H3K18 lactylation promotes the progression of arsenite-related idiopathic pulmonary fibrosis via YTHDF1/m6A/NREP.

As epigenetic modifications, lactylation and N6-methyladenosine (m6A) have attracted wide attention. Arsenite is an environmental pollutant that has been proven to induce idiopathic pulmonary fibrosis (IPF). However, the molecular mechanisms of lactylation and m6A methylation are unclear in arsenite-related IPF (As-IPF). In view of the limited understanding of molecular mechanism of m6A and lactylation in As-IPF, MeRIP-seq, RNA-seq and ChIP-seq were analyzed to verify the target gene regulated by m6A and H3K18 lactylation (H3K18la). We found that, for As-IPF, the global levels of m6A, levels of YTHDF1 and m6A-modified neuronal protein 3.1 (NREP) were elevated in alveolar epithelial cells (AECs). The secretion levels of TGF-ß1 were increased via YTHDF1/m6A/NREP, which promoted the fibroblast-to-myofibroblast transition (FMT). Further, extracellular lactate from myofibroblasts elevated levels of the global lactylation (Kla) and H3K18la via the lactate monocarboxylate transporter 1 (MCT1), and, in AECs, H3K18la facilitated the transcription of Ythdf1. This report highlights the role of crosstalk between AECs and myofibroblasts via lactylation and m6A and the significance of H3K18la regulation of YTHDF1 in the progression of As-IPF, which may be useful for finding effective therapeutic targets.

Continuous culture of anaerobic fungi enables growth and metabolic flux tuning without use of genetic tools.

Anaerobic gut fungi (AGF) have potential to valorize lignocellulosic biomass owing to their diverse repertoire of carbohydrate-active enzymes (CAZymes). However, AGF metabolism is poorly understood, and no stable genetic tools are available to manipulate growth and metabolic flux to enhance production of specific targets, e.g., cells, CAZymes, or metabolites. Herein, a cost-effective, Arduino-based, continuous-flow anaerobic bioreactor with online optical density control is presented to probe metabolism and predictably tune fluxes in Caecomyces churrovis. Varying the C. churrovis turbidostat setpoint titer reliably controlled growth rate (from 0.04 to 0.20 h-1), metabolic flux, and production rates of acetate, formate, lactate, and ethanol. Bioreactor setpoints to maximize production of each product were identified, and all continuous production rates significantly exceed batch rates. Formate spike-ins increased lactate flux and decreased acetate, ethanol, and formate fluxes. The bioreactor and turbidostat culture schemes demonstrated here offer tools to tailor AGF fermentations to application-specific hydrolysate product profiles.

Impaired gut microbiota-mediated short-chain fatty acid production precedes morbidity and mortality in people with HIV.

Antiretroviral therapy (ART) has dramatically lengthened lifespan among people with HIV (PWH), but this population experiences heightened rates of inflammation-related comorbidities. HIV-associated inflammation is linked with an altered microbiome; whether such alterations precede inflammation-related comorbidities or occur as their consequence remains unknown. We find that ART-treated PWH exhibit depletion of gut-resident bacteria that produce short-chain fatty acids (SCFAs)-crucial microbial metabolites with anti-inflammatory properties. Prior reports establish that fecal SCFA concentrations are not depleted in PWH. We find that gut-microbiota-mediated SCFA production capacity is better reflected in serum than in feces and that PWH exhibit reduced serum SCFA, which associates with inflammatory markers. Leveraging stool and serum samples collected prior to comorbidity onset, we find that HIV-specific microbiome alterations precede morbidity and mortality in ART-treated PWH. Among these microbiome alterations, reduced microbiome-mediated conversion of lactate to propionate precedes mortality in PWH. Thus, gut microbial fiber/lactate conversion to SCFAs may modulate HIV-associated comorbidity risk.

TIM-3/Gal-9 interaction affects glucose and lipid metabolism in acute myeloid leukemia cell lines.

Introduction: T-cell immunoglobulin and mucin domain-3 (TIM-3) is a transmembrane molecule first identified as an immunoregulator. This molecule is also expressed on leukemic cells in acute myeloid leukemia and master cell survival and proliferation. In this study, we aimed to explore the effect of TIM-3 interaction with its ligand galectin-9 (Gal-9) on glucose and lipid metabolism in AML cell lines. Methods: HL-60 and THP-1 cell lines, representing M3 and M5 AML subtypes, respectively, were cultured under appropriate conditions. The expression of TIM-3 on the cell surface was ascertained by flow cytometric assay. We used real-time PCR to examine the mRNA expression of GLUT-1, HK-2, PFKFB-3, G6PD, ACC-1, ATGL, and CPT-1A; colorimetric assays to measure the concentration of glucose, lactate, GSH, and the enzymatic activity of G6PD; MTT assay to determine cellular proliferation; and gas chromatography-mass spectrometry (GC-MS) to designate FFAs. Results: We observed the significant upregulated expression of GLUT-1, HK-2, PFKFB-3, ACC-1, CPT-1A, and G6PD and the enzymatic activity of G6PD in a time-dependent manner in the presence of Gal-9 compared to the PMA and control groups in both HL-60 and THP-1 cell lines (p > 0.05). Moreover, the elevation of extracellular free fatty acids, glucose consumption, lactate release, the concentration of cellular glutathione (GSH) and cell proliferation were significantly higher in the presence of Gal-9 compared to the PMA and control groups in both cell lines (p < 0.05). Conclusion: TIM-3/Gal-9 ligation on AML cell lines results in aerobic glycolysis and altered lipid metabolism and also protects cells from oxidative stress, all in favor of leukemic cell survival and proliferation.

Lactate dehydrogenase A inhibition prevents RANKL-induced osteoclastogenesis by reducing enhanced glycolysis.

Osteoclasts are multinucleated, specializes bone-resorbing cells that are derived from the monocyte/macrophage lineage. Excessive resorbing activities of osteoclasts are involved in destructive bone diseases. The detailed mechanism of acidification at the bone adhesion surface during the bone resorption process of osteoclasts remains to be defined. During glycolysis, pyruvate proceeds to the tricarboxylic cycle under aerobic conditions and pyruvate is converted to lactate via lactate dehydrogenase A (LDHA) under anaerobic conditions. However, tumor cells produce ATP during aerobic glycolysis and large amounts of pyruvate are converted to lactate and H+ by LDHA. Lactate and H+ are excreted outside the cell, whereby they are involved in invasion of tumor cells due to the pH drop around the cell. In this study, we focused on aerobic glycolysis and investigated the production of lactate by LDHA in osteoclasts. Expression of LDHA and monocarboxylate transporter 4 (MCT4) was upregulated during osteoclast differentiation. Intracellular and extracellular lactate levels increased with upregulation of LDHA and MCT4, respectively. FX11 (an LDHA inhibitor) inhibited osteoclast differentiation and suppressed the bone-resorbing activity of osteoclasts. We propose that inhibition of LDHA may represent a novel therapeutic strategy for controlling excessive bone resorption in osteoporosis and rheumatoid arthritis.

Prognostic factors and evaluation methods of acute kidney injury among sepsis patients with pulmonary infection.

OBJECTIVE: Acute kidney injury (AKI) is difficult to detect in the early stages, yet is commonly associated with sepsis and infectious shock, with pulmonary infection being the most frequent culprit. This study aimed to estimate risk factors and their effects on 28-day survival among sepsis patients with pulmonary infection complicated by AKI and assessed the prognostic values of some detection indicators. PATIENTS AND METHODS: From February 2019 to July 2021, the data of 151 patients admitted to the emergency intensive care unit (EICU) of Nanjing First Hospital with pulmonary infection complicated with sepsis were collected in this retrospective study. The patients were categorized into two groups (survivors and non-survivors) depending on the 28-day survival, compared their clinical characteristics, and analyzed the predictors of survival. RESULTS: Cox regression analysis revealed that serum cystatin-C level, serum lactate level, and the Acute Physiology and Chronic Health Evaluation II (APACHE II) scoring system were independent risk factors for 28-day survival. In predicting 28-day survival, the area under the receiver operating characteristic curve (ROC) for serum Cystatin-C level, serum lactate level, APACHE II score, and the three combinations was 0.74, 0.67, 0.71, and 0.86, respectively. Accordingly, the sensitivity and specificity of the three indicators of 28-day survival were 87.50% and 66.67%, respectively, which were superior to individual indicators. CONCLUSIONS: Sepsis patients with pulmonary infection have a high risk of AKI, and multiple risk factors contribute to this risk. AKI patients may also be adversely affected by a variety of factors, including APACHE II scores, serum Cystatin-C levels, and serum lactate levels, all of which are commonly used to assess the outcomes.

A systemic analysis of monocarboxylate transporters in ovarian cancer and possible therapeutic interventions.

Monocarboxylate transporters (MCTs) play an immense role in metabolically active solid tumors by regulating concentration-dependent transport of different important monocarboxylates including pyruvate and lactate and are encoded by the SLC16A family of genes. Given the vast array of functions, these transporters play in oncogenesis, our objective was to look into the association of MCT1 (SLC16A1), MCT2 (SLC16A7), MCT3 (SLC16A8), and MCT4 (SLC16A3) with Epithelial ovarian cancer (EOC) pathophysiology by exploiting various publicly available databases and web resources. Few of the in silico findings were confirmed via in vitro experiments in EOC cell lines, SKOV3 and OAW-42. MCT1 and MCT4 were found to be upregulated at the mRNA level in OC tissues compared to normal. However, only higher level of MCT4 mRNA was found to be associated with poor patient survival. MCT4 was positively correlated with gene families responsible for invasion, migration, and immune modification, proving it to be one of the most important MCTs for therapeutic intervention. We compared the effects of MCT1/2 blocker SR13800 and a broad-spectrum MCT blocker α-Cyano Hydroxy Cinnamic Acid (α-CHCA) and discovered that α-CHCA has a greater effect on diminishing the invasive behavior of the cancer cells than MCT1/2 blocker SR13800. From our study, MCT4 has emerged as a prospective marker for predicting poor patient outcomes and a potential therapeutic target.

Intraoperative Use of Compensatory Reserve Measurement in Orthotopic Liver Transplant: Improved Sensitivity for the Prediction of Hypovolemic Events.

INTRODUCTION: The compensatory reserve measurement (CRM) is a continuous non-invasive monitoring technology that measures the summation of all physiological mechanisms involved in the compensatory response to central hypovolemia. The CRM is displayed on a 0% to 100% scale. The objective of this study is to characterize the use of CRM in the operative setting and determine its ability to predict hypovolemic events compared to standard vital signs. Orthotopic liver transplant was used as the reference procedure because of the predictable occurrence of significant hemodynamic shifts. METHODS: A prospective observational cohort study was conducted on 22 consecutive patients undergoing orthotopic liver transplant. The subjects were monitored in accordance with the standard of care. The CRM data were collected concurrently with intraoperative staff blinded to the outputs. The data were stored on secure devices on encrypted files. Based on prior literature, subgroup analysis was performed for high-tolerance (good compensators) and low-tolerance (poor compensators) groups, which was based on a shock index threshold of 0.9. Threshold events were defined as follows: CRM below 60% (CRM60), systolic blood pressure (SBP) below 90 mmHg (SBP90), and heart rate (HR) above 100 beats per minute (HR100). RESULTS: Complete data were captured in 22 subjects as a result of device malfunction or procedure cancellation. Sensitivity analysis was performed for the detection of hypovolemia at the time of the event. CRM60 was the most sensitive (62.6%) when compared to other threshold measures such as SBP90 (30.6%), HR100 (23.1%), elevated lactate (54.6%), and a drop in hemoglobin (41.7%). The number of patients meeting the CRM60 threshold at the time of the first transfusion (TFX) was higher when compared to SBP90 and HR100 in the overall group (P = .001 and P < .001, respectively) and both the high-tolerance (P = .002 and P = .001, respectively) and low-tolerance groups (P = .016 and P = .001, respectively). Similar results supporting the higher sensitivity of CRM were observed when comparing the number of patients below the threshold at the time of the first vasopressor administration. Start time was standardized so that the time-to-threshold signals for hemodynamic and laboratory parameters could be compared. The median time-to-CRM signal detection before the TFX event was -15.0 minutes (i.e., 15 minutes before TFX). There was no difference when compared to the SBP threshold (median time -5.0 minutes, P = .64) but was significantly sooner when compared to HR (P = .006), lactate (P = .002), and hemoglobin (P < .001). CONCLUSIONS: At the time of the first TFX, the CRM had a higher rate of detection of a hypovolemic event compared to SBP and HR, indicating a higher sensitivity for the detection of the first hypovolemic event. When combined with all hypovolemic events, sensitivity analysis showed that CRM60 provides the earlier predictive capability. Given that SBP is the clinical standard of care for the initiation of TFX, the finding that median time to event detection was statistically similar between CRM60 and SBP90 was not unexpected. When compared to other measures of hypovolemia, the CRM consistently showed earlier detection of hypovolemic events. Although this study had a small sample size, it produced significant results and can serve as a proof of concept for future large-scale studies.

Plant Life with and without Oxygen: A Metabolomics Approach.

Oxygen deficiency is an environmental challenge which affects plant growth, the development and distribution in land and aquatic ecosystems, as well as crop yield losses worldwide. The capacity to exist in the conditions of deficiency or the complete lack of oxygen depends on a number of anatomic, developmental and molecular adaptations. The lack of molecular oxygen leads to an inhibition of aerobic respiration, which causes energy starvation and the acceleration of glycolysis passing into fermentations. We focus on systemic metabolic alterations revealed with the different approaches of metabolomics. Oxygen deprivation stimulates the accumulation of glucose, pyruvate and lactate, indicating the acceleration of the sugar metabolism, glycolysis and lactic fermentation, respectively. Among the Krebs-cycle metabolites, only the succinate level increases. Amino acids related to glycolysis, including the phosphoglycerate family (Ser and Gly), shikimate family (Phe, Tyr and Trp) and pyruvate family (Ala, Leu and Val), are greatly elevated. Members of the Asp family (Asn, Lys, Met, Thr and Ile), as well as the Glu family (Glu, Pro, Arg and GABA), accumulate as well. These metabolites are important members of the metabolic signature of oxygen deficiency in plants, linking glycolysis with an altered Krebs cycle and allowing alternative pathways of NAD(P)H reoxidation to avoid the excessive accumulation of toxic fermentation products (lactate, acetaldehyde, ethanol). Reoxygenation induces the downregulation of the levels of major anaerobically induced metabolites, including lactate, succinate and amino acids, especially members of the pyruvate family (Ala, Leu and Val), Tyr and Glu family (GABA and Glu) and Asp family (Asn, Met, Thr and Ile). The metabolic profiles during native and environmental hypoxia are rather similar, consisting in the accumulation of fermentation products, succinate, fumarate and amino acids, particularly Ala, Gly and GABA. The most intriguing fact is that metabolic alterations during oxidative stress are very much similar, with plant response to oxygen deprivation but not to reoxygenation.

Dynamics of Capillary Lactate Levels in Patients with Out-of-Hospital Cardiac Arrest.

Background and Objectives: An effective strategy for cardiopulmonary resuscitation should be based on tissue perfusion. Our primary aim was to determine the association between capillary lactate values and initial rhythm as well as the probability of the return of spontaneous circulation in out-of-hospital cardiac arrest patients. Materials and Methods: This prospective observational cohort study included all patients with non-traumatic out-of-hospital cardiac arrest, older than 18 years, resuscitated by a prehospital emergency medical team between April 2020 and June 2021. Capillary lactate samples were collected at the time of arrival and every 10 min after the first measurement until the time of the return of spontaneous circulation (ROSC) or, if ROSC was not achieved, at the time of declaring death on the scene. Results: In total, 83 patients were enrolled in the study. ROSC was achieved in 28 patients (33.7%), 21 were admitted to hospital (26.3%), and 6 (7.23%) of them were discharged from hospital. At discharge, all patients had Cerebral Performance Category Scale 1 or 2. Initial capillary lactate values were significantly higher in patients with a non-shockable rhythm compared to the group with a shockable rhythm (9.19 ± 4.6 versus 6.43 ± 3.81; p = 0.037). A significant difference also persisted in a second value taken 10 min after the initial value (10.03 ± 5,19 versus 5.18 ± 3.47; p = 0.019). Capillary lactate values were higher in the ROSC group and non-ROSC group at the time of restored circulation (11.10 ± 6.59 and 6.77 ± 4.23, respectively; p = 0.047). Conclusions: Capillary lactate values are significantly higher in patients with a non-shockable first rhythm in out-of-hospital cardiac arrest (OHCA). There is also a significantly different rise in capillary lactate levels in patients with ROSC.

Progesterone Activates the Histone Lactylation-Hif1α-glycolysis Feedback Loop to Promote Decidualization.

Decidualization is a progesterone-dependent cellular differentiation process that is essential for establishing pregnancy. Robust activation of glycolysis and lactate synthesis during decidualization is remarkable, but their developmental functions remain largely unknown. Herein, we identify that endometrial lactate production plays a critical role in establishing local histone lactylation, a newly identified histone modification, and is important for ensuring normal decidualization. Enhanced endometrial glycolysis is the hallmark metabolic change and is tightly coupled with H4K12la during decidualization. Inhibition of histone lactylation impaired decidualization, in either physiological conception or in vivo and in vitro induced decidualization models. Mechanistic study based on CUT&Tag and ATAC-seq revealed that a transcriptional factor hypoxia-inducible factor 1 α (Hif1α) is the critical regulatory target of H4K12la, and in turn forms an H4K12la-Hif1α-glycolysis feedback loop to drive decidualization. Moreover, we demonstrate that the loop is directly activated by progesterone during decidualization. Our study not only advances the current knowledge of the role of lactate in regulating uterine function, but also establishes a novel functional link among the major endocrine factors, endometrial metabolic change, and epigenetic modification during endometrial remodeling. These findings present valuable clues to develop clinical intervention strategies to improve pregnancy outcomes following both natural conception and assisted reproduction.

Risk factors for in-hospital mortality after emergency colorectal surgery in octogenarians: results of a cohort study from a referral center.

PURPOSE: The objective of this study was to investigate predictive factors of mortality in emergency colorectal surgery in octogenarian patients. METHODS: It is a retrospective cohort study conducted at a single-institution tertiary referral center. Consecutive patients who underwent emergency colorectal surgery between January 2015 and January 2020 were identified. The primary endpoint was 30-day mortality. Univariate and multivariate analyses were performed using a logistic regression model. RESULTS: A total of 111 patients were identified (43 men, 68 women). Mean age was 85.7 ± 3.7 years (80-96). Main diagnoses included complicated sigmoiditis in 38 patients (34.3%), cancer in 35 patients (31.5%), and ischemic colitis in 31 patients (27.9%). An ASA score of 3 or higher was observed in 88.3% of patients. The mean Charlson score was 5.9. The Possum score was 35.9% for mortality and 79.3% for morbidity. The 30-day mortality rate was 25.2%. Univariate analysis of preoperative risk factors for mortality shows that the history of valvular heart disease (p = 0.008), intensive care unit provenance (p = 0.003), preoperative sepsis (p < 0.001), diagnosis of ischemic colitis (p = 0.012), creatinine (p = 0.006) and lactate levels (p = 0.01) were significantly associated with 30-day mortality, and patients coming from home had a lower 30-day mortality rate (p = 0.018). Intraoperative variables associated with 30-day mortality included ileostomy creation (p = 0.022) and temporary laparostomy (p = 0.004). At multivariate analysis, only lactate (p = 0.032) and creatinine levels (p = 0.027) were found to be independent predictors of 30-day mortality, home provenance was an independent protective factor (p = 0.004). Mean follow-up was 3.4 years. Survival at 1 and 3 years was 57.6 and 47.7%. CONCLUSION: Emergency colorectal surgery is challenging. However, age should not be a contraindication. The 30-day mortality rate (25.2%) is one of the lowest in the literature. Hyperlactatemia (> 2mmol/L) and creatinine levels appear to be independent predictors of mortality.

High fat diet reveals sex-specific fecal and liver metabolic alterations in C57BL/6J obese mice.

Obesity is a major health concern that poses significant risks for many other diseases, including diabetes, cardiovascular disease, and cancer. Prevalence of these diseases varies by biological sex. This study utilizes a mouse (C57BL/6J) model of obesity to analyze liver and fecal metabolic profiles at various time points of dietary exposure: 5, 9, and 12 months in control or high fat diet (HFD)-exposed mice. Our study discovered that the female HFD group has a more discernable perturbation and set of significant changes in metabolic profiles than the male HFD group. In the female mice, HFD fecal metabolites including pyruvate, aspartate, and glutamate were lower than control diet-exposed mice after both 9th and 12th month exposure time points, while lactate and alanine were significantly downregulated only at the 12th month. Perturbations of liver metabolic profiles were observed in both male and female HFD groups, compared to controls at the 12th month. Overall, the female HFD group showed higher lactate and glutathione levels compared to controls, while the male HFD group showed higher levels of glutamine and taurine compared to controls. These metabolite-based findings in both fecal and liver samples for a diet-induced effect of obesity may help guide future pioneering discoveries relating to the analysis and prevention of obesity in people, especially for females.

Impact of combined chronic exposure to low-dose bisphenol A and fructose on serum adipocytokines and the energy target metabolome in white adipose tissue.

Background: Adipose tissue is a dynamic endocrine organ that plays a key role in regulating metabolic homeostasis. Previous studies confirmed that bisphenol A (BPA) or fructose can interfere with the function of adipose tissue. Nonetheless, knowledge on how exposure to BPA and fructose impacts energy metabolism in adipose tissue remains limited.Purpose: To determine impact of combined chronic exposure to low-dose bisphenol A and fructose on serum adipocytokines and the energy target metabolome in white adipose tissue.Method: 57 energy metabolic intermediates in adipose tissue and 7 adipocytokines in serum from Sprague Dawley rats were examined after combined exposure to two levels of BPA (lower dose: 0.25, and higher dose: 25 µg/kg every other day) and 5% fructose for 6 months.Results: combined exposure to lower-dose BPA and fructose significantly increased omentin-1, pyruvic acid, adenosine triphosphate (ATP), adenosine monophosphate (AMP), inosine monophosphate (IMP), inosine, and l-lactate; however, these parameters were not significantly affected by higher-dose BPA combined with fructose. Interestingly, the level of succinate (an intermediate of the citric acid cycle) increased dose-dependently in adipose tissue, and the level of apelin 13 (a versatile adipocytokine) decreased dose-dependently in serum after combined exposure to BPA and fructose. Phosphoenolpyruvic acid, phenyl-lactate, and ornithine were significantly correlated with asprosin, omentin-1, apelin, apelin 13, and adiponectin, while l-tyrosine was significantly correlated with irisin and a-FABP under combined exposure to BPA and fructose.Conclusions: these findings indicated that lower-dose BPA combined with fructose could amplify the impact on glycolysis, energy storage, and purine nucleotide biosynthesis in adipose tissue, and adipocytokines, such as omentin-1 and apelin 13, may be related to metabolic interference induced by BPA and fructose exposure.

The Effects of 24-h Fasting on Exercise Performance and Metabolic Parameters in a Pilot Study of Female CrossFit Athletes.

Many studies have tested intermittent fasting (IF) in athletes, but its effects on female CrossFit athletes remain relatively unexplored in the existing literature. The aim of this study was to evaluate and compare the effects of 24-h IF on the physical performance of female CrossFit practitioners. Eleven female CrossFit athletes (age: 30.91 ± 3.42, weight: 65.26 ± 7.55 kg, height: 1.66 ± 0.05 m) participated in the study. The study used a crossover design with fasting and eating conditions. Participants completed an exercise test, standing long jump, and handgrip strength assessment. Hydration status, heart rate, blood lactate, blood glucose, rates of perceived exertion, and hunger were measured. Results showed significant differences in blood lactate concentration (F = 5.435, p = 0.042, η2p = 0.352). Resting blood lactate concentration was significantly lower in the fasting trial than in the eating trial (p < 0.001), but post-exercise blood lactate concentrations were higher in the fasting trial than in the eating trial (p < 0.001). No differences were found in performance times (p > 0.05). In conclusion, this pilot study of females suggests that 24-h fasting does not impair exercise performance or negatively affect physiological parameters in CrossFit athletes.

Effects of a forced-air warming system and warmed intravenous fluids on hemodynamic parameters, shivering, and time to awakening in elderly patients undergoing open cardiac surgery.

Background: As one of the most common postoperative complications, hypothermia is the main cause of numerous problems during treatment, especially in elderly patients with decreased cardiac reserves. Objectives: The aim of the present study was to compare the effects of forced-air warming system (FAWS), warmed intravenous fluids (WIVFs) and routine method on hemodynamic parameters, arterial blood gases (ABGs), shivering, and time to awakening in elderly patients undergoing open cardiac surgery (OCS). Methods: This clinical randomized controlled trial was conducted on 94 elderly patients who underwent OCS at Ayatollah Rouhani Hospital, Babol, Iran. They were divided into three groups, namely FAWS (n=31), WIVFs (n=31) and routine rewarming method (RRWM, with a blanket) (n=32). The data were then recorded in a checklist. Descriptive and inferential statistics were performed using SPSS 26 at a significance level of less than 0.05. Results: The findings demonstrated that the degree of hypothermia had a significant decreasing trend in the groups receiving FAWS and WIVFs (P=0.002). Additionally, increased respiratory rate (P=0.013), higher bicarbonate (HCO3-) levels on arrival up to 4 hours after surgery (P=0.045), reduced lactate level (P=0.005), normal base excess (BE) and accelerated time to awakening (P=0.004) were observed in patients receiving FAWS. There was no significant difference in the study groups regarding shivering. Conclusion: The results revealed that FAWS could mitigate the degree of hypothermia, increase body temperature and decrease the postoperative serum lactate levels. Moreover, BE as one of the most important parameters for ABGs, could remain at a normal level. Besides, the use of FAWS could lead to early awakening, and thus facilitate weaning and extubation of these patients.

Glucose upregulates amphiregulin in oral dysplastic keratinocytes: A potential role in diabetes-associated oral carcinogenesis.

BACKGROUND: Compelling evidence implicates diabetes-associated hyperglycemia as a promoter of tumor progression in oral potentially malignant disorders (OPMD). Yet, information on hyperglycemia-induced cell signaling networks in oral oncology remains limited. Our group recently reported that glucose-rich conditions significantly enhance oral dysplastic keratinocyte viability and migration through epidermal growth factor receptor (EGFR) activation, a pathway strongly linked to oral carcinogenesis. Here, we investigated the basal metabolic phenotype in these cells and whether specific glucose-responsive EGFR ligands mediate these responses. METHODS: Cell energy phenotype and lactate concentration were evaluated via commercially available assays. EGFR ligands in response to normal (5 mM) or high (20 mM) glucose were analyzed by quantitative real-time PCR, ELISA, and western blotting. Cell viability and migration assays were performed in the presence of pharmacological inhibitors or RNA interference. RESULTS: When compared to normal keratinocytes, basal glycolysis in oral dysplastic keratinocytes was significantly elevated. In highly glycolytic cells, high glucose-activated EGFR increasing viability and migration. Notably, we identified amphiregulin (AREG) as the predominant glucose-induced EGFR ligand. Indeed, enhanced cell migration in response to high glucose was blunted by EGFR inhibitor cetuximab and AREG siRNA. Conversely, AREG treatment under normal glucose conditions significantly increased cell viability, migration, lactate levels, and expression of glycolytic marker pyruvate kinase M2. CONCLUSION: These novel findings point to AREG as a potential high glucose-induced EGFR activating ligand in highly glycolytic oral dysplastic keratinocytes. Future studies are warranted to gain more insight into the role of AREG in hyperglycemia-associated OPMD tumor progression.

Circular RNA P4HB promotes glycolysis and tumor progression by binding with PKM2 in lung adenocarcinoma.

BACKGROUND: Emerging evidence indicates that circular RNAs (circRNAs) play vital roles in tumor progression, including lung adenocarcinomas (LUAD). However, the mechanisms by which circRNAs promote the progression of LUAD still require further investigation. METHODS: Quantitative real-time PCR was performed to detect the expression of circP4HB in LUAD tissues and cells. Then, Kaplan-Meier analysis was used to determine the prognostic value of circP4HB expression. We employed RNA pull-down, RNA immunoprecipitation, mass spectrometry, cells fraction, glucose consumption, lactate production, pyruvate kinase M2 (PKM2) activity, and macrophage polarization assays to uncover the underlying mechanisms of circP4HB in LUAD. RESULTS: We found that circP4HB is upregulated in LUAD tissues and correlated with advanced TNM stages and lymph node metastasis. LUAD patients with high circP4HB expression had poor prognoses. Functionally, circP4HB promoted LUAD progression in vivo and in vitro. Upregulated circP4HB increased glucose consumption, lactate production and accelerated aerobic glycolysis in LUAD cells. Mechanically, circP4HB mainly accumulated in the cytoplasm of LUAD cells and bound with PKM2 and subsequently upregulating PKM2 enzymatic activity by increasing its tetramer formation. Additionally, circP4HB promoted M2 macrophage phenotype shift via targeting PKM2. Finally, rescue assays further confirmed that circP4HB could promote LUAD cell progression through its interaction with PKM2. CONCLUSION: These results demonstrate that circP4HB could promote LUAD progression, indicating circP4HB might be a potential therapeutic target of LUAD.

Maintenance of internal load despite a stepwise reduction in external load during moderate intensity heart rate clamped cycling with acute graded normobaric hypoxia in males.

OBJECTIVES: To investigate the acute effects of graded hypoxia on external and internal loads during 60 min of endurance cycling at a clamped heart rate. DESIGN: Repeated measures. METHODS: On separate visits, 16 trained males cycled for 60 min at a clamped heart rate corresponding to 80 % of their first ventilatory threshold at sea-level and 2500 m, 3000 m, 3500 m and 4000 m simulated altitudes (inspired oxygen fractions of 20.9 %, 15.4 %, 14.5 %, 13.6 % and 12.7 %, respectively). Markers of external (power output) and internal (blood lactate concentration, tissue saturation index, cardio-respiratory and perceptual responses) loads were measured every 15 min during cycling. Neuromuscular function of knee extensors was characterised pre- and post-exercise. RESULTS: Compared to sea-level (101 ±â€¯22 W), there was a stepwise reduction in power output with increasing hypoxia severity (-17.9 ±â€¯8.9 %, -27.1 ±â€¯10.7 %, -34.2 ±â€¯12.0 % and - 44.6 ±â€¯15.1 % at 2500 m, 3000 m, 3500 m, and 4000 m, respectively, all p < 0.05). Blood lactate and tissue saturation index were not different across hypoxia severities, and perceptual responses were exacerbated at 4000 m only, with increased breathing difficulty. Knee extensor torque decreased post-exercise (-14.5 ±â€¯9.0 %, p < 0.05), independent of condition. CONCLUSIONS: Increasing hypoxia severity reduces cycling power output and arterial oxygen saturation in a stepwise fashion without affecting exercise responses between sea-level and simulated altitudes up to 3500 m despite breathing difficulty being elevated at 4000 m.

Training vs. racing: A comparison of arrhythmias and the repeatability of findings in Thoroughbred Chuckwagon racehorses.

Arrhythmias are commonly reported in exercising horses, however due to regulatory constraints electrocardiograms (ECGs) are acquired during training but not competition, raising questions about the repeatability of findings. The aims were (1) compare training and competition arrhythmias and (2) describe the repeatability of arrhythmias during maximal-intensity exercise. A convenience sample of 52 healthy Thoroughbreds (aged 8.7 ± 2.5 years) competing in the World Professional Chuckwagon Association were obtained, totaling 152 training or competition ECGs (2-7 ECGs/horse). Speed, heart rate (HR) and arrhythmias (supraventricular premature complex, SVPC; ventricular premature complex, VPC) were examined. Pre- and post-recovery (approximately 6 min) blood samples measured lactate and high-sensitivity troponin-T. Training and competition arrythmias were compared (Friedman's test) and reliability of repeated ECGs assessed (intraclass correlation; P < 0.05). Training vs. competition: Forty horses had clean tracing from training and competition (n = 80 ECGs); the number and type of arrhythmias were not different. In training, VPCs were present in 7/40 horses (median [interquartile range, IQR]/ECG; range; 0 [0,0]; 0-4) and 9/40 horses (0 [0,0]; 0-5) in active-recovery. In competition, VPCs were present in 7/40 horses (0 [0,0]; 0-8) and 8/40 horses (0 [0,0]; 0-5) in active-recovery. Arrhythmias were primarily single premature complexes. Training and competition speed, HR, lactate and troponin-T did not differ however, sampling was too early for peak serum Troponin-T levels. Repeatability: total arrhythmias between serial ECGs did not differ. The reliability to detect SVPCs and VPCs was poor to moderate, and poor, respectively. Overall, the total number of arrhythmias was repeatable, but the reliability of arrhythmia type was poor to moderate.