REVIEW | doi:10.20944/preprints202009.0299.v1
Subject: Biology, Physiology Keywords: Lactate Shuttle; Lactate; Exercise; Postabsorptive Metabolism; Postprandial Metabolism; Gene Adaptation; Muscle; Fiber Type; Gluconeogenesis; Glycogenolysis
Online: 13 September 2020 (16:31:28 CEST)
After a Century it is time to turn the page on understanding of lactate metabolism and appreciate that lactate shuttling as an important component of intermediary metabolism in vivo. Cell-Cell and intracellular Lactate Shuttles fulfill purposes of energy substrate production and distribution as well as cell signaling under fully aerobic conditions. Recognition of lactate shuttling came first in studies of physical exercise where roles of driver and recipient cells and tissues were obvious. Moreover, the presence of lactate shuttling as part of postprandial glucose disposal has been recognized. Mitochondrial respiration creates the physiological sink for lactate disposal in vivo. Repeated lactate exposure from regular exercise results in adaptive processes such as mitochondrial biogenesis and other healthful circulatory and neurological characteristic such as improved physical work capacity, metabolic flexibility and cognition. The importance of lactate and lactate shuttling in healthful living is further emphasized when lactate signaling and shuttling are dysregulated as occur in illness and injury. Like a Phoenix, lactate rises again in importance in 21st Century Biology.
REVIEW | doi:10.20944/preprints202202.0353.v1
Subject: Life Sciences, Endocrinology & Metabolomics Keywords: Diabetic; Chronic Kidney Disease; Metformin; Acidosis Lactate
Online: 28 February 2022 (09:28:33 CET)
Background: Diabetes Mellitus is a metabolite disorder with parameters of high blood sugar levels. In the management of diabetes can be used the drug metformin is the gold of choice to achieve a therapeutic effect and rarely causes side effects of the drug, but it still has debate view. However, if used in excessive doses for patients with kidney disease, it will be contraindicated with side effects such as lactic acidosis. Objective: This study aims to evaluate the side effect of Metformin for diabetic kidney diseases (DKD) patients. Method: This study used the Narrative Review Method that was obtained from 2011 to 2021, in the English language from PubMed, Google Scholar, and Cochrane Library. Results: Metformin is at the forefront of the treatment of type 2 diabetes mellitus (DM2). Metformin is likely to have lactic acidosis-related adverse effects in chronic kidney disease (CKD) patients, such as increased arterial lactate. Lactic acidosis is defined as an increase in arterial lactate with an indicator of more than five mmol/L and an arterial blood pH of less than 7.35. Metformin-induced lactate levels are considered to be below the parameters. DKD risk factors can be conceptually classified as several susceptibility factors, initiation factors, and developmental factors. The two most prominent risk factors are hyperglycemia and hypertension. Conclusion: Metformin can increase lactate levels in CKD patients but is still below the parameters of lactic acidosis. This study may have some weaknesses and requires further prospective research to validate the results.
ARTICLE | doi:10.20944/preprints202008.0034.v1
Subject: Medicine & Pharmacology, Sport Sciences & Therapy Keywords: Acupuncture; lactate; heart rate; physical performance; sustainability
Online: 2 August 2020 (14:46:22 CEST)
Studies have demonstrated the positive effects of acupuncture on athletic performance. The aim of this study was to determine the acute effects of acupuncture on heart rate, the perceived exertion scale and lactate levels in recreational athletes. Fifteen competitive males engaged in HIIT. The characteristic was 29.86±2.51 years old, heart rate reserve 59.00±3.33, lactate 3.17±0.50 mM/DL. The subjects were submitted to two exercise sessions. Both training sessions consisted of 10 burpees, 12 thrusters and 14 box jumps (75 cm high) for 12 minutes. Activity intensity was between 85 and 95% of maximum heart rate. Acupuncture points: ST36, L3, LI11. The student’s t-test was adopted, Shapiro-Wilk test was applied for normality, and Pearson correlation. There was a positive correlation of r = 0.69 between lactate levels and heart rate. Lactate: Lac1 15.00±1.18 – Lac2 19.59± 1.46 p= 0.0001*; Heart 1rate: HRF 163.71±7.27 – HRF2 177.60±6.99 p=0.0001*; Blood pressure: SBP1 174.86±1.57 – SBP2 180.86±1.77 p= 0.0001*; PES1: 19.4±1.14; PES2 16.8±0.84 p= 0.0001*; weight1 – 182,57±12,05; weight 2 206,43±11,39 p=0.0325*. Acupuncture increased lactate accumulation, heart rate and blood pressure, suggesting that the exertion reached after acupuncture is higher than without acupuncture. The acupuncture technics improved the athlete performance.
REVIEW | doi:10.20944/preprints202208.0452.v1
Subject: Biology, Other Keywords: lactate; lactic acid; glycolysis; carcinogenesis; malignant tumor; evolutionary oncology; Warburg effect
Online: 26 August 2022 (07:13:46 CEST)
The role of lactic acid (lactate) in cell metabolism has been significantly revised in recent dec-ades. Initially, lactic acid was attributed to the role of a toxic end product of metabolism, which accumulation in the cell and extracellular space leads to acidosis, muscle pain and other adverse effects. However, it has now become obvious that lactate is not only a universal fuel molecule and the main substrate for gluconeogenesis, but also one of the most ancient metabolites with signaling function, which has a wide range of regulatory activity. The Warburg effect described 100 years ago (that means intensification of glycolysis associated with high lactate production), which is characteristic of many malignant tumors, confirms the key role of lactate not only in physiological conditions, but also in pathologies. The study of lactate’s role in the malignant transformation becomes more relevant in the light of the “atavistic theory of carcinogenesis,” which suggests that tumor cells return to a more primitive hereditary phenotype during micro-evolution. In this review, we attempted to summarize the accumulated knowledges about the functions of lactate in cell metabolism and its role in the process of carcinogenesis, and to con-sider the possible evolutionary significance of the Warburg effect.
ARTICLE | doi:10.20944/preprints202005.0065.v1
Subject: Life Sciences, Molecular Biology Keywords: memory formation; moonlighting protein; protein-protein interaction; astrocyte-neuron lactate shuttle
Online: 5 May 2020 (06:09:47 CEST)
Long-term potentiation (LTP) is a molecular basis of memory formation. Here, we demonstrate that LTP critically depends on muscle fructose 1,6-bisphosphatase 2 (Fbp2) – a glyconeogenic enzyme and moonlighting protein protecting mitochondria against stress. We show that LTP induction regulates Fbp2 association with neuronal mitochondria and Camk2, and that the Fbp2-Camk2 interaction correlates with Camk2 autophosphorylation. Silencing of Fbp2 expression or simultaneous inhibition and tetramerization of the enzyme with a synthetic effector mimicking the action of physiological inhibitors (NAD+ and AMP) abolishes Camk2 autoactivation and blocks formation of the early phase of LTP and expression of the late phase LTP markers. Astrocyte-derived lactate reduces NAD+/NADH ratio in neurons and thus, diminishes the pool of tetrameric and increases the fraction of dimeric Fbp2. We therefore hypothesize that this NAD+-level-dependent increase of the Fbp2 dimer/tetramer ratio might be a crucial mechanism in which astrocyte-neuron lactate shuttle stimulates LTP formation.
REVIEW | doi:10.20944/preprints202109.0511.v1
Subject: Medicine & Pharmacology, Other Keywords: Wound; chronic wound; hypoxia; Lactate; Acidosis; Alkalosis; neoangiogenesis; ECM; Polylactide; polylactide membranes
Online: 30 September 2021 (12:18:52 CEST)
: Over time, we have come to recognize a very complex network of physiological changes enabling wound healing. An immunological process enables the body to distinguish damaged cells and begin a cleaning mechanism by separating damaged proteins and cells with matrix metallopro-teinases, a complement reaction, and free radicals. A wide variety of cell functions help to rebuild new tissue, dependent on energy provision and oxygen supply. Like in an optimized "biorector," disturbance can lead to prolonged healing. One of the earliest investigated local factors is the pH of wounds, studied in close relation to the local perfusion, oxygen tension, and lactate concentration. Granulation tissue with the wrong pH can hinder fibroblast and keratinocyte division and pro-liferation, as well as skin graft takes. Methods for influencing the pH have been tested, such as occlusion and acidification by the topical application of acidic media. In most trials, this has not changed the wound's pH to an acidic one, but it has reduced the strong alkalinity of deeper or chronic wound. Energy provision is essential for all repair processes. New insights into the metabolism of cells have changed the definition of lactate from a waste product to an indispensable energy provider in normoxic and hypoxic conditions. Neovascularization depends on oxygen provision and lactate, signaling hypoxic conditions even under normoxic conditions. An appropriate pH is necessary for successful skin grafting; hypoxia can change the pH of wounds. This review describes the close interconnections between the local lactate levels, metabolism, healing mechanisms, and pH. Furthermore, it analyzes and evaluates the different possible ways to support metabolism, such as lactate enhancement and pH adjustment. The aim of wound treatment must be the optimization of all these components. Therefore, the role of lactate and its influence on wound healing in acute and chronic wounds will be assessed.
Subject: Chemistry, Analytical Chemistry Keywords: hyperoxaluria; oxalate; inhibitor; small molecule drug; glycolate oxidase; lactate dehydrogenase; liver selective distribution
Online: 31 December 2020 (08:59:47 CET)
Primary hyperoxalurias (PHs) are a group of inherited alterations of the hepatic glyoxylate metabolism. PHs classification based on gene mutations parallel a variety of enzymatic defects, and all involve the harmful accumulation of calcium oxalate crystals that produce systemic damage. These geographically widespread rare diseases have a deep impact in the life quality of the patients. Until recently, treatments were limited to palliative measures and kidney/liver transplants in the most severe forms. Efforts made to develop pharmacological treatments succeeded with the biotechnological agent lumasiran, a siRNA product against glycolate oxidase, which has become the first effective therapy to treat PH1. However, small molecule drugs have classically been preferred since they benefit from experience and have better pharmacological properties. The development of small molecule inhibitors designed against key enzymes of glyoxylate metabolism is on the focus of research. Enzyme inhibitors are successful and widely used in several diseases and their pharmacokinetic advantages are well known. In PHs, effective enzymatic targets have been determined and characterized for drug design and interesting inhibitory activities have been achieved both in vitro and in vivo. This review describes the most recent advances towards the development of small molecule enzyme inhibitors in the treatment of PHs, introducing the multi-target approach as a more effective and safe therapeutic option.
ARTICLE | doi:10.20944/preprints201912.0311.v1
Subject: Life Sciences, Biotechnology Keywords: adipose tissue; mesenchymal stem cells; regenerative medicine; lipocell; extracellular matrix preservation; ringer’s lactate; liposuction
Online: 24 December 2019 (07:53:44 CET)
This work aims to characterize a new method to recover low-manipulated human adipose tissue, enriched of adipose tissue-derived mesenchymal stem cells (ATD-MSCs) for autologous use in regenerative medicine applications. Lipoaspirated fat collected from patients was processed through Lipocell, a II-a medical device for dialysis of adipose tissue, by varying filter sizes and washing solutions. ATD-MSCs yield was measured with flow cytometry after SVF isolation in fresh and cultured samples. Purification from oil and blood was measured after centrifugation with spectrophotometer analysis. Extracellular matrix preservation was assessed through H&E staining and biochemical assay for total collagen, type-2 collagen, and GAGs quantification. Flow cytometry showed a 2-fold increase of ATD-MSCs yield in treated samples in comparison with untreated lipoaspirate; no differences where reported when varying filter size. The association of dialysis and washing thoroughly removed blood and oil from samples. Tissue architecture and extracellular matrix integrity were unaltered after Lipocell processing. Dialysis procedure associated with Ringer’s lactate preserves the proliferation ability of ATD-MSCs in cell culture. The characterization of the product shows that Lipocell is an efficient method to purify the tissue from undesired byproducts, preserving ATD-MSCs vitality and ECM integrity, resulting in a promising tool for regenerative medicine applications.
ARTICLE | doi:10.20944/preprints202202.0290.v1
Subject: Materials Science, Biomaterials Keywords: calcium lactate pentahydrate; monocalcium phosphate monohydrate; mechanical activation; powder; brushite; monetite; calcium pyrophosphate; ceramics; biocompatibility
Online: 23 February 2022 (12:07:43 CET)
Ceramic samples based on b-calcium pyrophosphate b-Ca2P2O7 were prepared using firing at 900, 1000, and 1100 oC from powders of g-calcium pyrophosphate g-Ca2P2O7 with preset molar ratios Ca/P=1; 0,975 and 0,95. To prepare powders of g-calcium pyrophosphate g-Ca2P2O7 with preset molar ratio Ca/P=1; 0,975 and 0,95 powder mixtures based on calcium lactate pentahydrate Ca(C3H5O3)2⋅5H2O and, monocalcium phosphate monohydrate Ca(H2PO4)2⋅H2O were treated in an aqua medium in mechanical activation conditions, dried, disaggregated in acetone, and heat-treated at 600 oC. The phase composition of powder mixtures after treatment if planetary mill in aqua medium included both brushite CaHPO4⋅2H2O or monetite CaHPO4, and starting salts. The phase composition of all powder mixtures after disaggregation in acetone in planetary mill included monetite CaHPO4 and starting salts. After heat treatment at 600 oC according to the XRD data phase composition of all powder mixtures was presented by g-calcium pyrophosphate g-Ca2P2O7. The grain size of ceramics increased both with the growth of firing temperature and with decreasing of molar ratio Ca/P of powder mixtures. Calcium polyphosphate (t melt =960–968 oC) formed from monocalcium phosphate monohydrate Ca(H2PO4)2⋅H2O acted like a liquid phase sintering additive. It was confirmed by tests in vitro, that prepared ceramic materials with preset molar ratio Ca/P=1; 0,975 and 0,95 and phase composition presented by b-calcium pyrophosphate b-Ca2P2O7 according to XRD data were biocompatible and could maintain bone cells proliferation.
ARTICLE | doi:10.3390/sci2020043
Subject: Keywords: lactate dehydrogenase; alanine transaminase; MDR2 knockout; dissolution dynamic nuclear polarization; perfused precision cut liver slices
Online: 10 June 2020 (00:00:00 CEST)
The clinical characterization of small hepatocellular carcinoma (HCC) lesions in the liver and differentiation from heterogeneous inflammatory or fibrotic background is important for early detection and treatment. Metabolic monitoring of hyperpolarized 13C-labeled substrates has been suggested as a new avenue for diagnostic magnetic resonance. The metabolism of hyperpolarized [1-13C]pyruvate was monitored in mouse precision-cut liver slices (PCLS) of aged MDR2-KO mice, which served as a model for heterogeneous liver and HCC that develops similarly to the human disease. The relative in-cell activities of lactate dehydrogenase (LDH) to alanine transaminase (ALT) were found to be 0.40 ± 0.06 (n = 3) in healthy livers (from healthy mice), 0.90 ± 0.27 (n = 3) in heterogeneously inflamed liver, and 1.84 ± 0.46 (n = 3) in HCC. Thus, the in-cell LDH/ALT activities ratio was found to correlate with the progression of the disease. The results suggest that the LDH/ALT activities ratio may be useful in the assessment of liver disease. Because the technology used here is translational to both small liver samples that may be obtained from image-guided biopsy (i.e., ex vivo investigation) and to the intact liver (i.e., in a non-invasive MRI scan), these results may provide a path for differentiating heterogeneous liver from HCC in human subjects.
ARTICLE | doi:10.20944/preprints202104.0195.v1
Subject: Medicine & Pharmacology, Allergology Keywords: doubly labeled water; total energy expenditure; physical activity level; lactate threshold, physical fitness; International Physical Activity Questionnaire
Online: 7 April 2021 (11:32:02 CEST)
Adequate energy intake is critical for the healthy longevity of older adults, and the estimated energy requirement is determined by total energy expenditure (TEE). We aimed to identify the relationship between measured aerobic capacity and TEE, activity energy expenditure (AEE) or physical activity level (PAL) with the doubly labeled water (DLW) methods in the advanced older adults. A total of 12 physically independent older adults (10 males and 2 females) aged between 81 to 94 years participated in this study. Aerobic capacity was evaluated according to the lactate threshold (LT). TEE under free-living conditions was assessed using the DLW method, and self-reported physical activity was obtained through the Japanese version of the International Physical Activity Questionnaire (IPAQ). LT was significantly positively correlated with TEE, AEE, and PAL after adjustment for age and sex (ρ= 0.77 (P<0.01), 0.86 (p<0.01), and 0.86 (p<0.01), respectively). We found the LT as an aerobic capacity is positively and independently correlated with TEE, AEE or PAL. The present results suggest that maintaining aerobic capacity is an important factor for preventing frailty, although further research is needed to multisite studies and many samples.
ARTICLE | doi:10.20944/preprints202209.0488.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: carrot juice; human gut microbiota; fermentation; prebiotic; lactate; Lactobacillus fermentum; Lactobacillus salivarius; Lactobacillus mucosae; Bacteroides uniformis; Enterococcus faecium
Online: 30 September 2022 (11:19:07 CEST)
Carrot juice and its associated beverage products are well-known healthy drinks all over the world. However, what effect carrot juice has on the human gut microbiota and how it is fermented by the intestinal microbes have not been studied. Here, using an in vitro model of anaerobic fermentation, we demonstrated that carrot juice could be fermented into lactate and acetate by the human gut microbiota. 16S high-throughput sequencing and bioinformatic analyses indicated that fermentation of carrot juice could significantly change the composition of the human gut microbiome. Interestingly, carrot juice remarkably increased the abundances of beneficial bacteria, including Lactobacillus fermentum, Lactobacillus salivarius, Lactobacillus mucosae and Bacteroides uniformis and decreased the population of opportunistic pathogenic bacteria, such as Enterococcus faecium in the gut. Collectively, our study illustrates a favorable effect of carrot juice on the human gut microbiota and lays a foundation for the development of carrot juice as a novel prebiotic agent.
REVIEW | doi:10.20944/preprints202203.0170.v2
Subject: Life Sciences, Molecular Biology Keywords: cancer; DNA informational entropy; cell compartmentation; evolutionary Biology; lactate dehydrogenase (LDH); lactic acid; metabolism; thermodynamic entropy; Warburg effect
Online: 17 March 2022 (03:37:53 CET)
Attempts to find and quantify the supposed low entropy of organisms and its preservation are revised. Absolute entropy of the mixed components of non-living biomass (around -1.6 x 103 J K-1 L-1) is the reference to which other entropy decreases would be ascribed to life. Compartmentation of metabolites and departure from the equilibrium of metabolic reactions account for 1 and 40-50 J K-1 L-1, respectively, decreases of entropy and, though small, are distinctive features of living tissues. DNA and proteins do not supply significant decreases of thermodynamic entropy, but their low informational entropy is relevant for life and its evolution. No other living feature contributes significantly to the low entropy associated to life. The photosynthetic conversion of radiant energy to biomass energy accounts for the most of entropy (2.8 x 105 J K-1 carbon kg-1) produced by living beings. The comparative very low entropy produced in other processes (around 4.8 x102 J K-1 L-1 day-1 in human body) must be rapidly exported outside as heat to preserve the low entropy decreases due to compartmentation and non-equilibrium metabolism. Enzymes and genes are described whose control minimize the rate of production of entropy and could explain selective pressures in biological evolution and the rapid proliferation of cancer cells.
REVIEW | doi:10.20944/preprints202102.0277.v1
Subject: Life Sciences, Biochemistry Keywords: energy metabolism; oligodendrocyte; oligodendrocyte progenitor cell; myelin; remyelination; multiple sclerosis; glucose; ketone bodies; lactate; N-acetyl aspartate; demyelination
Online: 11 February 2021 (10:57:28 CET)
Central nervous system (CNS) myelin has a crucial role in accelerating the propagation of action potentials and providing trophic support to the axons. Defective myelination and lack of myelin regeneration following demyelination can both lead to axonal pathology and neurodegeneration. Energy deficit has been evoked as an important contributor to various CNS disorders, including multiple sclerosis (MS). This suggests that dysregulation of energy homeostasis in oligodendroglia may be an important contributor to myelin dysfunction and lack of repair observed in the disease. This article will focus on energy metabolism pathways in oligodendroglial cells and highlight differences dependent on the maturation stage of the cell. In addition, it will emphasize that the use of alternative energy sources by oligodendroglia may be required to save glucose for functions that cannot be fulfilled by other metabolites, thus ensuring sufficient energy input for both myelin synthesis and trophic support to the axons. Finally, it will point out that neuropathological findings in a subtype of MS lesions likely reflect defective oligodendroglial energy homeostasis in the disease.
ARTICLE | doi:10.20944/preprints202107.0503.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Cytotoxicity; Glioblastoma multiform; Lactate dehydrogenase (LDH); Poly D- L-lactic-co-glycolic acid (PLGA); U-87 MG glioma cell lines
Online: 21 July 2021 (16:37:21 CEST)
PHLNs (polymeric lipid hybrid nanoparticles) are core–shell nanoparticle structures made up of polymer cores and lipid shells that have properties similar to both polymeric nanoparticles and liposomes. Methotrexate (MTX) loaded PLHNPs containing tween 80, phosphatidylcholine, poly D, L-lactic-co-glycolic acid (PLGA) & glyceryl tripalmitate prepared using solvent injection & homogenization method for glioblastoma treatment option. The MTX loaded PLHNPs optimized by Box–Behnken design to minimize particle size, higher entrapment efficacy, and maximize MTX concentration in the brain at 4h. The particle size, entrapment efficacy, concentration of drug in brain at 4h, zeta potential and AUC(Brain)/AUC(Plasma) ratio were in the range of 173.51-233.37nm, 70.56-86.34%, 6.38-12.38 μg/mL, 25.78-36.31mV & 1.02-5.32. in-vitro drug release studies, cellular internalization of optimized formulation against U-87 MG shows good anticancer effects.
CASE REPORT | doi:10.20944/preprints201801.0227.v1
Subject: Life Sciences, Other Keywords: Lactate dehydrogenase (LDH), Computed Tomography (CT), Glomerular filtration rate (GFR), C reactive protein (CRP), Angiotensin converting enzyme inhibitor (ACEI) Angiotensin receptor blocker (ARB), Kidney Urinary bladder ( KUB), Dimercapto Succinic Acid (DMSA)
Online: 24 January 2018 (11:41:15 CET)
Renal artery thrombosis is a sporadic serious clinical condition which potentially cause renal infarction. Diagnosis of renal infarction can be delayed or missed due to non specific clinical presentation and overlapping appearance of medical and surgical phenomena. Early diagnosis supported by biochemical and radiological findings while appropriate management potentially improve morbidity and mortality. Persistent abdominal or flank pain with raised LDH and proteinuria on background of thromboembolism risk factors supports the diagnosis. Despite the rarity of the disease rapid identification with prompt medical or endovascular intervention could prevent irreversible renal parenchymal damage.