Decrease In Lactate Levels Research Articles

Tumor-Selective Nano-Dispatcher Enforced Cancer Immunotherapeutic Effects via Regulating Lactate Metabolism and Activating Toll-Like Receptors.

The development of tumors relies on lactate metabolic reprogramming to facilitate their unchecked growth and evade immune surveillance. This poses a significant challenge to the efficacy of antitumor immunity. To address this, a tumor-selective nano-dispatcher, PIMDQ/Syro-RNP, to enforce the immunotherapeutic effect through regulation of lactate metabolism and activation of toll-like receptors is developed. By using the tumor-targeting properties of c-RGD, the system can effectively deliver monocarboxylate transporters 4 (MCT4) inhibitor (Syro) to inhibit lactate efflux in tumor cells, leading to decreased lactate levels in the tumor microenvironment (TME) and increased accumulation within tumor cells. The reduction of lactate in TME will reduce the nutritional support for regulatory T cells (Tregs) and promote the effector function of T cells. The accumulation of lactate in tumor cells will lead to tumor death due to cellular acidosis. In addition, it will also reduce the uptake of glucose by tumor cells, reduce nutrient plunder, and further weaken the inhibition of T cell function. Furthermore, the pH-responsive release of Toll-like receptors (TLR)7/8 agonist IMDQ within the TME activates dendritic cells (DCs) and promotes the infiltration of T cells. These findings offer a promising approach for enhancing tumor immune response through targeted metabolic interventions.

The Effects of L-Citrulline and Malic Acid on Substrate Utilisation and Lactate Elimination

Endurance athletes often aim to improve their aerobic metabolism. The aim of this pilot study was to examine if malic acid and L-citrulline supplementation can improve aerobic metabolism and lactate elimination. Nine young (23.9 ± 1.9 years) recreational male athletes participated in this study. Following a standardised breakfast and a body composition analysis (InBody720), 6000 mg of citrulline and 3000 mg of malic acid or a placebo of 300 mL of water were consumed on three separate days in a cross-over design using a double-blind method. Sixty minutes after the supplementation, participants completed a ramp bicycle spiroergometer protocol (35 W/3 min) until reaching a respiratory exchange ratio (RER) of 1.1, followed by a 9 min active recovery. Cadence, heart rate (HR), rate of perceived exertion (RPE), respiratory parameters and lactate levels were registered. The RPExHR value was calculated to accurately characterise exhaustion. During the exercise protocol, citrulline supplementation induced significantly lower RER values at 70-105-140 W compared to malic acid and the placebo, respectively. There was no difference in lactate levels neither during rest nor at RER 1.1. RPExHR rate values were significantly lower after malic acid supplementation compared to placebo at 175 and 210 W. Power at RER 1.1 was higher after malic acid (+4 W) and citrulline (+5 W) supplementation. Although the supplementation failed to decrease lactate levels, lower RER and RPE values may indicate a performance-enhancing benefit.

Apelin-13 administration allows for norepinephrine sparing in a rat model of cecal ligation and puncture-induced septic shock

BackgroundInfusion of exogenous catecholamines (i.e., norepinephrine [NE] and dobutamine) is a recommended treatment for septic shock with myocardial dysfunction. However, sustained catecholamine infusion is linked to cardiac toxicity and impaired responsiveness. Several pre-clinical and clinical studies have investigated the use of alternative vasopressors in the treatment of septic shock, with limited benefits and generally no effect on mortality. Apelin-13 (APL-13) is an endogenous positive inotrope and vasoactive peptide and has been demonstrated cardioprotective with vasomodulator and sparing life effects in animal models of septic shock. A primary objective of this study was to evaluate the NE-sparing effect of APL-13 infusion in an experimental sepsis-induced hypotension.MethodsFor this goal, sepsis was induced by cecal ligation and puncture (CLP) in male rats and the arterial blood pressure (BP) monitored continuously via a carotid catheter. Monitoring, fluid resuscitation and experimental treatments were performed on conscious animals. Based on pilot assays, normal saline fluid resuscitation (2.5 mL/Kg/h) was initiated 3 h post-CLP and maintained up to the endpoint. Thus, titrated doses of NE, with or without fixed-doses of APL-13 or the apelin receptor antagonist F13A co-infusion were started when 20% decrease of systolic BP (SBP) from baseline was achieved, to restore SBP values ≥ 115 ± 1.5 mmHg (baseline average ± SEM).ResultsA reduction in mean NE dose was observed with APL-13 but not F13A co-infusion at pre-determined treatment time of 4.5 ± 0.5 h (17.37 ± 1.74 µg/Kg/h [APL-13] vs. 25.64 ± 2.61 µg/Kg/h [Control NE] vs. 28.60 ± 4.79 µg/Kg/min [F13A], P = 0.0491). A 60% decrease in NE infusion rate over time was observed with APL-13 co-infusion, (p = 0.008 vs NE alone), while F13A co-infusion increased the NE infusion rate over time by 218% (p = 0.003 vs NE + APL-13). Associated improvements in cardiac function are likely mediated by (i) enhanced left ventricular end-diastolic volume (0.18 ± 0.02 mL [Control NE] vs. 0.30 ± 0.03 mL [APL-13], P = 0.0051), stroke volume (0.11 ± 0.01 mL [Control NE] vs. 0.21 ± 0.01 mL [APL-13], P < 0.001) and cardiac output (67.57 ± 8.63 mL/min [Control NE] vs. 112.20 ± 8.53 mL/min [APL-13], P = 0.0036), and (ii) a reduced effective arterial elastance (920.6 ± 81.4 mmHg/mL/min [Control NE] vs. 497.633.44 mmHg/mL/min. [APL-13], P = 0.0002). APL-13 administration was also associated with a decrease in lactate levels compared to animals only receiving NE (7.08 ± 0.40 [Control NE] vs. 4.78 ± 0.60 [APL-13], P < 0.01).ConclusionAPL-13 exhibits NE-sparing benefits in the treatment of sepsis-induced shock, potentially reducing deleterious effects of prolonged exogenous catecholamine administration.

Introduction of ex vivo perfusion of extended-criteria donor hearts in a single center in Asia.

The shortage of organs for heart transplantation has created a need to explore the use of extended-criteria organs. We report the preliminary use of normothermic TransMedics Organ Care System-an ex vivo approach to preserve extended-criteria brain-dead donor hearts. This System maintains a normal temperature, provides continuous perfusion and oxygenation, reduces ischemic time, and enables additional viability assessment options. In a retrospective single-centre study conducted from April 2020 to March 2023, four extended criteria brain-dead donor hearts were perfused and monitored using the Organ Care System. Suitability for transplantation was assessed based on stable or decreasing lactate levels, along with appropriate perfusion parameters. The Organ Care for use of the Organ Care System were coronary artery disease, left ventricular hypertrophy, high-dose inotrope use in the donor, a downtime exceeding 20min, and a left ventricular ejection fraction of 40-50%. Three out of the four donor hearts were transplanted, while one was discarded due to rising lactate concentration. The three recipients had a higher surgical risk profile for heart transplant. All showed normal cardiac function and no primary graft dysfunction postoperatively. At 2-3years post-transplant, all recipients have a ventricular function of > 60%, with only one showing evidence of mild rejection. The Organ Care System enables the successful transplantation of marginal donor organs in high-risk recipients, showcasing the feasibility of recruiting donors with extended criteria. This technique is safe and promising, expanding the donor pool and addressing the organ shortage in heart transplantation in Hong Kong.

Vibration Emissions Reduce Boar Sperm Quality via Disrupting Its Metabolism.

Artificial insemination (AI) with liquid-preserved semen has recently become common in pig breeding. The semen doses are produced in a centralized manner at the boar stud and then subsequently distributed and transported to sow farms. However, vibration emissions during transportation by logistic vehicles may adversely affect the quality of boar sperm. Therefore, this study aimed to explore the impact of vibration-induced emissions on sperm quality and function under simulated transportation conditions. Each time, ejaculates from all 15 boars were collected and then pooled together to minimize individual variations, and the sample was split using an extender for dilution. Different rotational speeds (0 rpm, 80 rpm, 140 rpm, 200 rpm) were utilized to simulate varying intensities of vibration exposure using an orbital shaker, considering different transportation times (0 h, 3 h, and 6 h). Subsequently, evaluations were conducted regarding sperm motility, plasma membrane integrity, acrosome integrity, mitochondrial function, adenosine triphosphate (ATP) levels, mitochondrial reactive oxygen species (ROS) levels, pH, glycolytic pathway enzyme activities, and capacitation following exposure to vibration emissions. Both vibration time and intensity impact sperm motility, plasma membrane integrity, and acrosomal integrity. Vibration exposure significantly reduced sperm ATP levels, mitochondrial membrane potential, and the levels of mitochondria-encoded proteins (MT-ND1, MT-ND6) (p < 0.05). After vibration emission treatment, the pH value and mitochondrial ROS levels significantly increased (p < 0.05). Inhibition of sperm glycolysis was observed, with reduced activities of hexokinase (HK), pyruvate kinase (PK), and lactate dehydrogenase (LDH), along with decreased lactate levels (p < 0.05). Additionally, sperm tyrosine phosphorylation levels were significantly reduced by vibration emissions compared to the control group (p < 0.05). After the vibration emission treatment, the number of sperm bound to each square millimeter of oviduct explants decreased significantly compared to the control group (p < 0.05). Similarly, compared to the control group, using semen subjected to vibration stress for AI results in significantly reduced pregnancy rates, total born litter size, live-born litter size, and healthy born litter size (p < 0.05).

Serial daily lactate levels association with 30-day outcome in cardiogenic shock patients treated with VA-ECMO: a post-hoc analysis of the HYPO-ECMO study

BackgroundReliable predictors of outcomes in venoarterial extracorporeal membrane oxygenation (VA-ECMO) therapy are limited. While elevated lactate levels over time have been linked to outcomes in cardiogenic shock (CS), their significance in VA-ECMO-treated patients remains inconclusive.MethodsWe conducted a post hoc analysis of data from the HYPO-ECMO trial, which compared normothermia to moderate hypothermia in CS patients supported by VA-ECMO. We examined daily lactate levels collected over a week to assess their correlation with 30-day mortality.ResultsAmong the 318 out of 334 patients (95%) with baseline lactate measurements, 66 had normal levels (< 2.2 mmol/l, 21%). No difference was found in lactate course between moderate hypothermia and normothermia groups. Lactate levels were consistently higher in non-survivors at each time point (p = 0.0002). Baseline hyperlactatemia was associated with an increased risk of death (Hazard Ratio [HR]: 1.85 (1.12–3.05), p = 0.016). When considering all time points, lactate levels during the ICU stay were significantly and gradually associated with a higher risk of death (p < 0.0001). In the overall population, a decrease in lactate levels was not linked to 30-day mortality. However, patients with baseline hyperlactatemia exhibited a more significant decrease in lactate levels from day one to seven (p < 0.0001). In this group, survivors had a significantly greater decrease in lactate levels at day 1 compared to non-survivors (63% (48–77) versus 57% (21–75), p = 0.026). Patients experiencing a secondary increase in lactate (24%) had a worse prognosis (Hazard Ratio: 1.78 (1.21–2.61), p = 0.004), regardless of both baseline lactate levels and the occurrence of severe ischemic adverse events (intestinal and/or limb ischemia).ConclusionsThe consistent and significant association between lactate levels, whether assessed at baseline or during ICU treatment, and the risk of mortality underscores the pivotal prognostic relevance of lactate levels in patients with CS undergoing VA-ECMO therapy. The study findings provide some novel insights, regarding the trend profile and the relevance of a second peak during the 7 day period after ECMO start.Trial Registration identifier NCT02754193 registered on 2016–04–12.

LncRNA PWRN1 inhibits the progression of hepatocellular carcinoma by activating PKM2 activity

Hepatocellular carcinoma (HCC) is one of the most prevalent and leading causes of cancer-related mortality worldwide. Long non-coding RNAs (lncRNAs) have been demonstrated to play vital roles in cancer development and progression. The lncRNA PWRN1 (PWRN1), acts as a tumor suppressor factor, which is low expressed in some cancers. However, the molecular mechanisms underlying the effects of PWRN1, especially the regulatory relationship with RNA binding protein in HCC remain largely unknown. In the present study, we demonstrated that PWRN1 was significantly down-regulated in HCC and correlated with better prognosis; furthermore, gain-of-function experiments showed that PWRN1 inhibited the proliferation of HCC cells. We further found that PWRN1 up-regulated pyruvate kinase activity and thus hinders the proliferation of HCC in vitro and in vivo. Mechanistically, pyruvate kinase M2 (PKM2) was bound to it and maintained the high activity state of PKM2, thereby hindering PKM2 from entering the nucleus in the form of low-activity dimers, reducing the expression of c-Myc downstream gene LDHA, leading to a decrease in lactate levels, and inhibiting the growth of tumor cells. In addition, PWRN1 was found to inhibit aerobic glycolysis. Finally, TEPP-46, a pyruvate kinase activator, appeared to inhibit HCC proliferation by maintaining tetramer stability and increasing pyruvate kinase activity. Taken together, our results provide new insights into the biology hindering HCC proliferation and indicate that PWRN1 in combination with PKM2 activators might represent a novel therapeutic target for HCC.

Therapeutic influence of simvastatin on MCF-7 and MDA-MB-231 breast cancer cells via mitochondrial depletion and improvement in chemosensitivity of cytotoxic drugs

BackgroundBreast cancer is the most commonly diagnosed cancer worldwide with 2.26 million cases in 2020. Cancer heterogeneity is the major challenge before existing therapeutic modalities due to metabolic variability of the cells as Warburg and anti-Warburg both type of metabolic phenotypes has been reported as a major contributing factors for cancer progression, invasion, metastasis and relapse. Also, this metabolic variability is associated with chemo and radio-resistance and poor therapeutic outcomes. Therefore, in present study we put an attempt to understand how simvastatin exert its effects on two metabolically different cell types and second how this drug can affect mitochondrial biomass, mt-DNA and glycolysis in both the cell types. MethodsWe have observed effects of simvastatin on MCF-7 (dependent more on OXPHOS) and MDA-MB-231 (TNBC; more glycolytic with defected mitochondria) cells alone and after simvastatin pre-treatment followed by cytotoxic drugs including cisplatin, doxorubicin, gemcitabine, vincristine. We have conducted MTT assay for viability, cell death detection assay, apoptotic morphology study, scratch assay, transwell migration assay, lactate estimation in media (glycolysis parameter), mt-DNA to n-DNA ratio, mitotracker red (for mitochondrial membrane potential) and mitotracker green staining (for mitochondrial biomass) and qPCR to study expression of mitochondrial transcription factors and apoptotic genes including PGC-1α, NRF-1, NRF-2, TFAM, Bcl-2 and Bax. ResultsWe observed that 20 μM simvastatin (SIM) was most efficient dose for MCF-7, whereas 12.5 μM for MDA-MB-231 cells. Simvastatin itself caused a significant decrease in viability, increased cell death, and diminished wound closure in scratch assay as well as inhibited transwell migration. Also, the cells pre-treated with simvastatin for 72 h followed by treatment with cytotoxic drugs for 48 h increased chemo-sensitivity of cisplatin (CIS), doxorubicin (DOX), gemcitabine (GEM) and vincristine (VIN). SIM alone and in pre-treatment followed by cytotoxic drug treatment studies, there was a significant decrease in mitochondrial biomass and mitochondrial membrane potential (MMP), but also decreased glycolysis as evidenced by decrease in lactate levels in culture media. For inhibition of migratory potential, it was in the following order: CIS ˃ VIN ˃DOX˃ GEM, which was in the same order to diminish mitochondrial functionality (mt-DNA/n-DNA ratio, mitotracker green staining and a significant decrease in the expression of transcriptional factors of mitochondrial biogenesis). Contrastingly a decrease in the same order was observed in lactate concentration independent to the mitochondrial loss, but probably via inherent ability of the drugs to reduce lactate and glycolysis. However, for cell death, apoptotic phenotype, diminished expression of Bcl-2 along with increase in Bax and loss of viability, the efficiency of simvastatin alone and in pre-treatment studies was in the following order: VIN ˃ DOX˃GEM˃CIS, which was supported by loss of fluorescence of mitotracker red, suggested decrease in MMP; marker of cell death. ConclusionWe conclude that by using different doses simvastatin can target different metabolic phenotypes of breast cancer cells and can also increase the chemo-sensitivity of cytotoxic drugs, so that they can work efficiently at lower doses which will ultimately diminish the cost and toxicity issues.

Role of Albumin-corrected Anion Gap and Lactate Clearance in Predicting Mortality in Pediatric Intensive Care Patients.

Identifying mortality risk in critically ill children is central to diagnostic and treatment practices. For this purpose, scoring systems, such as the Pediatric Index of Mortality 3 (PIM 3), have been proposed; however, the role of biochemical markers, such as albumin-corrected anion gap (cAG) and lactate clearance (LC), in predicting mortality in pediatric intensive care unit (PICU) patients is yet to be explored. To evaluate the predictive value of the cAG and LC for mortality in pediatric patients admitted to a PICU. Retrospective single-center cohort study conducted at Akdeniz Hospital including patient data from eight medical-surgical PICU beds. Clinical and laboratory data from the time of PICU admission were collected, and patients were classified into based on their 0- and 6-hour of admission lactate levels into an LC(+) group (patients with normal or decreasing lactate levels) or an LC (-) group (increasing lactate levels). LC and cAG levels were compared using the Mann-Whitney U test and Student's t-test, respectively. Additionally, multiple logistic regression analysis was performed to evaluate the effect of LC and cAG on mortality. We included 825 patients in the study; the mortality rate was 8.6%. The absence of LC [adjusted odds ratio (AOR) =4.735; 95% confidence interval (CI): 2.163-10.367; p < 0.001], cAG (AOR =1.064; 95% CI: 1.010-1.122; p = 0.019) and PIM 3 (AOR = 1.871; 95% CI: 1.553-2.254; p < 0.001) were independent risk factors for mortality. Using the receiver operating characteristic curve analysis of PIM 3 as a predictor of mortality, area under the curve values of 0.832 (95% CI: 0.805-0.857; p < 0.001) for the original score and 0.858 for a revised PIM 3 score (based on the β coefficients obtained for cAG and LC; 95% CI 0.832-0.881; p < 0.001) were obtained, which was significantly different (p = 0.027). A cAG value > 18 at the time of PICU admission high lactate levels which do not decrease within 6 hours of hospitalization are associated with an increased risk of mortality. The revised PIM 3 score, which includes cAG and LC, is a better predictor of mortality than the classical PIM 3 score.

Comparative metabolomics analysis investigating the impact of melatonin-enriched diet on energy metabolism in the crayfish, Cherax destructor.

Melatonin is a multifunctional bioactive molecule present in almost all organisms and has been gradually used in the aquaculture industry in recent years. Energy metabolism is an essential process for individuals to maintain their life activities; however, the process through which melatonin regulates energy metabolism in aquatic animals remains unclear. The present study aimed to conduct a comprehensive analysis of the regulatory mechanism of melatonin for energy metabolism in Cherax destructor by combining metabolomics analysis with the detection of the key substance content, enzymatic activity, and gene expression levels in the energy metabolism process after culturing with dietary melatonin supplementation for 8weeks. Our results showed that dietary melatonin increased the content of glycogen, triglycerides, and free fatty acids; decreased lactate levels; and promoted the enzymatic activity of pyruvate kinase (PK), malate dehydrogenase (MDH), and acetyl-CoA carboxylase. The results of gene expression analysis showed that dietary melatonin also increased the expression levels of hexokinase, PK, MDH, lactate dehydrogenase, lipase, and fatty acid synthase genes. The results of metabolomics analysis showed that differentially expressed metabolites were significantly enriched in lysine degradation and glycerophospholipid metabolism. In conclusion, our study demonstrates that dietary melatonin increased oxidative phosphorylation, improved glucose utilization, and promoted storage of glycogen and lipids in C. destructor. These lipids are used not only for energy storage but also to maintain the structure and function of cell membranes. Our results further add to the understanding of the mechanisms of energy regulation by melatonin in crustaceans.

The effect of the physical exercise on the redox status of chil- dren with repaired congenital heart diseases

Purpose. Evaluation of the impact of the physical rehabilitation program with the inclusion of ubidecarenone on the redox status in children with repaired congenital heart diseases. Material and methods. Markers of free radical oxidation (lactate, pyruvate, lactate-to-pyruvate ratio) and antioxidant system (catalase, reduced glutathione and glutathione peroxidase) were studied in 84 children, including 48 children with repaired congenital heart diseases and 36 healthy peers. The main group consisted of 28 patients who performed a rehabilitation program using physical activity in combination with taking ubidecarenone for a year, the comparison group consisted of 20 children who received only ubidecarenone. Results. After the rehabilitation program was completed, both the main group and the comparison group had a significant (p &lt; 0.05) decrease in lactate levels, the ratio of lactate to pyruvate, and an increase in catalase and reduced RBC glutathione. The group of children who performed physical exercises had significantly lower levels of markers of free radical oxidation and higher values of markers of the antioxidant system than the patients from the comparison group. Conclusion. There are free radical oxidation and the antioxidant system impairments in children with repaired congenital heart diseases. The use of ubidecarenone reduces oxidative stress and increases antioxidant protection in children with repaired congenital heart diseases. The inclusion of physical activity in the rehabilitation program for children with repaired congenital heart diseases improves the redox status and increases the effectiveness of rehabilitation.

Effect of low-level laser therapy on quadriceps and foot muscle fatigue in children with spastic diplegia: a randomized controlled study

Spastic diplegia is the most common form of cerebral palsy; children with spastic diplegia are suffering from muscle fatigue and spasticity which lead to decreasing power of muscles, impaired motor control, and many functional abilities. The effect of low-level laser (LLL) has a good result as it improves muscles pain and spasticity and in decreasing lactate levels. Forty children were selected with spastic diplegia and were divided into two groups: A and B. Group A received low-level laser treatment (LLLT) with physiotherapy treatment. Group B got physiotherapy sessions. Pain intensity was assessed by the visual analog scale (VAS) of pain which is reliable from age 5, before treatment and after 1-month follow-up. Muscle fatigue and power were assessed by maximum voluntary isometric contraction (MVIC) before treatment and after 1-month follow-up. Also, we tested blood lactate level in both groups; all evaluations were done before treatment and after 1-month follow-up. We found a significant difference between the two groups in VAS and MVIC and blood lactate level test regarding low-level therapy after 1-month follow-up. There is a good effect of low-level laser in increasing muscle power, decreasing blood lactate level, and improving pain.

Reprogramming of glucose metabolism via PFKFB4 is critical in FGF16-driven invasion of breast cancer cells.

Fibroblast growth factors (FGFs) are expressed in both developing and adult tissues and play important roles in embryogenesis, tissue homeostasis, angiogenesis, and neoplastic transformation. Here, we report the elevated expression of FGF16 in human breast tumor and investigate its potential involvement in breast cancer progression. The onset of epithelial-mesenchymal transition (EMT), a prerequisite for cancer metastasis, was observed in human mammary epithelial cell-line MCF10A by FGF16. Further study unveiled that FGF16 alters mRNA expression of a set of extracellular matrix genes to promote cellular invasion. Cancer cells undergoing EMT often show metabolic alteration to sustain their continuous proliferation and energy-intensive migration. Similarly, FGF16 induced a significant metabolic shift toward aerobic glycolysis. At the molecular level, FGF16 enhanced GLUT3 expression to facilitate glucose transport into cells, which through aerobic glycolysis generates lactate. The bi-functional protein, 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 4 (PFKFB4) was found to be a mediator in FGF16-driven glycolysis and subsequent invasion. Furthermore, PFKFB4 was found to play a critical role in promoting lactate-induced cell invasion since silencing PFKFB4 decreased lactate level and rendered the cells less invasive. These findings support potential clinical intervention of any of the members of FGF16-GLUT3-PFKFB4 axis to control the invasion of breast cancer cells.

PDHA1 hyperacetylation-mediated lactate overproduction promotes sepsis-induced acute kidney injury via Fis1 lactylation

The increase of lactate is an independent risk factor for patients with sepsis-induced acute kidney injury (SAKI). However, whether elevated lactate directly promotes SAKI and its mechanism remain unclear. Here we revealed that downregulation of the deacetylase Sirtuin 3 (SIRT3) mediated the hyperacetylation and inactivation of pyruvate dehydrogenase E1 component subunit alpha (PDHA1), resulting in lactate overproduction in renal tubular epithelial cells. We then found that the incidence of SAKI and renal replacement therapy (RRT) in septic patients with blood lactate ≥ 4 mmol/L was increased significantly, compared with those in septic patients with blood lactate < 2 mmol/L. Further in vitro and in vivo experiments showed that additional lactate administration could directly promote SAKI. Mechanistically, lactate mediated the lactylation of mitochondrial fission 1 protein (Fis1) lysine 20 (Fis1 K20la). The increase in Fis1 K20la promoted excessive mitochondrial fission and subsequently induced ATP depletion, mitochondrial reactive oxygen species (mtROS) overproduction, and mitochondrial apoptosis. In contrast, PDHA1 activation with sodium dichloroacetate (DCA) or SIRT3 overexpression decreased lactate levels and Fis1 K20la, thereby alleviating SAKI. In conclusion, our results show that PDHA1 hyperacetylation and inactivation enhance lactate overproduction, which mediates Fis1 lactylation and exacerbates SAKI. Reducing lactate levels and Fis1 lactylation attenuate SAKI.

Oxygen carriers affect kidney immunogenicity during ex-vivo machine perfusion.

Normothermic ex-vivo machine perfusion provides a powerful tool to improve donor kidney preservation and a route for the delivery of pharmacological or gene therapeutic interventions prior to transplantation. However, perfusion at normothermic temperatures requires adequate tissue oxygenation to meet the physiological metabolic demand. For this purpose, the addition of appropriate oxygen carriers (OCs) to the perfusion solution is essential to ensure a sufficient oxygen supply and reduce the risk for tissue injury due to hypoxia. It is crucial that the selected OCs preserve the integrity and low immunogenicity of the graft. In this study, the effect of two OCs on the organ's integrity and immunogenicity was evaluated. Porcine kidneys were perfused ex-vivo for four hours using perfusion solutions supplemented with red blood cells (RBCs) as conventional OC, perfluorocarbon (PFC)-based OC, or Hemarina-M101 (M101), a lugworm hemoglobin-based OC named HEMO2life®, recently approved in Europe (i.e., CE obtained in October 2022). Perfusions with all OCs led to decreased lactate levels. Additionally, none of the OCs negatively affected renal morphology as determined by histological analyses. Remarkably, all OCs improved the perfusion solution by reducing the expression of pro-inflammatory mediators (IL-6, IL-8, TNFα) and adhesion molecules (ICAM-1) on both transcript and protein level, suggesting a beneficial effect of the OCs in maintaining the low immunogenicity of the graft. Thus, PFC-based OCs and M101 may constitute a promising alternative to RBCs during normothermic ex-vivo kidney perfusion.

Levosimendan in the Treatment of Patients with Severe Septic Cardiomyopathy.

(1) Background: The optimal treatment of septic cardiomyopathy (SCM) remains questionable. The aim of the study was to compare the treatment of SCM based on levosimendan versus the best available therapy. (2) Methods: We conducted an observational study including patients with severe septic cardiomyopathy and circulatory failure. (3) Results: Fourteen patients (61%) received levosimendan, and nine received other treatments. The patients in the levosimendan group were more severely ill [APACHE II: 23.5 (14, 37) vs. 14 (13, 28), respectively, p = 0.012], and there was a trend for more decompensated LV function depicted by the LVEF [15% (10, 20) vs. 25% (5, 30), respectively, p = 0.061]. However, they presented a significantly higher increase in LVEF after seven days [15% (10, 20) to 50% (30, 68) (p < 0.0001) vs. 25% (5, 30) to 25% (15, 50) (p = 0.309), and a significantly higher decrease in lactate levels during the first 24 h [4.5 (2.5, 14.4) to 2.85 (1.2, 15), p = 0.036 vs. 2.9 (2, 18.9) to 2.8 (1, 15), p = 0.536]. Seven-day survival (64.3% vs. 33.3%, p = 0.424) and ICU survival (50% vs. 22.2%, p = 0.172) were higher in the first group, although differences did not reach statistical significance. The degree of left ventricular impairment and the magnitude of EF improvement by the seventh-day post-SCM onset were associated with mortality in regression analysis. (4) Conclusions: Our study presents main hemodynamic data supporting the possible efficacy of levosimendan treatment in patients with severe SCM.

The long-term transport of Potamotrygon wallacei increases lactate levels and triggers oxidative stress in its brain: The protective role of recovery and the essential oil of Lippia alba

This study aimed to determine whether the long-term transport model of cururu stingray (Potamotrygon wallacei) could disturb the brain redox status and brain functions, including antioxidant defenses, signaling pathways activated by oxidative stress, and the physiological responses to transport-induced stress upon arrival and after its recovery; and also to identify how the addition of essential oil of Lippia alba (EOLA) in the water transport could influence on these changes. For this reason, the cururu stingrays were anesthetized with 200 mg/L eugenol and sampled by sectioning of the spinal cord before transport (n = 5), after 32 h-transport in the absence (n = 5) and presence of 10 μL/L of the EOLA (n = 5); and after recovery for 24 h and 48 h post-transport without and with EOLA (n = 5, each group) for blood and brain removal, totalizing 35 animals (four replicates). Transport triggered a rise in the levels of lactate in plasma and brain of cururu stingray on arrival. Besides, it increased the superoxide anion (O2•-) and hydrogen peroxide (H2O2) levels, and decreased the superoxide dismutase (SOD) 1 and 2, catalase, glutathione peroxidase (GPx) 1, and glutathione reductase (GR) activities, activated nuclear factor κB (NF-κB), led to glutathione oxidation, lipid peroxidation (measured through the thiobarbituric acid reactive substances (TBARS)), and elevated heat shock protein 70 (HSP70) levels in the cururu stingray brain. The addition of the EOLA to water protected brain against stress and oxidative stress on arrival, speeding up a process that could take until 48 h to occur in the absence of this additive. To reach this response, the EOLA decreased lactate levels in plasma and brain of cururu stingray, and also reduced O2•- and H2O2 levels, and NF-κB activation, increased SOD2, catalase, GPx1 and GR activities, decreased the ratio between oxidized and reduced glutathione, avoiding the increase in the TBARS levels in the brain tissue, and regulated the physiological responses to stress, as illustrated by low HSP70 levels found in it. These data make the addition of EOLA to the water even more recommended for long-term transport of cururu stingrays.

Functional and hormone changes in ice hockey players using Cytoflavin

The purpose of the study was to assess the effect of 35-day Cytoflavin consumption on hormonal status, blood lactate level and functional parameters in elite ice hockey players. Material and methods: the study included 60 male professional hockey players (aged 19 to 36 years) divided into two groups of 30 subjects. Group I underwent a course of metabolic therapy with the use of succinic acid (Cytoflavin) for 35 days. Group II whose pharmacological support included only "basic" sports nutrition did not include succinic acid preparations or other metabolic agents. All patients underwent blood pressure and heart rate measurements, laboratory tests, pulse oximetry, ergospirometry. Trends in lactate levels in the blood and hormonal status in athletes were assessed. Moreover, such parameters as testing time, maximum heart rate, maximum oxygen consumption (VO2max), aerobic and anaerobic threshold pulse, time to reach the aerobic and anaerobic threshold were analyzed. Results: athletes who received a course of metabolic therapy on the 35th day of the preparatory period showed a significant increase in the indicators of maximum oxygen consumption (VO2max), the time of the test and the time of the anaerobic threshold (p&lt;0.05), which, against the background of a statistically significant decrease in lactate levels (p=0.014) indicates an improvement in aerobic performance and the possibility of faster recovery of athletes after physical exertion compared with athletes who did not receive metabolic therapy with succinic acid. Conclusion: The results obtained allow us to recommend the use of step therapy with succinic acid as a metabolic therapy for professional hockey players in the preparatory period.

Relationship between peripheral ischemic microvascular reserve, persistent hyperlactatemia, and its temporal dynamics in sepsis: a post hoc study.

To measure the prognostic value of peripheral ischemic microvascular reserve in the context of persistent sepsis-induced hyperlactatemia and measure its influence on the temporal dynamics of lactate and the strength of association between these variables. This post hoc analysis of the peripheral perfusion index/postocclusive reactive hyperemia trial, an observational cohort study that enrolled patients with sepsis who persisted with lactate levels ≥ 2mmol/L after fluid resuscitation (with or without shock). Peripheral ischemic microvascular reserve was evaluated using the association of the peripheral perfusion index and postocclusive reactive hyperemia techniques. The cutoff point of ∆ peripheral perfusion index peak values (%) defined the groups with low (≤ 62%) and high peripheral ischemic microvascular reserve (> 62%). A total of 108 consecutive patients with persistent sepsis-induced hyperlactatemia were studied. The high peripheral ischemic microvascular reserve group showed higher 28-day mortality than the low peripheral ischemic microvascular reserve group (p < 0.01). The temporal dynamics of lactate within the first 48 hours showed a rapid decrease in lactate levels in the low peripheral ischemic microvascular reserve group (p < 0.01). However, this result was not reproduced in the linear mixed effects model. A weak correlation between peripheral ischemic microvascular reserve (%) and lactate level (mmol/L) was observed within the first 24 hours (r = 0.23; p < 0.05). The prognostic value of high peripheral ischemic microvascular reserve was confirmed in the context of persistent sepsis-induced hyperlactatemia. Although there was a weak positive correlation between peripheral ischemic microvascular reserve value and lactate level within the first 24 hours of sepsis diagnosis, the low peripheral ischemic microvascular reserve group appeared to have a faster decrease in lactate over the 48 hours of follow-up.

Hiperkapnik Solunum Yetmezliği Olan Hastalarda Karbondioksit Klirensinin Klinik Prognoza Etkisi

Aim: Hypercapnic respiratory failure is defined as a carbon dioxide (CO2) level &amp;gt;45 mmHg. High PaCO2 levels are related with increased mortality in acute exacerbation of COPD. In our study, we aimed to determine CO2 clearance value for predicting patients' prognosis. Material and Methods: 68 patients were included in the study. The patients were divided into two as, good and poor prognosis groups according to the outcome. The patients’ demographic information, comorbidities, vital parameters, blood gas results on admission (first measurement) and in the first sixth hour (second measurement), treatment, and outcomes were recorded in data forms. The relation between CO2 change and outcome was evaluated. Results: There was no statistically significant difference in CO2 clearance and delta pCO2 levels between the good and poor prognosis groups (11.7±12 vs. 6.2 ± 23, p=0.205 and -11.77±12.92 mmHg vs. -7.66±24.76 mmHg, p=0.281 respectively). NaHCO3 levels in the second measurement were higher than the first measurement in both good (23.89 ±5.28, 25.78±4.39, p&amp;lt;0.0001) and poor prognosis (23,26±6.05, 23.53 ± 5.05, p&amp;lt;0.0001) groups. And also, pCO2 levels in the second measurement was lower than the first measurement in the good (60.68 ± 11.89, 48.92 ± 14.02, p=0.007) and poor (68.04 ± 20.15, 61.76 ± 22.87, p=0.007) prognosis groups. There was also a significant decrease in lactate levels in the poor prognosis group between the first and the second measurements (p&amp;lt;0.001). Conclusion: Our study revealed that the CO2 clearance calculated in the first six hours in hypercarbic patients who came to the emergency department with shortness of breath was not useful in predicting the short-term prognosis of the patients. However, delta lactate and delta NaHCO3 levels significantly changed in the poor prognosis group.