Tissue Lactate Research Articles

Perfluorocarbon Enhanced Glasgow Oxygen Level Dependent (GOLD) Magnetic Resonance Metabolic Imaging Identifies the Penumbra Following Acute Ischemic Stroke

The ability to identify metabolically active and potentially salvageable ischaemic penumbra is crucial for improving treatment decisions in acute stroke patients. Our solution involves two complementary novel MRI techniques (Glasgow Oxygen Level Dependant (GOLD) Metabolic Imaging), which when combined with a perfluorocarbon (PFC) based oxygen carrier and hyperoxia can identify penumbra due to dynamic changes related to continued metabolism within this tissue compartment. Our aims were (i) to investigate whether PFC offers similar enhancement of the second technique (Lactate Change) as previously demonstrated for the T2*OC technique (ii) to demonstrate both GOLD metabolic imaging techniques working concurrently to identify penumbra, following administration of Oxycyte® (O-PFC) with hyperoxia.Methods: An established rat stroke model was utilised. Part-1: Following either saline or PFC, magnetic resonance spectroscopy was applied to investigate the effect of hyperoxia on lactate change in presumed penumbra. Part-2; rats received O-PFC prior to T2*OC (technique 1) and MR spectroscopic imaging, which was used to identify regions of tissue lactate change (technique 2) in response to hyperoxia. In order to validate the techniques, imaging was followed by [14C]2-deoxyglucose autoradiography to correlate tissue metabolic status to areas identified as penumbra.Results: Part-1: PFC+hyperoxia resulted in an enhanced reduction of lactate in the penumbra when compared to saline+hyperoxia. Part-2: Regions of brain tissue identified as potential penumbra by both GOLD metabolic imaging techniques utilising O-PFC, demonstrated maintained glucose metabolism as compared to adjacent core tissue.Conclusion: For the first time in vivo, enhancement of both GOLD metabolic imaging techniques has been demonstrated following intravenous O-PFC+hyperoxia to identify ischaemic penumbra. We have also presented preliminary evidence of the potential therapeutic benefit offered by O-PFC. These unique theranostic applications would enable treatment based on metabolic status of the brain tissue, independent of time from stroke onset, leading to increased uptake and safer use of currently available treatment options.

Differential effects of AMP-activated protein kinase in isolated rat atria subjected to simulated ischemia-reperfusion depending on the energetic substrates available.

AMP-activated protein kinase (AMPK) is a serine-threonine kinase that functions primarily as a metabolic sensor to coordinate anabolic and catabolic processes in the cell, via phosphorylation of multiple proteins involved in metabolic pathways, aimed to re-establish energy homeostasis at a cell-autonomous level. Myocardial ischemia and reperfusion represents a metabolic stress situation for myocytes. Whether AMPK plays a critical role in the metabolic and functional responses involved in these conditions remains uncertain. In this study, in order to gain a deeper insight into the role of endogenous AMPK activation during myocardial ischemia and reperfusion, we explored the effects of the pharmacological inhibition of AMPK on contractile function rat, contractile reserve, tissue lactate production, tissue ATP content, and cellular viability. For this aim, isolated atria subjected to simulated 75min ischemia-75min reperfusion (Is-Rs) in the presence or absence of the pharmacological inhibitor of AMPK (compound C) were used. Since in most clinical situations of ischemia-reperfusion the heart is exposed to high levels of fatty acids, the influence of palmitate present in the incubation medium was also investigated. The present results suggest that AMPK activity significantly increases during Is, remaining activated during Rs. The results support that intrinsic activation of AMPK has functional protective effects in the reperfused atria when glucose is the only available energetic substrate whereas it is deleterious when palmitate is also available. Cellular viability was not affected by either of these conditions.

Growth and metabolic parameters of common snook juveniles raised in freshwater with different water hardness

The adaptation of common snook Centropomus undecimalis to low salinities and freshwater has being widely studied, but the definition of the best water hardness levels may facilitate the adaptation and growth of this species in freshwater. Consequently, the aim of this study was to evaluate survival, growth and metabolic parameters (blood glucose and osmolality and lactate in plasma and tissues) of common snooks raised in freshwater with different water hardness levels. In an acute experiment, juveniles were transferred from seawater 35ppt to seawater 35ppt (control) and freshwater at 20, 100, 250, 500 or 1000 mg CaCO3L−1. Mortality after 96h was 100, 79.17, 58.33, 4,17 and 50%, respectively. In another experiment juveniles (initial weight 10.9±1.5g) were maintained for 60days in water hardness of 100, 500 or 1000mg CaCO3L−1 or seawater (control). No mortality was observed in this experiment. The best weight gain, specific growth rate and feed intake in freshwater (values not significantly different from seawater) was observed in common snooks kept at 100mg CaCO3L−1. Blood and hepatic glucose did not differ significantly between treatments. Muscle glucose levels were significantly lower in fish kept at 100 and 1000mg CaCO3L−1 than the other treatments. However, lactate levels were higher in the muscle of common snooks kept at 100 to 500 CaCO3mgL−1 and lactate in plasma was higher in those maintained at 1000mg CaCO3L−1. Plasma osmolality was not affected significantly by treatments. In conclusion, 100mg CaCO3L−1 is the best water hardness to raise common snooks in freshwater.

Oxamate Enhances the Anti-Inflammatory and Insulin-Sensitizing Effects of Metformin in Diabetic Mice

Metformin (MET) is the first-line drug for treating type 2 diabetes mellitus (T2DM). However, MET increases blood lactate levels in patients with T2DM. Lactate possesses proinflammatory properties and causes insulin resistance (IR). Oxamate (OXA), a lactate dehydrogenase inhibitor, can decrease tissue lactate production and blood lactate levels. This study was conducted to examine the effects of the combination of OXA and MET on inflammation, and IR in diabetic db/db mice. Supplementation of OXA to MET led to lowered tissue lactate production and serum lactate levels compared to MET alone, accompanied with further decreased tissue and blood levels of pro-inflammatory cytokines, along with better insulin sensitivity, beta-cell mass, and glycemic control in diabetic db/db mice. These results show that OXA enhances the anti-inflammatory and insulin-sensitizing effects of MET through the inhibition of tissue lactate production in db/db mice.

Abstract 1857: Early detection of pancreatic intraepithelial neoplasms (PanINs) in transgenic mouse model by hyperpolarized 13C metabolic magnetic resonance imaging

Abstract Pancreatic cancer, one of the most lethal solid tumors, is an aggressive disease that develops relatively symptom-free. Pre-invasive pancreatic intraepithelial neoplasias (PanINs) have been identified as precursor lesions to pancreatic cancer. While there is growing evidence supporting PanIN's genetic links to pancreatic cancer, there is no non-invasive method to detect them. There is an unmet need of novel strategies for detection of pancreatic cancer at the earliest stages, preferably at the stage of PanINs. Hyperpolarized magnetic resonance imaging (HP-MRI) has shown potential for early detection of cancers and monitoring therapeutic efficacy. Here we have employed in-vivo 13C pyruvate metabolic imaging and ex-vivo nuclear magnetic resonance (1H-NMR) metabolomics to identify and understand metabolic changes, to enable detection of early PanINs and its progression to advanced PanINs and pancreatic cancer. Genetically engineered mouse (GEM) models with progression of PanIN lesions and control animals, with no pancreatic lesions, were employed in this study. Hyperpolarization of pyruvate and in-vivo 13C MRS were performed using Hypersense (Oxford Instruments) and 7T MRI scanner with a dual tuned 1H/13C volume coil respectively. Tissue alanine and lactate concentrations were determined using a Bruker 500 MHz NMR spectrometer coupled with cryo-probe. Histology and immunohistochemistry were performed on excised tissue samples. P48Cre mice were used as controls and P48Cre;LSLKrasG12D mice were used for detection of early and advanced PanINs, which usually develop in these mice between 12 and 20 months. The imaging experiments were performed at the different stages of the disease. Progression of disease from tissue containing predominantly low-grade PanINs to tissue with high-grade PanINs showed a decreasing alanine/lactate concentration ratio. Real time in-vivo 13C MRS was used to measure non-invasively changes of alanine and lactate metabolites with disease progression and in control mice, following injection of hyperpolarized pyruvate. The alanine-to-lactate (Ala/Lac) signal intensity ratio was found decreased as the disease progressed from low-grade PanINs to high-grade PanINs. These results demonstrate that there are significant alterations of alanine transaminase (ALT) and lactate dehydrogenase (LDH) activities which favor the transformation of aggressive pancreatic cancer from PanINs lesion. Our results suggest that real-time conversion kinetic rate constants kPA(pyruvate-to-alanine) and kPL(pyruvate-to-lactate) can be used as metabolic imaging biomarkers for assessing the early stage of pancreatic diseases. Findings from this highly promising HP-MRI technique could be rapidly translated to the clinic for early detection of pancreatic cancer in patients at high risk for developing the disease. Citation Format: Prasanta Dutta, Yu Zhang, Michelle Zoltan, Marilina Mascaro, Erick Riquelme, Jaehyuk Lee, Anirban Maitra, Florencia McAllister, Pratip Bhattacharya. Early detection of pancreatic intraepithelial neoplasms (PanINs) in transgenic mouse model by hyperpolarized 13C metabolic magnetic resonance imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1857. doi:10.1158/1538-7445.AM2017-1857

Intermittent Ischemic Preconditioning Protects Against Hepatic Ischemia-Reperfusion Injury and Extensive Hepatectomy in Steatotic Rat Liver

ABSTRACTBackground: Hepatic steatosis causes severe liver damage and has deleterious effects when associated with ischemia-reperfusion mechanisms. Ischemic preconditioning (IPC) protects lean liver against prolonged ischemia by improving micro-circulation and reducing lipid peroxidation. We investigated the effect of intermittent IPC on liver ischemia-reperfusion injury (IRI) and extensive hepatectomy in severe hepatic steatosis. Methods: Severe hepatic steatosis was performed by 12–14 weeks of choline-free diet in 108 Wistar rats. We induced 30-minute ischemia-reperfusion manipulations and extensive hepatectomy with or without prior IPC in steatotic livers and after 6 and 24 hours of reperfusion blood transaminases, and IL6, TNFα, NO and Lactate in blood and liver tissue were measured. Results: Steatotic rats subjected to hepatic ischemia-reperfusion alone after extensive hepatectomy, showed severe liver damage with significantly increased values of AST, ALT, TNFα and Lactate and significantly reduced IL6 and NO, while no one rat survived for more than 29 hours. On the contrary, steatotic rats subjected to intermittent IPC, 24 hours before ischemia-reperfusion, presented increased 30-day survival (67%), lower values of AST, ALT, TNFα and Lactate, and increased IL6 and NO levels. Simple and intermittent IPC manipulations, 1 hour before the IRI and extended hepatectomy, did not prolong survival more than 57 and 98 hours, respectively. Simple IPC, 24 hours before IRI and extended hepatectomy had the lowest possible survival (16.7%).Conclusions: Hepatic steatosis and IRI after major liver surgery largely affect morbidity and mortality. Intermittent IPC, 24 hours before IRI and extensive hepatectomy, presents higher 30-day survival and improved liver function parameters.

Association between Brain and Kidney Near-Infrared Spectroscopy and Early Postresuscitation Mortality in Asphyxiated Newborn Piglets

Background: Early outcome predictors after delivery room cardiopulmonary resuscitation (CPR) of asphyxiated newborns are needed. Objectives: To investigate if cerebral (rScO₂) and renal (rSrO₂) tissue oxygen saturation 30 min after return of spontaneous circulation (ROSC) are different between surviving versus nonsurviving piglets with asphyxia-induced cardiac arrest and CPR. Further, to investigate the relationship of rScO₂ and rSrO₂ to cardiac output (CO), blood pressure (BP), and biochemical variables 30 min and 4 h after ROSC. Methods: Anesthetized, mechanically ventilated piglets (1-3 days, 1.7-2.4 kg) were used. rScO₂, rSrO₂, SpO₂, right common carotid artery flow, and arterial BP were measured continuously. CO was measured with echocardiography. The piglets were asphyxiated until cardiac arrest and resuscitated. Piglets that survived 4 h after ROSC (n = 12) were compared with piglets that died before planned euthanasia at 4 h (n = 13). Left ventricular, and kidney and brain tissue lactate were analyzed. Correlations between variables were assessed. Results: Thirty minutes after ROSC, median rSrO₂ (43% [n = 10] vs. 25% [n = 2], p = 0.003) but not rScO₂ (46% [41-55] [n = 10] vs. 40% [22-45] [n = 5], p = 0.08) was higher in survivors than in nonsurvivors. Arterial lactate was negatively correlated and pH positively correlated with rScO₂ and rSrO₂. Left ventricular, but not kidney or brain lactate was negatively correlated with rScO₂ and rSrO₂. There was no correlation between CO or BP and rScO₂ or rSrO₂. Conclusions: Despite satisfactory CO and BP vital organ oxygenation can be poor. Tissue oxygen saturation, pH, and lactate, as measures of anaerobic metabolism, may reflect vital organ oxygenation and outcome.

Increased nutrient availability in dense breast tissue of postmenopausal women in vivo

Metabolic reprogramming is a hallmark of cancer. Nutrient availability in the tissue microenvironment determines cellular events and may play a role in breast carcinogenesis. High mammographic density is an independent risk factor for breast cancer. Whether nutrient availability differs in normal breast tissues with various densities is unknown. Therefore we investigated whether breast tissues with various densities exhibited differences in nutrient availability. Healthy postmenopausal women from the regular mammographic screening program who had either predominantly fatty breast tissue (nondense), n = 18, or extremely dense breast tissue (dense), n = 20, were included. Microdialysis was performed for the in vivo sampling of amino acids (AAs), analyzed by ultra-high performance liquid chromatography with tandem mass spectroscopy, glucose, lactate and vascular endothelial growth factor (VEGF) in breast tissues and, as a control, in abdominal subcutaneous (s.c.) fat. We found that dense breast tissue exhibited significantly increased levels of 20 proteinogenic AAs and that 18 of these AAs correlated significantly with VEGF. No differences were found in the s.c. fat, except for one AA, suggesting tissue-specific alterations in the breast. Glucose and lactate were unaltered. Our findings provide novel insights into the biology of dense breast tissue that may be explored for breast cancer prevention strategies.

An experimental study of a rat model of emphysema induced by cigarette smoke exposure and the effect of Survanta therapy

The present study was performed to test the therapeutic effects of Survanta (an exogenous surfactant) on a Wistar rat model of emphysema. Thirty-five adult male Wistar rats were divided randomly into the following groups; control subgroups Ia&b (n=14); emphysematous model subgroups IIa,b&c (n=21) exposed to cigarette smoke (CS), received phosphate buffer solution (PBS) and Survanta respectively. The levels of serum myeloperoxidase (MPO), lung tissue lactate dehydrogenase (LDH), alkaline phosphatase (ALP) as well as antioxidants: catalase (CAT), superoxide dismutase (SOD) and oxidative stress: malondialdehyde (MDA) markers were measured. Immunohistochemical staining of the lung was applied with anti-P53, anti- tumor necrosis factor (TNFα) and anti-proliferating cell nuclear antigen (PCNA) to reveal the changes of the lung structure. The mean linear intercepts (MLI) of alveoli were measured to assess alveolar size. In emphysematous rats, the serum level of MPO and tissue LDH, ALP & MDA were significantly increased while; CAT and SOD were significantly decreased. Pictures analysis for all immunostains was clearly increased. In Survanta treated group, a significant improvement in all previously mentioned findings while; no improvement in alveolar diameter was detected. These results conclusively demonstrate that Survanta administration improves the inflammatory biochemical and histochemical parameters of the emphysematous lung.

Accumulation of lactate in the rat brain during hyperammonaemia is not associated with impaired mitochondrial respiratory capacity

In acute liver failure (ALF) cerebral oedema and high intracranial pressure (ICP) are potentially deadly complications. Astrocytes cultured in ammonia have shown mitochondrial dysfunction and in rat models of liver failure, de novo lactate production in the brain has been observed and has led to a hypothesis of compromised brain metabolism during ALF. In contrast, normal lactate levels are found in cerebral microdialysate of ALF patients and the oxygen: glucose ratio of cerebral metabolic rates remains normal. To investigate this inconsistency we studied the mitochondrial function in brain tissue with respirometry in animal models of hyperammonaemia. Wistar rats with systemic inflammation induced by lipopolysaccharide or liver insufficiency induced by 90% hepatectomy were given ammonium or sodium acetate for 120min. A cerebral cortex homogenate was studied with respirometry and substrates of the citric acid cycle, uncouplers and inhibitors of the mitochondrial complexes were successively added to investigate the mitochondrial function in detail. In a separate dose-response experiment cortex from healthy rats was incubated for 120min in ammonium acetate in concentrations up to 80mM prior to respirometry. Hyperammonaemia was associated with elevated ICP and increased tissue lactate concentration. No difference between groups was found in total respiratory capacity or the function of individual mitochondrial complexes. Ammonium in concentrations of 40 and 80mM reduced the respiratory capacity in vitro. In conclusion, acute hyperammonaemia leads to elevated ICP and cerebral lactate accumulation. We found no indications of impaired oxidative metabolism in vivo but only in vitro at extreme concentrations of ammonium.

Magnetic Resonance Spectroscopy to Study Glycolytic Metabolism During Autophagy.

Cancer cells undergoing starvation- and treatment-induced autophagy were found to exhibit reduced intracellular lactate, reduced rates of steady-state lactate excretion and reduced real-time pyruvate-lactate exchange rates, indicating that glycolytic metabolism was altered in autophagic cells. In this chapter, we describe the technical details of the use of 1H-magnetic resonance spectroscopy (MRS) to measure endogenous cellular concentrations of lactate and glucose in autophagic cells and tissues, how to measure the rate of steady-state lactate excretion and glucose uptake by 1H-MRS in autophagic cells, and details of the real-time measurement of [1-13C] pyruvate to lactate exchange in autophagic cells by 13C-MRS-DNP (dynamic nuclear polarization).

Non-invasive diagnosis of papillary thyroid microcarcinoma: a NMR-based metabolomics approach.

Papillary thyroid microcarcinoma (PTMC) is a subtype of papillary thyroid carcinoma (PTC). Because its diameter is less than 10 mm, diagnosing it accurately is difficult with traditional methods such as image examinations and FNA (Fine Needle Aspiration). Investigating the metabolic changes induced by PTMC may enhance the understanding of its pathogenesis and provide important information for a new diagnosis method and treatment plan. In this study, high resolution magic angle spin (HRMAS) spectroscopy and 1H-nuclear magnetic resonance (1H-NMR) spectroscopy were used to screen metabolic changes in thyroid tissues and plasma from PTMC patients respectively. The results revealed reduced levels of fatty acids and elevated levels of several amino acids (phenylalanine, tyrosine, lactate, serine, cystine, lysine, glutamine/glutamate, taurine, leucine, alanine, isoleucine and valine) in thyroid tissues, as well as reduced levels of amino acids such as valine, tyrosine, proline, lysine, leucine and elevated levels of glucose, mannose, pyruvate and 3-hydroxybutyrate in plasma, are involved in the metabolic alterations in PTMC. In addition, a receiver operating characteristic (ROC) curve model for PTMC prediction was able to classify cases with good sensitivity and specificity using 9 significant changed metabolites in plasma. This work illustrates that the NMR-based metabolomics approach is capable of providing more sensitive diagnostic results and more systematic therapeutic information for PTMC.

Microdialysis as a Part of Invasive Cerebral Monitoring During Porcine Septic Shock.

Metabolic changes in critically ill patients with endotoxin-induced septic shock are measured primarily by techniques that afford organ-specific metabolic monitoring based on interstitial fluid samples. The present study was designed to evaluate the role of cerebral microdialysis (MD) as a part of invasive neuromonitoring during endotoxemia in a porcine model. Continuous endotoxin infusion was administered to 7 female pigs and, in addition to hemodynamic monitoring and blood chemistry, interstitial lactate, pyruvate, glucose and glycerol concentrations in muscle, liver, and cerebral tissue were measured via in vivo MD for an observation period of 180 minutes. The cerebral concentrations of lactate and glycerol showed no significant increases, whereas the hepatic and muscular levels rose dramatically under endotoxemia. However, the lactate/pyruvate ratio and especially the lactate/glucose ratio showed a profound and significant increase in brain tissue as well. Cerebral perfusion pressure decreased from 77 to 50 mm Hg without reaching pathologic values. Although our results confirm the special protection of the brain during endotoxemia compared with other organs, early metabolic changes become evident by increasing lactate/pyruvate ratio and lactate/glucose ratio. MD appears to be a suitable additional technique in invasive neuromonitoring for obtaining early information about metabolic deterioration in the brain during septic shock.

Evaluation of oxidative stress markers in the heart and liver of rainbow trout (Oncorhynchus mykiss walbaum) exposed to the formalin.

The aim of this study was to examine change in lipid and protein oxidation biomarkers, transamination enzymes and lactate dehydrogenase activities, lactate and pyruvate levels in liver and heart tissue of rainbow trout (Oncorhynchus mykiss Walbaum) that was exposed to formalin baths. Increase of 2-thiobarbituric acid reactive substances and carbonyl derivatives of protein oxidative destruction was noticed only in cardiac tissue of formalin-exposed fish. Activity of lactate dehydrogenase and lactate level in the cardiac tissue were elevated, indicating active glycolysis. Effects of formalin disinfection were different in both tissues. Aldehydic and ketonic derivatives of oxidatively modified proteins in liver were consistently reduced upon exposure to the formalin. In support of this, decrease in alanine and aspartate aminotransferases was noticed. Formalin disinfection of rainbow trout results in metabolic plasticity, predominantly in liver with decreased levels of oxidative stress biomarkers and aminotransferases activity. Formalin-induced oxidative stress in the cardiac tissue was more considerable.

Diagnostic value of MRS-quantified brain tissue lactate level in identifying children with mitochondrial disorders

ObjectivesMagnetic resonance spectroscopy (MRS) of children with or without neurometabolic disease is used for the first time for quantitative assessment of brain tissue lactate signals, to elaborate on previous suggestions of MRS-detected lactate as a marker of mitochondrial disease.MethodsMultivoxel MRS of a transverse plane of brain tissue cranial to the ventricles was performed in 88 children suspected of having neurometabolic disease, divided into ‘definite’ (n = 17, ≥1 major criteria), ‘probable’ (n = 10, ≥2 minor criteria), ‘possible’ (n = 17, 1 minor criterion) and ‘unlikely’ mitochondrial disease (n = 44, none of the criteria). Lactate levels, expressed in standardized arbitrary units or relative to creatine, were derived from summed signals from all voxels. Ten ‘unlikely’ children with a normal neurological exam served as the MRS reference subgroup. For 61 of 88 children, CSF lactate values were obtained.ResultsMRS lactate level (>12 arbitrary units) and the lactate-to-creatine ratio (L/Cr >0.22) differed significantly between the definite and the unlikely group (p = 0.015 and p = 0.001, respectively). MRS L/Cr also differentiated between the probable and the MRS reference subgroup (p = 0.03). No significant group differences were found for CSF lactate.ConclusionMRS-quantified brain tissue lactate levels can serve as diagnostic marker for identifying mitochondrial disease in children.Key points• MRS-detected brain tissue lactate levels can be quantified.• MRS lactate and lactate/Cr are increased in children with mitochondrial disease.• CSF lactate is less suitable as marker of mitochondrial disease.

A comparison of constant acceleration swimming speeds when acceleration rates are different with critical swimming speeds in Chinese bream under two oxygen tensions.

To investigate the effect of acceleration rates on the constant acceleration test speed (U cat) and to compare U cat with the critical swimming speed (U crit) in Chinese bream (Parabramis pekinensis), the U cat test at acceleration rates of 0.05, 0.1, 0.2, 0.4 and 0.8cms(-2) and the U crit test in juvenile fish at 20°C in either normoxia (>90% saturation oxygen tension) or hypoxia (30% saturation) were compared. The lactate concentration ([lactate]) of white muscle, liver and plasma and the glycogen concentration ([glycogen]) of white muscle and liver were also measured to identify whether tissue substrate depletion or tissue lactate accumulation correlated with exhaustion. The U cat decreased with the acceleration rate, and there was no significant difference between U crit and U cat at lower acceleration rates. Hypoxia resulted in lower U cat and U crit, and the difference increased with decreased acceleration rates of the U cat test, possibly due to the increased contribution of aerobic components in U crit or U cat at low acceleration rates. Hypoxia elicited a significant decrease in muscle [glycogen] and an increase in muscle and liver [lactate] in resting fish. All post-exercise fish had similar muscle [lactate], suggesting that tissue lactate accumulation may correlate with exercise exhaustion. Unlike hypoxia, exercise induced an increase in muscle [lactate] and a significant increase in plasma [lactate], which were worthy of further investigation. The similar swimming speed and biochemical indicators after exercise in the U crit and U cat groups at low acceleration rates suggested that U cat can be an alternative for the more frequently adopted protocols in U crit in Chinese bream and possibly in other cyprinid fish species.

Oxamate Improves Glycemic Control and Insulin Sensitivity via Inhibition of Tissue Lactate Production in db/db Mice.

Oxamate (OXA) is a pyruvate analogue that directly inhibits the lactate dehydrogenase (LDH)-catalyzed conversion process of pyruvate into lactate. Earlier and recent studies have shown elevated blood lactate levels among insulin-resistant and type 2 diabetes subjects and that blood lactate levels independently predicted the development of incident diabetes. To explore the potential of OXA in the treatment of diabetes, db/db mice were treated with OXA in vivo. Treatment of OXA (350–750 mg/kg of body weight) for 12 weeks was shown to decrease body weight gain and blood glucose and HbA1c levels and improve insulin secretion, the morphology of pancreatic islets, and insulin sensitivity in db/db mice. Meanwhile, OXA reduced the lactate production of adipose tissue and skeletal muscle and serum lactate levels and decreased serum levels of TG, FFA, CRP, IL-6, and TNF-α in db/db mice. The PCR array showed that OXA downregulated the expression of Tnf, Il6, leptin, Cxcr3, Map2k1, and Ikbkb, and upregulated the expression of Irs2, Nfkbia, and Pde3b in the skeletal muscle of db/db mice. Interestingly, LDH-A expression increased in the islet cells of db/db mice, and both treatment of OXA and pioglitazone decreased LDH-A expression, which might be related to the improvement of insulin secretion. Taken together, increased lactate production of adipose tissue and skeletal muscle may be at least partially responsible for insulin resistance and diabetes in db/db mice. OXA improved glycemic control and insulin sensitivity in db/db mice primarily via inhibition of tissue lactate production. Oxamic acid derivatives may be a potential drug for the treatment of type 2 diabetes.

Lactate and glucose measurement in subepidermal tissue using minimally invasive microperfusion needle.

Knowing the concentrations of biological substances can help ascertain physiological and pathological states. In the present study, a minimally invasive microperfusion needle was developed for measuring the concentrations of biological substances in subepidermal tissue. The microperfusion needle has a flow channel with a perforated membrane through which biological substances from subepidermal tissue are extracted. Since this device uses a thin steel acupuncture needle as the base substrate, it has sufficient rigidity for insertion through the skin. The efficacy of the needle was examined by measuring lactate and glucose concentrations in mice. Lactate was injected intraperitoneally, and changes in lactate concentrations in subepidermal tissue over time were measured using the device. Lactate concentrations of blood were also measured as a reference. Lactate was successfully collected using the microperfusion needle, and the lactate concentration of perfused saline was significantly correlated with blood lactate concentration. Glucose solution was administered orally, and the glucose concentration of perfused saline was also correlated with blood glucose concentration. The newly developed microperfusion needle can be used for minimally invasive monitoring of the concentrations of biological substances.

Handheld Capillary Blood Lactate Analyzer as an Accessible and Cost-Effective Prognostic Tool for the Assessment of Death and Heart Failure Occurrence during Long-Term Follow-Up.

Impact of tissue lactate accumulation on prognosis after acute myocardial infarction (AMI) is biased. The study aimed to assess the prognostic role of lactate concentration (LC) in patients with AMI during one year of follow-up. 145 consecutive patients admitted due to AMI were enrolled. The data on the frequency of endpoint occurrence (defined as I, death; II, heart failure (HF); and III, recurrent myocardial infarction (re-MI)) were collected. The patients were divided into group A (LC below the cut-off value) and group B (LC above the cut-off value) for the endpoints according to receiver operating characteristic (ROC) analysis. The cumulative survival rate was 99% in group I-A and 85% in group I-B (p = 0.0004, log-rank test). The HF-free survival rate was 95% in group II-A and 82% in group II-B (p = 0.0095, log-rank test). The re-MI-free survival rate did not differ between groups. A multivariate Cox analysis showed a statistically significant influence of LC on death [Hazard Ratio (HR): 1.41, 95% Confidence Interval (CI) (1.13–1.76), and p = 0.002] and HF [HR: 1.21, 95% CI (1.05–1.4), and p = 0.007] with no impact on re-MI occurrence. LC in capillary blood may be considered a useful prognostic marker of late-onset heart failure and death after AMI.

Hyperbaric oxygen therapy ameliorates acute brain injury after porcine intracerebral hemorrhage at high altitude.

IntroductionIntracerebral hemorrhage (ICH) at high altitude is not well understood to date. This study investigates the effects of high altitude on ICH, and examines the acute neuroprotection of hyperbaric oxygen (HBO) therapy against high-altitude ICH.MethodsMinipigs were placed in a hypobaric chamber for 72 h before the operation. ICH was induced by an infusion of autologous arterial blood (3 ml) into the right basal ganglia. Animals in the high-altitude ICH group received HBO therapy (2.5 ATA for 60 min) 30 min after ICH. Blood gas, blood glucose and brain tissue oxygen partial pressure (PbtO2) were monitored continuously for animals from all groups, as were microdialysis products including glucose, lactate, pyruvate and glutamate in perihematomal tissue from 3 to 12 h post-ICH.ResultsHigh-altitude ICH animals showed significantly lower PbtO2, higher lactate/pyruvate ratio (LPR) and glutamate levels than low-altitude ICH animals. More severe neurological deficits, brain edema and neuronal damage were also observed in high-altitude ICH. After HBO therapy, PbtO2 was significantly increased and LPR and glutamate levels were significantly decreased. Brain edema, neurological deficits and neuronal damage were also ameliorated.ConclusionsThe data suggested a more serious disturbance of tissue oxygenation and cerebral metabolism in the acute stage after ICH at high altitude. Early HBO treatment reduced acute brain injury, perhaps through a mechanism involving the amelioration of the derangement of cerebral oxygenation and metabolism following high-altitude ICH.