might promote the formation of glycated proteins in vivo with potential adverse consequences. OBJECTIVE: The aim of this study was to examine if d-Ribose would promote the formation of glycated proteins in vivo following exercise in training thoroughbred racehorses. METHODS: Two groups of horses received the supplement (30 and 50 g d-Ribose daily) for 17 weeks, during which period the horses were subjected to low-intensity exercises followed by high-intensity exercises. Blood samples were analyzed for glycated plasma proteins at baseline and following the 2 exercise regimens. RESULTS: This study shows that long-term ingestion of d-Ribose at 30-50 g a day does not promote the formation of glycated plasma proteins in thoroughbred racehorses. Ribose supplementation also protected the horses from cramping while enhancing muscle recovery at the same time. No adverse effects were reported. CONCLUSION: Ribose supplementation is safe and does not cause glycation in vivo. This investigation also establishes safety of d-Ribose in thoroughbred racehorses, suggesting similar implications in humans as well.

Evaluation of D-ribose pharmacokinetics, dose proportionality, food effect, and pharmacodynamics after oral solution administration in healthy male and female subjects.

This was a double blind, randomized, crossover study of three periods evaluating pharmacokinetics and pharmacodynamics in 12 healthy, adult subjects after administration of D-ribose powder for oral solution, 2.5, 5.0, and 10.0 g, under fasting conditions followed by an open label, randomized, fourth period assessing the effect of food on the pharmacokinetics of D- ribose (10.0 g) under fed conditions with either a high fat (HF, N = 6) or high carbohydrate (HC, N = 6) meal. D-ribose was absorbed rapidly with mean Tmax ranging between 18 and 30 minutes. Cmax and AUC increased more than proportionally with dose indicating increased absorption and saturation of metabolism. When D-ribose was administered with meals, Tmax was unchanged; however, Cmax and AUC decreased by 42.6% and 40.8%, respectively with HF and 69.1% and 64.9%, respectively with HC. The amount of D-ribose in urine ranged from 4.15% to 7.20% of the administered dose. Dose-related decreases in serum glucose up to 26.3 mg/dL (30.3% of baseline) occurred in the first 60 minutes post dose and insulin response attained a dose-related peak 15 minutes post dose. D-ribose was generally safe and well tolerated in the dose range studied.

Relationship between postmortem changes and browning of boiled, dried, and seasoned product made from Japanese common squid (Tedarodes pacificus) mantle muscle.

To clarify the process that possibly causes discoloration in boiled, dried, and seasoned squid products ("sakiika" or "ikakun" in Japanese), we investigated the relationship of squid freshness with the rate of browning using the boiled, freeze-dried, and ground squid product model. ATP and its related compounds in Japanese common squid (Tedarodes pacificus) decomposed gradually during storage, yielding hypoxanthine and ribose at 24 h postmortem. The browning rate of the model during preservation as revealed by the increase of the b* value showed a high coefficient in the linear regression against ribose content (R2 = 0.767). Only the model made from the squid stored for 24 h postmortem turned brown. These results strongly suggest that ribose produced during storage plays a major role in the browning of dried and seasoned squid products.

Pharmacological and nutritional treatment trials in McArdle disease.

A systematic review of evidence for randomised controlled trials using pharmacologic and nutritional therapies in McArdle disease was undertaken. Primary outcome measures included any objective assessment of exercise endurance. Secondary outcome measures included changes in metabolic parameters, subjective measures such as quality of life scores and adverse outcomes. Ten randomised controlled trials were identified. Two trials low dose creatine (60 mg/kg/day) and oral sucrose 75 g prior to exercise demonstrated a positive effect.

Ribose versus dextrose supplementation, association with rowing performance: a double-blind study.

OBJECTIVE: It has been hypothesized that ribose supplementation rapidly replenishes adenosine triphosphate stores and thereby improves exercise performance. We compared the effects of ribose versus dextrose on rowing performance. DESIGN: Double-blind randomized trial. SETTING: Rowing team training area of large midwestern university. PARTICIPANTS: Thirty-one women collegiate rowers. INTERVENTIONS: We studied the effects of ribose versus dextrose supplementation (10 g each in 8 oz water) for 8 weeks before and after practice and 2000-m time trials. OUTCOME MEASUREMENTS AND RESULTS: In the time trials, the dextrose group showed significantly more improvement at 8 weeks than the ribose group (median, 15.2 vs. 5.2 s; P = 0.031). CONCLUSIONS: We doubt ribose impaired, and hypothesize dextrose enhanced, rowing performance. Further research is needed to define what role, if any, dextrose and ribose play as athletic supplements.

Effects of therapeutic ribose levels on human lymphocyte proliferation in vitro.

Ribose has been used successfully in the treatment of ischemic heart disease and muscular enzyme deficiencies, and its administration also facilitates the diagnosis of coronary artery disease by influencing thallium-201 scintigraphy. Concerns about the safety of ribose therapy have been triggered by reports about inhibitory effects of ribose on cell proliferation in vitro. This study examines possible side effects of ribose on human lymphocytes. Unstimulated and mitogen-stimulated human lymphocytes were incubated with ribose concentrations associated with high-dose oral administration, i.e., 3.5 mM, and with two- (7 mM) and tenfold (35 mM) higher concentrations. Cell cultures with matching glucose concentrations served as controls. Incorporation of [3H]thymidine into cells was used to measure cell proliferation. No significant inhibition of human lymphocyte proliferation in vitro was observed in mitogen-stimulated cells. Unstimulated cultures showed significant inhibition only at 35 mM ribose. It is concluded that ribose plasma levels associated with high-dose oral administration do not inhibit human lymphocyte proliferation in vitro. No evidence was found that short-term ribose therapy is harmful to human lymphocytes.

[Influence of ribose on 2,3-diphosphoglycerate concentrations in human erythrocytes]. / Der Einfluss von Ribose auf die 2, 3-Diphosphoglycerat-Konzentration menschlicher erythrozyten

The effect of ribose on the 2,3-diphosphoglycerate concentration (2,3-DPG) of human red blood cells was investigated and compared to the effect of inosine. Ribose as well as inosine increases 2,3-DPG. Most impressing effects can be demonstrated on stored blood, which is poor in 2,3-DPG concentration. Physiologic 2,3-DPG-concentrations, however, may be increased too. Generally the effect of inosine is greater than the effect of ribose. When ribose is applicated intravenously a slight increase in 2,3-DPG is found. Both compounds own characteristic side-effects, which diminish their value for therapeutical purposes.