Gender-Specific Metabolomics Approach to Kidney Cancer

Renal cell carcinoma (RCC) is the most common form of kidney malignancy. RCC is more common among men with a 2/1 male/female incidence ratio worldwide. Given the underlying epidemiological differences in the RCC incidence between males and females, we explored the gender specific 1H NMR serum metabolic profiles of RCC patients and their matched controls. A number of differential metabolites were shared by male and female RCC patients. These RCC specific changes included lower lactate, threonine, histidine, and choline levels together with increased levels of pyruvate, N-acetylated glycoproteins, beta-hydroxybutyrate, acetoacetate, and lysine. Additionally, serum lactate/pyruvate ratio was a strong predictor of RCC status regardless of gender. Although only moderate changes in metabolic profiles were observed between control males and females there were substantial gender related differences among RCC patients. Gender specific metabolic features associated with RCC status were identified suggesting that different metabolic panels could be leveraged for a more precise diagnostic.

Age-related changes in the parameters of carbohydrate metabolism and supply of vitamins B1, B2 in residents of two northern regions

A great deal of research was being done in studying of the age-related characteristics of carbohydrate metabolism and the provision of vitamins B1, B2 among the population of the Subarctic (SR) and Arctic (AR) regions, differing in the extreme natural and climatic-geographic living conditions. The surveyed population was divided into five age groups: 16-21, 22-35, 36-45, 46-60 and 61-74 years old. The parameters of carbohydrate metabolism (glucose, lactate, pyruvate) were determined in the blood serum, the content of thiamine (thiamin diphosphate effect) and riboflavin - in hemolysates, and the values of the lactate/pyruvate ratio (Lac/Pyr) were calculated. Statistical data processing was performed by nonparametric methods. An increase in glucose levels was found in persons of older age groups. Age-related fluctuations of metabolites of carbohydrate metabolism were manifested by a lower content of lactate and the value of the Lac/Pyr ratio in persons aged 16-21 years. Regardless of the age and region of the survey, there were revealed high lactate concentrations, Lac/Pyr values and reduced pyruvate levels, as well as low glucose levels in group aged 16-21 year in AR. For vitamins B1, B2, no pronounced age-related changes were observed, while the content of riboflavin was higher in persons of SR. Moderate hypovitaminosis of thiamin was detected in 13-20,1% and 6,1-22,7% of cases in SR and AR, pronounced - 8,3-11,6% and 4,6-23,5%, respectively, vitamin B2 deficiency was noted in 19,4-23,9% of persons in the AR and in 33,8-42,9% of persons in the AR. Vitamins in both regions at different age periods contributed to the formation of levels of indicators of carbohydrate metabolism: glucose and pyruvate in SR, lactate in AR.

Bedside microdialysis for detection of early brain injury after out-of-hospital cardiac arrest

Bedside detection and early treatment of lasting cerebral ischemia may improve outcome after out-of-hospital cardiac arrest (OHCA). This feasibility study explores the possibilities to use microdialysis (MD) for continuous monitoring of cerebral energy metabolism by analyzing the draining cerebral venous blood. Eighteen comatose patients were continuously monitored with jugular bulb and radial artery (reference) MD following resuscitation. Median time from cardiac arrest to MD was 300 min (IQR 230–390) with median monitoring time 60 h (IQR 40–81). The lactate/pyruvate ratio in cerebral venous blood was increased during the first 20 h after OHCA, and significant differences in time-averaged mean MD metabolites between jugular venous and artery measurements, were documented (p < 0.02). In patients with unfavorable outcome (72%), cerebral venous lactate and pyruvate levels remained elevated during the study period. In conclusion, the study indicates that jugular bulb microdialysis (JBM) is feasible and safe. Biochemical signs of lasting ischemia and mitochondrial dysfunction are frequent and associated with unfavorable outcome. The technique may be used in comatose OHCA patients to monitor biochemical variables reflecting ongoing brain damage and support individualized treatment early after resuscitation.

Lack of Age-related Respiratory Changes in Daphnia

Aging is a multifaceted process of accumulation of damages and waste in cells and tissues; age-related changes in mitochondria and in respiratory metabolism have been in the focus of aging research for decades. Here we investigated age-related changes in respiration rates, lactate/pyruvate ratio, a commonly used proxy for NAD+/NADH balance, and mitochondrial membrane potential in 4 genotypes of an emerging model organism for aging research, a cyclic parthenogen Daphnia magna. We show that total body weight-adjusted respiration rate decreases with age, although this decrease is small in magnitude and not observed in anaesthetized animals, thus likely to be accounted for by decrease in locomotion and feeding activity. Lactate/pyruvate ratio and mitochondrial membrane potential (Ψmt) showed no age-related changes, with a possible exception of mt measured in the optical lobe and in epipodites (excretory organs) in which Ψmt showed a maximum at middle age. We conclude that actuarial senescence in Daphnia is not caused by a decline in respiratory metabolism and discuss possible mechanisms of maintaining mitochondrial healthspan throughout the lifespan.

Early detection of complications in pancreas transplants by microdialysis catheters, an observational feasibility study

Background Despite advances in immunosuppression and surgical technique, pancreas transplantation is encumbered with a high rate of complication and graft losses. Particularly, venous graft thrombi occur relatively frequently and are rarely detected before the transplant is irreversibly damaged. Methods To detect complications early, when the grafts are potentially salvageable, we placed microdialysis catheters anteriorly and posteriorly to the graft in a cohort of 34 consecutive patients. Glucose, lactate, pyruvate, and glycerol were measured at the bedside every 1–2 hours. Results Nine patients with graft venous thrombosis had significant lactate and lactate–to-pyruvate-ratio increases without concomitant rise in blood glucose or clinical symptoms. The median lactate in these patients was significantly higher in both catheters compared to non-events (n = 15). Out of the nine thrombi, four grafts underwent successful angiographic extraction, one did not require intervention and four grafts were irreversibly damaged and explanted. Four patients with enteric anastomosis leakages had significantly higher glycerol measurements compared to non-events. As with the venous thrombi, lactate and lactate-to-pyruvate ratio were also increased in six patients with graft surrounding hematomas. Conclusions Bedside monitoring with microdialysis catheters is a promising surveillance modality of pancreatic grafts, but differentiating between the various pathologies proves challenging.

A DIFFERENTIATED APPROACH TO INFUSION-TRANSFUSION THERAPY FOR LARGE BLOOD LOSS IN PATIENTS WITH POLYTRAUMA

With polytrauma, more than 30% of victims are diagnosed with severe blood loss, grade III MARINO of the leading components is transfusion therapy, which aims to restore the erythron system and improve the functional state of the oxygen transport system. The addition to intensive care of substances that affect lipid peroxidation and energy status of cells can reduce the number of heterogeneous transfusions and thus reduce the number of complications in the postoperative period. Such substances may be a solution of ceruloplasmin with a leading antioxidant effect and a solution of D-fructose-1,6-diphosphate sodium salt of the hydrate with an energetic effect. Criteria for exposure to these substances should be indicators such as blood levels of hemoglobin, phosphorus, malonic dialdehyde and lactate / pyruvate ratio.

Early Metabolic and Inflammatory Intraperitoneal Changes After Rectum Perforation

Purpose: Anastomotic leakage (AL) is the most dreaded complication in rectal surgery. It has a great impact on postoperative morbidity and mortality. This animal model, in which we have studied postoperative metabolic and inflammatory changes, is designed to imitate an AL.Methods: Twelve pigs were randomized into 2 groups. In the experimental group, an iatrogenic rectal perforation was performed, with the control group having a sham operation. The 2 groups were followed for 10 hours after operation with regard to vital parameters, arterial lactate, and cytokines interleukin (IL) 1, IL6, and IL10 in the blood and intraperitoneally. Intraperitoneal microdialysis analyses of glucose, lactate, glycerol, and pyruvate were performed and the lactate/pyruvate ratio was calculated.Results: Glucose levels were lower in the experimental group after 4 hours. After 7 hours, lactate and lactate/pyruvate ratio was higher in the experimental group. At the same time intraperitoneal cytokines IL6 and IL10 were higher in the experimental group. Blood samples showed higher IL6 after 7 hours in the experimental group. Conclusion: In this study, several significant differences between the groups in metabolic and inflammatory values weredetected. Further clinical studies are recommended to evaluate the importance of intraperitoneal metabolic and inflammatory analyses as a diagnostic tool for early identification of an AL.

The extracellular lactate-to-pyruvate ratio modulates the sensitivity to oxidative stress-induced apoptosis via the cytosolic NADH/NAD+ redox state

The advantages of the Warburg effect on tumor growth and progression are well recognized. However, the relevance of the Warburg effect for the inherent resistance to apoptosis of cancer cells has received much less attention. Here, we show here that the Warburg effect modulates the extracellular lactate-to-pyruvate ratio, which profoundly regulates the sensitivity towards apoptosis induced by oxidative stress in several cell lines. To induce oxidative stress, we used the rapid apoptosis inducer Raptinal. We observed that medium conditioned by HepG2 cells has a high lactate-to-pyruvate ratio and confers resistance to Raptinal-induced apoptosis. In addition, imposing a high extracellular lactate-to-pyruvate ratio in media reduces the cytosolic NADH/NAD+ redox state and protects against Raptinal-induced apoptosis. Conversely, a low extracellular lactate-to-pyruvate ratio oxidizes the cytosolic NADH/NAD+ redox state and sensitizes HepG2 cells to oxidative stress-induced apoptosis. Mechanistically, a high extracellular lactate-to-pyruvate ratio decreases the activation of JNK and Bax under oxidative stress, thereby inhibiting the intrinsic apoptotic pathway. Our observations demonstrate that the Warburg effect of cancer cells generates an anti-apoptotic extracellular environment by elevating the extracellular lactate-to-pyruvate ratio which desensitizes cancer cells towards apoptotic insults. Consequently, our study suggests that the Warburg effect can be targeted to reverse the lactate-to-pyruvate ratios in the tumor microenvironment and thereby re-sensitize cancer cells to oxidative stress-inducing therapies.

Rehabilitation Improves Mitochondrial Energetics in Progressive Multiple Sclerosis: The Significant Role of Robot-Assisted Gait Training and of the Personalized Intensity

Abnormal levels of pyruvate and lactate were reported in multiple sclerosis (MS). We studied the response of markers of mitochondrial function to rehabilitation in relation to type, intensity and endurance performance in severely disabled MS patients. Forty-six progressive MS patients were randomized to receive 12 walking sessions of robot-assisted gait training (RAGT, n = 23) or conventional overground therapy (CT, n = 23). Ten healthy subjects were also studied. Blood samples were collected to determine lactate, pyruvate, and glutathione levels and lactate/pyruvate ratio pre–post rehabilitation. In vivo muscle metabolism and endurance walking capacity were assessed by resting muscle oxygen consumption (rmVO2) using near-infrared spectroscopy and by six-minute walking distance (6MWD), respectively. The levels of mitochondrial biomarkers and rmVO2, altered at baseline with respect to healthy subjects, improved after rehabilitation in the whole population. In the two groups, an enhanced response was observed after RAGT compared to CT for lactate (p = 0.012), glutathione (<0.001), lactate/pyruvate ratio (p = 0.08) and rmVO2 (p = 0.07). Metabolic biomarkers and 6MWD improvements were exclusively correlated with a training speed markedly below individual gait speed. In severely disabled MS patients, rehabilitation rebalanced altered serum metabolic and muscle parameters, with RAGT being more effective than CT. A determinable slow training speed was associated with better metabolic and functional recovery. Trial Registration: ClinicalTrials.gov NCT02421731.