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Intrahepatic cholangiocarcinoma (iCCA) is a fatal malignancy of the biliary system. The lack of a detailed understanding of oncogenic signaling or global gene expression alterations has impeded clinical iCCA diagnosis and therapy. The role of protein lactylation, a newly unraveled post-translational modification that orchestrates gene expression, remains largely elusive in the pathogenesis of iCCA. Proteomics analysis of clinical iCCA specimens and adjacent tissues was performed to screen for proteins aberrantly lactylated in iCCA. Mass spectrometry, macromolecule interaction and cell behavioral studies were employed to identify the specific lactylation sites on the candidate protein(s) and to decipher the downstream mechanisms responsible for iCCA development, which were subsequently validated using a xenograft tumor model and clinical samples. Nucleolin (NCL), the most abundant RNA-binding protein in the nucleolus, was identified as a functional lactylation target that correlates with iCCA occurrence and progression. NCL was lactylated predominantly at lysine 477 by the acyltransferase P300 in response to a hyperactivity of glycolysis, and promoted the proliferation and invasion of iCCA cells. Mechanistically, lactylated NCL bound to the primary transcript of MAP kinase-activating death domain protein (MADD) and led to efficient translation of MADD by circumventing alternative splicing that generates a premature termination codon. NCL lactylation, MADD translation and subsequent ERK activation promoted xenograft tumor growth and were associated with overall survival in patients with iCCA. NCL is lactylated to upregulate MADD through an RNA splicing-dependent mechanism, which potentiates iCCA pathogenesis via the MAPK pathway. Our findings reveal a novel link between metabolic reprogramming and canonical tumor-initiating events, and uncover biomarkers that can potentially be used for prognostic evaluation or targeted treatment of iCCA. Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive liver malignancy with largely uncharacterized pathogenetic mechanisms. Herein, we demonstrated that glycolysis promotes P300-catalyzed lactylation of nucleolin, which upregulates MAP kinase-activating death domain protein (MADD) through precise mRNA splicing and activates ERK signaling to drive iCCA development. These findings unravel a novel link between metabolic rewiring and canonical oncogenic pathways, and reveal new biomarkers for prognostic assessment and targeting of clinical iCCA. [Display omitted] • Nucleolin is a lactylation target that mediates iCCA pathogenesis. • Nucleolin is lactylated predominantly at lysine 477 by P300 in glycolytic iCCA cells. • Lactylated nucleolin upregulates MADD by preventing RNA mis-splicing. • Lactylated nucleolin/MADD/pERK predicts poor prognosis of patients with iCCA. [ABSTRACT FROM AUTHOR]

Utilizing ammonium in wastewater is a prospective way to reduce costs for bioproduction by photosynthetic organisms. A model cyanobacterium Synechocystis sp. PCC 6803 takes advantage of tolerance to ammonium compared to other microalgae. However, in this study, we report that Synechocystis growth was inhibited when cultured in a medium containing ammonium. This may be due to the pH decreasing below 6 caused by consuming ammonium. Transcriptomic analysis by RNA-seq revealed that the expression of the genes for proteases, chaperones, and antioxidant-scavenging enzymes was induced, but photosynthetic components were repressed. Although these regulations are similar to the previous studies on acidic stress in nitrate-containing culture, the expression of genes such as sigD , slr0042 , slr0373 , slr0374 , and slr1501 was different, indicating that these phenomena are not simply identical to the known responses to acidic stress. The expression of the genes for photosynthesis, gluconeogenesis, and nitrogen assimilation was repressed, and glycolysis and the tricarboxylic acid cycle were induced. Despite the up-regulation of the carbon catabolism and down-regulation of nitrogen assimilation, the 2-oxoglutarate content in the ammonium-grown cells was lower than that in the nitrate-grown cells, and the contents of the major amino acids, such as Glu, Ala, Asp, and Gly were decreased, while the minor amino acids were the same or increased, especially Arg, Lys, Val, and Ile. These results demonstrated that the acidic stress induced by the consumption of ammonium ions differs from the sudden pH drop, and the Synechocystis cell manages amino acid levels to endure carbon limitation under the stress. [ABSTRACT FROM AUTHOR]

The microenvironment within solid tumors often becomes acidic due to various factors associated with abnormal metabolism and cellular activities, including increased lactate production as a result of dysregulated tumor glycolysis. Recently, we have identified multiple tumor microenvironment (TME) factors that potentiate regulatory T (T reg) cell function in evading anti-tumor immunosurveillance. Despite the strong correlation between lactate and acidity, the potential roles of acidity in intratumoral T reg cell adaptation and underlying molecular mechanisms have gone largely unstudied. In this study, we demonstrate that acidity significantly enhances immunosuppressive functions of nT reg cells, but not iT reg cells, without altering the expression of either FoxP3 or the cell surface receptors CD25, CTLA4, or GITR in these cells. Surprisingly, the addition of lactate, often considered a major contributor to increased acidity of the TME, completely abolished the acidity-induced enhancement of nT reg suppressive functions. Consistently, metabolic flux analyses showed elevated basal mitochondrial respiratory capacity and ATP-coupled respiration in acidity-treated nT reg cells without altering glycolytic capacity. Genome-wide transcriptome and metabolomics analyses revealed alterations in multiple metabolic pathways, particularly the one-carbon folate metabolism pathway, with reduced SAM, folate, and glutathione, in nT reg cells exposed to low pH conditions. Addition of a one-carbon metabolic contributor, formate, diminished the acidity-induced enhancement in nT reg cell suppressive functions, but neither SAM nor glutathione could reverse the phenotype. Remarkably, in vitro transient treatment of nT reg cells resulted in sustained enhancement of their functions, as evidenced by more vigorous tumor growth observed in mice adoptively receiving acidity-treated nT reg cells. Further analysis of intratumoral infiltrated T cells confirmed a significant reduction in CD8+ T cell frequency and their granzyme B production. In summary, our study elucidates how acidity-mediated metabolic reprogramming leads to sustained Treg-mediated tumor immune evasion. • Acidity enhances T reg cell suppressive functions independent of lactate in vitro and in vivo. • T reg cell oxidative metabolic capacity increases as a result of exposure to acidity. • Treatment with acidity results in T reg cell transcriptional and metabolic changes in one-carbon folate metabolism. • Exposure to acidity ex vivo for 48 hours facilitates increased T reg suppressive functions against T eff cells in the TME and promotes tumor growth in the MC38 colon cancer model. • Treatment of T reg cells with acidity and formate restores suppressive capacity induced by acidity and decreases tumor burden in the MC38 colon cancer model. [ABSTRACT FROM AUTHOR]

Sugar serves as the primary energy source for mammals, with glucose metabolism facilitating energy acquisition in human cells. The proper functioning of intracellular glucose metabolism is essential for the maintenance of orderly and healthy physiological activities. Tumor cells, characterized by uncontrolled growth, exhibit dysregulated proliferation and apoptosis processes, leading to abnormal alterations in glucose metabolism. Specifically, tumor cells exhibit a shift towards aerobic glycolysis, resulting in the production of lactic acid that can be utilized as a metabolic intermediate for sustained tumor cell growth. This article provides a comprehensive overview of the enzymes involved in glucose metabolism and the alterations in gene expression that occur during tumor progression. It also examines the current research on targeting abnormal glucose metabolism processes for tumor treatment and discusses potential future directions for utilizing glucose metabolism as a therapeutic target. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is recognized as an aggressive cancer that is characterized by significant metabolic reprogramming. Here, we applied spatial metabolomics to achieve high-throughput, in situ identification of metabolites within the liver metastases of AML mice. Alterations at metabolite and protein levels were further mapped out and validated by integrating untargeted metabolomics and proteomics. This study showed a downregulation in arginine's contribution to polyamine biosynthesis and urea cycle, coupled with an upregulation of the creatine metabolism. The upregulation of creatine synthetases Gatm and Gamt, as well as the creatine transporter Slc6a8, resulted in a marked accumulation of creatine within tumor foci. This process further enhances oxidative phosphorylation and glycolysis of leukemia cells, thereby boosting ATP production to foster proliferation and infiltration. Importantly, we discovered that inhibiting Slc6a8 can counter these detrimental effects, offering a new strategy for treating AML by targeting metabolic pathways. The creatine pathway significantly upregulated in the metabolic reprogramming of AML mice, driven by both biosynthesis and the creatine transporter Slc6a8. The elevated creatine supports metastatic leukemia cell survival by enhancing OXPHOS and glycolysis. The Slc6a8 inhibitor ompenaclid could effectively inhibit AML cell proliferation and infiltration both in vitro and in vivo. [Display omitted] [ABSTRACT FROM AUTHOR]

Intervertebral Disc Degeneration (IVDD) is one of the leading causes of low back pain, significantly impacting both individuals and society. This study aimed to investigate the significance of macrophage infiltration and the role of macrophage-secreted platelet-derived growth factor-BB (PDGF-BB) in IVDD progression. To confirm the protective function of macrophage-derived PDGF-BB on nucleus pulposus cells (NPCs), we employed Lysm-Cre transgenic mice to genetically ablate PDGF-B within the myeloid cells. Immunohistochemistry was utilized to detect the expression of glycolytic enzymes and pyroptosis-related proteins during the process of IVDD. Western blot, RT-PCR, ELISA and immunofluorescence were used to detect the protective effect of recombinant PDGF-BB on NPCs. Macrophage-derived PDGF-BB deficiency resulted in the loss of NPCs and the increased ossification of cartilage endplates during lumbar disc degeneration. Also, PDGF-BB deficiency triggered the inhibition of glycolytic enzymes' expression and the activation of pathways related to pyroptosis in the nucleus pulposus. Mechanistically, our results suggest that PDGF-BB predominantly conveys its protective influence on NPCs through the PDGF receptor- beta (PDGFR-β)/ thioredoxin-interacting protein pathway. The absence of PDGF-BB originating from macrophages expedites the advancement of IVDD, whereas the application of PDGF-BB treatment holds the potential for retarding intervertebral disc degeneration in the human body. [ABSTRACT FROM AUTHOR]

Mitochondrial transporters facilitate the translocation of metabolites between the cytoplasm and mitochondria and are critical for mitochondrial functional integrity. Although many mitochondrial transporters are associated with metabolic diseases, how they regulate mitochondrial function and their metabolic contributions at the cellular level are largely unknown. Here, we show that mitochondrial thiamine pyrophosphate (TPP) transporter SLC25A19 is required for mitochondrial respiration. SLC25A19 deficiency leads to reduced cell viability, increased integrated stress response (ISR), enhanced glycolysis and elevated cell sensitivity to 2-deoxyglucose (2-DG) treatment. Through a series of biochemical assays, we found that the depletion of mitochondrial NADH is the primary cause of the impaired mitochondrial respiration in SLC25A19 deficient cells. We also showed involvement of SLC25A19 in regulating the enzymatic activities of complexes I and III, the tricarboxylic acid (TCA) cycle, malate-aspartate shuttle and amino acid metabolism. Consistently, addition of idebenone, an analog of coenzyme Q10, restores mitochondrial respiration and cell viability in SLC25A19 deficient cells. Together, our findings provide new insight into the functions of SLC25A19 in mitochondrial and cellular physiology, and suggest that restoring mitochondrial respiration could be a novel strategy for treating SLC25A19-associated disorders. [Display omitted] • Loss of SLC25A19 leads to mitochondrial NADH depletion, thereby inhibiting mitochondrial respiration. • SLC25A19 is required for complex I and complex III enzyme activities. • Loss of SLC25A19 causes mitochondrial integrated stress response. • Idebenone rescues mitochondrial respiration in SLC25A19 deficient cells. [ABSTRACT FROM AUTHOR]

Fibrosis is the tissue scarring characterized by excess deposition of extracellular matrix (ECM) proteins, mainly collagens. A fibrotic response can take place in any tissue of the body and is the result of an imbalanced reaction to inflammation and wound healing. Metabolism has emerged as a major driver of fibrotic diseases. While glycolytic shifts appear to be a key metabolic switch in activated stromal ECM-producing cells, several other cell types such as immune cells, whose functions are intricately connected to their metabolic characteristics, form a complex network of pro-fibrotic cellular crosstalk. This review purports to clarify shared and particular cellular responses and mechanisms across organs and etiologies. We discuss the impact of the cell-type specific metabolic reprogramming in fibrotic diseases in both experimental and human pathology settings, providing a rationale for new therapeutic interventions based on metabolism-targeted antifibrotic agents. [Display omitted] • Cell-type-specific metabolic alterations represent a major driver of organ fibrosis. • Defective mitochondrial function in parenchymal cells contributes to fibrogenesis. • Glycolysis is key for the activation of stromal extracellular matrix-producing cells. • Metabolism-targeting drugs have emerged as promising antifibrotic agents. [ABSTRACT FROM AUTHOR]

The circadian clock and cancer cell metabolism mutually regulate each other through regulation of oncogenes or the tumor microenvironment. Dysregulation of the circadian clock broadly impacts cancer cell metabolism and survival. The core clock genes possess noncanonical and transcription activity-independent functions to reprogram cancer cell metabolism. The circadian clock and cell metabolism are both dysregulated in cancer cells through intrinsic cell-autonomous mechanisms and external influences from the tumor microenvironment. The intricate interplay between the circadian clock and cancer cell metabolism exerts control over various metabolic processes, including aerobic glycolysis, de novo nucleotide synthesis, glutamine and protein metabolism, lipid metabolism, mitochondrial metabolism, and redox homeostasis in cancer cells. Importantly, oncogenic signaling can confer a moonlighting function on core clock genes, effectively reshaping cellular metabolism to fuel cancer cell proliferation and drive tumor growth. These interwoven regulatory mechanisms constitute a distinctive feature of cancer cell metabolism. [ABSTRACT FROM AUTHOR]

Vγ9Vδ2 T cells are under investigation as alternative effector cells for adoptive cell therapy (ACT) in cancer. Despite promising in vitro results, anti-tumor efficacies in early clinical studies have been lower than expected, which could be ascribed to the complex interplay of tumor and immune cell metabolism competing for the same nutrients in the tumor microenvironment. To contribute to the scarce knowledge regarding gamma delta T-cell metabolism, we investigated the metabolic phenotype of 25-day-expanded Vγ9Vδ2 T cells and how it is intertwined with functionality. We found that Vγ9Vδ2 T cells displayed a quiescent metabolism, utilizing both glycolysis and oxidative phosphorylation (OXPHOS) for energy production, as measured in Seahorse assays. Upon T-cell receptor activation, both pathways were upregulated, and inhibition with metabolic inhibitors showed that Vγ9Vδ2 T cells were dependent on glycolysis and the pentose phosphate pathway for proliferation. The dependency on glucose for proliferation was confirmed in glucose-free conditions. Cytotoxicity against malignant melanoma was reduced by glycolysis inhibition but not OXPHOS inhibition. These findings lay the groundwork for further studies on manipulation of Vγ9Vδ2 T-cell metabolism for improved ACT outcome. [Display omitted] [ABSTRACT FROM AUTHOR]

The autoimmune destruction of β-cells in type-1 diabetes (T1D) is a multifactorial and poorly understood phenomenon. A major contribution to this autoimmune attack is the generation of autoantigens triggered by β-cell dysfunction. Under hypoxia, cells shift to anaerobic glycolysis, regulated by hypoxia-inducible factor (HIF)-1α. This adaptation ensures energy production through increased glycolytic flux and decreased oxidative phosphorylation. Dysregulation of glycolysis contributes to β-cell dysfunction in diabetes. HIF-1α activation in β-cells impacts both in vivo and in vitro insulin secretion and systemic glucose levels. HIF-1α also modulates immune cell phenotype, potentially influencing autoimmune destruction of β-cells. Although more studies are needed, prolyl-hydroxylase inhibitors, which stabilize HIF-1α, show promise as T1D therapeutics by protecting β-cells against cellular stress. Type 1 diabetes (T1D) is a common autoimmune disease in which dysregulated glucose metabolism is a key feature. T1D is both poorly understood and in need of improved therapeutics. Hypoxia is frequently encountered in multiple tissues in T1D patients including the pancreas and sites of diabetic complications. Hypoxia-inducible factor (HIF)-1, a ubiquitous master regulator of the adaptive response to hypoxia, promotes glucose metabolism through transcriptional and non-transcriptional mechanisms and alters disease progression in multiple preclinical T1D models. However, how HIF-1 activation in β-cells of the pancreas and immune cells (two key cell types in T1D) ultimately affects disease progression remains controversial. We discuss recent advances in our understanding of the role of hypoxia/HIF-1-induced glycolysis in T1D and explore the possible use of drugs targeting this pathway as potential new therapeutics. [ABSTRACT FROM AUTHOR]

Virus infection is a major threat to human health and remains a significant cause of death to date. Macrophages are important innate immune cells that exhibit indispensable roles in controlling virus replication. It was recently reported that metabolic adaption determines the functional state of macrophages. Thus, to further unravel the crucial factors involving in metabolic adaption of macrophages might provide the potential candidates for optimizing their anti-viral capabilities. RT-PCR, Western blotting, virus plaque assay and HE were used to evaluate the viral load in virus-infected Tipe1 M-KO and Tipe1 f/f mice or cultured macrophages. RNA sequencing were performed with Tipe1 M-KOor Tipe1 f/f BMDMs upon virus infection. Extracellular acidification rate (ECAR) was applied for analyzing glycolysis rate in virus-infected BMDMs. Co-immunoprecipitation (Co-IP) assay and LC-MS/MS were used to determine the potential interacting proteins of TIPE1. TIPE1 level was significantly reduced in BMDMs infected with either RNA viruses or DNA virus. Deficiency of Tipe1 in macrophages increased viral load and aggravated tissue damage. Mechanistically, TIPE1 suppressed the glycolytic capacity of macrophages through interacting with PKM2 and promoting its ubiquitination degradation, which in turn decreased HIF1α transcription and viral replication in macrophages. TIPE1 functions as a novel regulator for metabolic reprogramming and virus infection in macrophages. [Display omitted] • TIPE1 restricts viral replication in macrophages. • TIPE1 curtails glycolytic metabolism in virus-infected macrophages. • TIPE1 interacts with PKM2 and promotes its ubiquitination degradation. • TIPE1 disturbs PKM2/HIF1α regulatory loop leading to glycolytic reprogramming of macrophages. [ABSTRACT FROM AUTHOR]

Cancer and senescent cells share many metabolic features that contribute to their common and unique cellular states. Senescent cells alter both glucose and non-glucose metabolism, including glycolysis, mitochondrial respiration, fatty acid oxidation, and glutaminolysis, to meet their bioenergetic, biosynthetic, and redox homeostatic needs. Senescent cells sustain metabolic signaling pathways in a hardwired manner to direct their metabolic alterations toward pathological anabolic processes. Senescent cells may rely on protein degradation pathways to mitigate errors caused by their hyperactivated anabolism, such as the senescence-associated secretory phenotype (SASP). Targeting senescence metabolism, analogous to targeting cancer metabolism, sensitizes senescent cells or suppresses the SASP, thereby serving as a new therapeutic modality for senotherapy. Cellular metabolism is a flexible and plastic network that often dictates physiological and pathological states of the cell, including differentiation, cancer, and aging. Recent advances in cancer metabolism represent a tremendous opportunity to treat cancer by targeting its altered metabolism. Interestingly, despite their stable growth arrest, senescent cells – a critical component of the aging process – undergo metabolic changes similar to cancer metabolism. A deeper understanding of the similarities and differences between these disparate pathological conditions will help identify which metabolic reprogramming is most relevant to the therapeutic liabilities of senescence. Here, we compare and contrast cancer and senescence metabolism and discuss how metabolic therapies can be established as a new modality of senotherapy for healthy aging. [ABSTRACT FROM AUTHOR]

Studies have shown that EMT (epithelial-mesenchymal transition) and energy metabolism influence each other, and it is unclear whether the trophoblast energy metabolism phenotype is dominated by glycolysis or mitochondrial respiration, and the relationship between trophoblast energy metabolism and EMT is still unclear. Exosomes were isolated from the DSC of URSA patients and their miRNA profile was characterized by miRNA sequencing. Wound healing assays and transwell assays were used to assess the invasion and migration ability of trophoblasts. Mitochondrial stress and glycolysis stress test were used to evaluate energy metabolism phenotype of trophoblast. Luciferase reporter assays, qRT-PCR and WB were conducted to uncover the underlying mechanism. Finally, animal experiments were employed to explore the effect of DSC-exos on embryo absorption in mice. Our results showed that URSA-DSC-exos suppressed trophoblast EMT to reduce their migration and invasion, miR-22-5p_R-1 was the most upregulated miRNAs. URSA-DSC-exos can suppress trophoblast MGS (metabolic switch from mitochondrial respiration to glycolysis) and inhibit trophoblast migration and invasion by transferring miR-22-5p_R-1. Mechanistically, miR-22-5p_R-1 suppress trophoblast MGS and inhibit trophoblast EMT by directly suppressing PDK4 expression at the post-transcriptional level. Furthermore, in vivo experiment suggested that URSA-DSC-exos aggravated embryo absorption in mice. Clinically, PDK4 and EMT molecule were aberrant in villous of URSA patients, and negative correlations were found between miR-22-5p_R-1 and PDK4. Our findings indicated that URSA-DSC-exos induced MGS obstacle playing an important role in intercellular communication between trophoblast and DSC, illuminating a novel mechanism in DSC regulation of trophoblasts and their role in URSA. • MiR-22-5p_R-1 was the most upregulated miRNAs in URSA-DSC-exos. • URSA-DSC-exos can transmit miR-22-5p_R-1 to trophoblasts which targeted PDK4. • Metabolism reprogramming plays an important role in regulating trophoblast EMT. • PDK4 is a key molecule that regulates the trophoblast's MGS and induce EMT. • Low expression of PDK4 inhibited the trophoblast EMT in URSA patients. [ABSTRACT FROM AUTHOR]

Metabolic networks are fundamental to cellular processes, driving energy production, biosynthesis, redox regulation, and cellular signaling. Recent advancements in metabolic research tools have provided unprecedented insights into cellular metabolism. Among these tools, the extracellular flux analyzer stands out for its real-time measurement of key metabolic parameters: glycolysis, mitochondrial respiration, and fatty acid oxidation, leading to its widespread use. This review provides a comprehensive summary of the basic principles and workflow of the extracellular flux assay (the Seahorse assay) and its diverse applications. We highlight the assay's versatility across various biological models, including cancer cells, immunocytes, Caenorhabditis elegans, tissues, isolated mitochondria, and three-dimensional structures such as organoids, and summarize key considerations for using extracellular flux assay in these models. Additionally, we discuss the limitations of the Seahorse assay and propose future directions for its development. This review aims to enhance the understanding of extracellular flux assay and its significance in biological studies. [ABSTRACT FROM AUTHOR]

[Display omitted] • LPS-activated MSCs promote the expression of NLRP3 and the production of IL-10. • NLRP3 upregulates Glut1 expression and promotes glycolysis in MSCs. • Overexpression of Glut1 enhanced the therapeutic effect of Nlrp3 KO MSCs against DSS-induced colitis. • NLRP3 activation promotes IL-10 production by upregulating glycolysis levels, heightening the protective effects of MSCs treatment on DSS-induced colitis. Numerous studies demonstrated that NLRP3 has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Mesenchymal stem cells (MSCs) regulated the NLRP3 inflammasome, which has emerged as a novel therapeutic approach for treating IBD. The exact role of NLRP3 in regulating MSCs' function is unclear. Our study aimed to explore how NLRP3 affects the therapeutic effects of MSCs in colitis. We extracted MSCs from the bone marrow of C57BL/6 mice and Nlrp3 KO mice, and identified them using differentiation assays and flow cytometry. In vitro , Both WT MSCs and Nlrp3 KO MSCs were stimulated with inflammatory factor Lipopolysaccharide (LPS), and only WT MSCs were stimulated with varying concentrations of the NLRP3 inhibitor MCC950, then, quantified IL-10 levels in the supernatant. RNA-seq was performed to examine gene expression patterns and Seahorse was used to assess oxidative phosphorylation (OXPHOS) and glycolysis levels. Western blot was used to evaluate protein expression. In vivo , we treated DSS-induced colitis with either WT or Nlrp3 KO MSCs, monitoring weight, measuring colon length, and further evaluation. We also treated DSS-induced colitis with pretreated MSCs (BAY876, oe-Glut1, or oe-NLRP3), following the same experimental procedures as described above. Our results demonstrate that Nlrp3 deletion did not affect MSC phenotypes, but rather promoted osteogenic differentiation. However, the absence of Nlrp3 reduced IL-10 production in MSCs in the presence of LPS, leading to impaired protection on DSS-induced colitis. Conversely, overexpression of NLRP3 promotes the production of IL-10, enhancing therapeutic effects. Further investigation revealed that Nlrp3 deficiency downregulated Glut1 expression and glycolysis activation in MSCs, resulting in decreased IL-10 production. Notably, overexpressing Glut1 in Nlrp3 KO MSCs restored their therapeutic effect that was previously dampened due to Nlrp3 deletion. Our findings demonstrate that NLRP3 heightens the therapeutic effects of MSC treatment on DSS-induced colitis. [ABSTRACT FROM AUTHOR]

[Display omitted] Stem cells remain in a quiescent state for long-term maintenance and preservation of potency; this process requires fine-tuning regulatory mechanisms. In this study, we identified the epigenetic landscape along the developmental trajectory of skeletal stem cells (SSCs) in skeletogenesis governed by a key regulator, Ptip (also known as Paxip1, Pax interaction with transcription-activation domain protein-1). Our results showed that Ptip is required for maintaining the quiescence and potency of SSCs, and loss of Ptip in type II collagen (Col2)+ progenitors causes abnormal activation and differentiation of SSCs, impaired growth plate morphogenesis, and long bone dysplasia. We also found that Ptip suppressed the glycolysis of SSCs through downregulation of phosphoglycerate kinase 1 (Pgk1) by repressing histone H3 lysine 27 acetylation (H3K27ac) at the promoter region. Notably, inhibition of glycolysis improved the function of SSCs despite Ptip deficiency. To the best of our knowledge, this is the first study to establish an epigenetic framework based on Ptip, which safeguards skeletal stem cell quiescence and potency through metabolic control. This framework is expected to improve SSC-based treatments of bone developmental disorders. [ABSTRACT FROM AUTHOR]

Nutrient or energy deprivation, especially glucose restriction, is a promising anticancer therapeutic approach. However, establishing a precise and potent deprivation strategy remains a formidable task. The Golgi morphology is crucial in maintaining the function of transport proteins (such as GLUT1) driving glycolysis. Thus, in this study, we present a "Golgi-customized Trojan horse" based on tellurium loaded with apigenin (4′,5,7-trihydroxyflavone) and human serum albumin, which was able to induce GLUT1 plasma membrane localization disturbance via Golgi dispersal leading to the inhibition of tumor glycolysis. Diamond-shaped delivery system can efficiently penetrate into cells as a gift like Trojan horse, which decomposes into tellurite induced by intrinsically high H 2 O 2 and GSH levels. Consequently, tellurite acts as released warriors causing up to 3.8-fold increase in Golgi apparatus area due to the down-regulation of GOLPH3. Further, this affects GLUT1 membrane localization and glucose transport disturbance. Simultaneously, apigenin hinders ongoing glycolysis and causes significant decrease in ATP level. Collectively, our "Golgi-customized Trojan horse" demonstrates a potent antitumor activity because of its capability to deprive energy resources of cancer cells. This study not only expands the applications of tellurium-based nanomaterials in the biomedicine but also provides insights into glycolysis restriction for anticancer therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Schistosoma mansoni lactate dehydrogenase (LDH) is allosterically regulated by ATP and FBP. • The active site of LDH from S. mansoni closely resembles that of prokaryotic LDHs. • The inhibition of LDH by ATP benefits the free-living, glycogen-consuming stages. • In the presence of glucose, FBP levels increase, neutralizing the inhibition by ATP. • This effect of FBP prevents fatally high FBP levels after entering the final host. Lactate dehydrogenase (LDH) from Schistosoma mansoni has peculiar properties for a eukaryotic LDH. Schistosomal LDH (SmLDH) isolated from schistosomes, and the recombinantly expressed protein, are strongly inhibited by ATP, which is neutralized by fructose-1,6-bisphosphate (FBP). In the conserved FBP/anion binding site we identified two residues in SmLDH (Val187 and Tyr190) that differ from the conserved residues in LDHs of other eukaryotes, but are identical to conserved residues in FBP-sensitive prokaryotic LDHs. Three-dimensional (3D) models were generated to compare the structure of SmLDH with other LDHs. These models indicated that residues Val187, and especially Tyr190, play a crucial role in the interaction of FBP with the anion pocket of SmLDH. These 3D models of SmLDH are also consistent with a competitive model of SmLDH inhibition in which ATP (inhibitor) and FBP (activator) compete for binding in a well-defined anion pocket. The model of bound ATP predicts a distortion of the nearby key catalytic residue His195, resulting in enzyme inhibition. To investigate a possible physiological role of this allosteric regulation of LDH in schistosomes we made a kinetic model in which the allosteric regulation of the glycolytic enzymes can be varied. The model showed that inhibition of LDH by ATP prevents fermentation to lactate in the free-living stages in water and ensures complete oxidation via the Krebs cycle of the endogenous glycogen reserves. This mechanism of allosteric inhibition by ATP prevents the untimely depletion of these glycogen reserves, the only fuel of the free-living cercariae. Neutralization by FBP of this ATP inhibition of LDH prevents accumulation of glycolytic intermediates when S. mansoni schistosomula are confronted with the sudden large increase in glucose availability upon penetration of the final host. It appears that the LDH of S. mansoni is special and well suited to deal with the variations in glucose availability the parasite encounters during its life cycle. [ABSTRACT FROM AUTHOR]

Understanding the tumor redox status is important for efficient cancer treatment. Here, we noninvasively detected changes in the redox environment of tumors before and after cancer treatment in the same individuals using a novel compact and portable electron paramagnetic resonance imaging (EPRI) device and compared the results with glycolytic information obtained through autoradiography using 2-deoxy-2-[18F]fluoro- d -glucose ([18F]FDG). Human colon cancer HCT116 xenografts were used in the mice. We used 3-carbamoyl-PROXYL (3CP) as a paramagnetic and redox status probe for the EPRI of tumors. The first EPRI was followed by the intraperitoneal administration of buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, or X-ray irradiation of the tumor. A second EPRI was performed on the following day. Autoradiography was performed after the second EPRI. After imaging, the tumor sections were evaluated by histological analysis and the amount of reducing substances in the tumor was measured. BSO treatment and X-ray irradiation significantly decreased the rate of 3CP reduction in tumors. Redox maps of tumors obtained from EPRI can be compared with tissue sections of approximately the same cross section. BSO treatment reduced glutathione levels in tumors, whereas X-ray irradiation did not alter the levels of any of the reducing substances. Comparison of the redox map with the autoradiography of [18F]FDG revealed that regions with high reducing power in the tumor were active in glucose metabolism; however, this correlation disappeared after X-ray irradiation. These results suggest that the novel compact and portable EPRI device is suitable for multimodal imaging, which can be used to study tumor redox status and therapeutic efficacy in cancer, and for combined analysis with other imaging modalities. [Display omitted] • Redox status change by cancer treatment were visualized in vivo by EPRI device. • Redox maps generated from EPR images were compared with tissue sections. • X-ray irradiation induced tissue oxidation in the redox environment of the tumor. • Comparison of redox maps and autoradiographic images of the tumor was enabled. [ABSTRACT FROM AUTHOR]

Neuronal energy metabolism dysregulation is involved in various pathologies of Ischemia-reperfusion (I/R), yet the role of RGMA in neuronal metabolic reprogramming has not been reported. In this study, we found that RGMA expression significantly increased after I/R, and compared to control mice, mice with MCAO/R showed an increase in glycolytic metabolic products and the expression of glycolytic pathway proteins. Furthermore, RGMA levels are closely related to neuronal energy metabolism. We discovered that knockdown of RGMA can shift neuronal energy metabolism towards oxidative phosphorylation and the pentose phosphate pathway, thereby protecting mice from ischemic reperfusion injury. Mechanistically, knockdown of RGMA can downregulate PGK1 expression, reducing the increase in glycolytic flux following ischemia reperfusion. Moreover, we found that knockdown of RGMA can reduce the interaction between USP10 and PGK1, thus affecting the ubiquitination degradation of PGK1. In summary, our data suggest that RGMA may regulate neuronal energy metabolism by inhibiting the USP10-mediated deubiquitination of PGK1, thus protecting it from I/R injury. This study provides new ideas for clarifying the intrinsic mechanism of neuronal damage after I/R. [Display omitted] • We investigated the expression and biological function of RGMA in I/R, including in cellular and animal models. • Knockdown of RGMA may improve neuronal damage after I/R by regulating energy metabolism. • Knockdown of RGMA regulates PGK1 protein stability by attenuating the USP10-mediated deubiquitin-proteasome pathway. [ABSTRACT FROM AUTHOR]

The process of cellular respiration occurs for energy production through catabolic reactions, generally with glucose as the first process step. In the present work, we introduce a novel concept for understanding this process, based on our conclusion that glucose metabolism is coupled to the pentose phosphate pathway (PPP) and extra-mitochondrial oxidative phosphorylation in a closed-loop process. According to the current standard model of glycolysis, glucose is first converted to glucose 6-phosphate (glucose 6-P) and then to fructose 6-phosphate, glyceraldehyde 3-phosphate and pyruvate, which then enters the Krebs cycle in the mitochondria. However, it is more likely that the pyruvate will be converted to lactate. In the PPP, glucose 6-P is branched off from glycolysis and used to produce NADPH and ribulose 5-phosphate (ribulose 5-P). Ribulose 5-P can be converted to fructose 6-P and glyceraldehyde 3-P. In our view, a circular process can take place in which the ribulose 5-P produced by the PPP enters the glycolysis pathway and is then retrogradely converted to glucose 6-P. This process is repeated several times until the complete degradation of glucose 6-P. The role of mitochondria in this process is to degrade lipids by beta-oxidation and produce acetyl-CoA; the function of producing ATP appears to be only secondary. This proposed new concept of cellular bioenergetics allows the resolution of some previously unresolved controversies related to cellular respiration and provides a deeper understanding of metabolic processes in the cell, including new insights into the Warburg effect. • Cellular respiration: still not fully understood and several anomalies discovered. • We present a new model of cellular energy metabolism. • Our model: glucose metabolism is coupled to the pentose phosphate pathway and extra-mitochondrial oxidative phosphorylation. • ATP production appears to be only a secondary function of the mitochondria. [ABSTRACT FROM AUTHOR]

Trauma is a term used to encompass a wide range of pathologies. It results in a complex response initially described in 1942 as an acute 'ebb' phase of catabolism followed by anabolism in the 'flow phase'. Others have described the process as a 'nervous' initial phase, closely followed by an 'immune' phase which then develops into a late 'endocrine' phase. Initially there is a shift to anaerobic glycolysis in the resulting hypoxic environment. Hypotension and tachycardia occur alongside increased vessel permeability and vasodilatation. Lipolysis and glycogenolysis have key roles in substrate supply, with insulin resistance and increased gluconeogenesis resulting in ongoing hyperglycaemia but with relatively poor utilization. Proteolysis of skeletal muscle to supply energy substrates can result in limitations in wound healing and rehabilitation. Acutely, acidosis and hypothermia are implicated in trauma-induced coagulopathy, with tissue hypoperfusion an additional risk factor. Hypercoagulability may also be seen, due to impaired anticoagulant activity, particularly in penetrating trauma. Neutrophils and macrophages are attracted to injured sites as part of the immune response, alongside both a cytokine and acute phase protein response. Clinicians should understand these processes and implicate measures to limit the potential adverse effects of the body's metabolic response. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming is a mechanism by which cancer cells alter their metabolic patterns to promote cell proliferation and growth, thereby enabling their resistance to external stress. 2-Deoxy- D -glucose (2DG) can eliminate their energy source by inhibiting glucose glycolysis, leading to cancer cell death through starvation. However, a compensatory increase in mitochondrial metabolism inhibits its efficacy. Herein, we propose a synergistic approach that combines photodynamic therapy (PDT) with starvation therapy to address this challenge. To monitor the nanodrugs and determine the optimal triggering time for precise tumor therapy, a multifunctional nano-platform comprising lanthanide-doped nanoparticle (LnNP) cores was constructed and combined with mesoporous silicon shells loaded with 2DG and photosensitizer chlorin e6 (Ce6) in the mesopore channels. Under 980 nm near-infrared light excitation, the downshifted 1550 nm fluorescence signal in the second near-infrared (NIR-II, 1000–1700 nm) window from the LnNPs was used to monitor the accumulation of nanomaterials in tumors. Furthermore, upconverted 650 nm light excited the Ce6 to generate singlet oxygen for PDT, which damaged mitochondrial function and enhanced the efficacy of 2DG by inhibiting hexokinase 2 and lactate dehydrogenase A expressions. As a result, glucose metabolism reprogramming was inhibited and the efficiency of starvation therapy was significantly enhanced. Overall, the proposed NIR-II bioimaging-guided PDT-augmented starvation therapy, which simultaneously inhibited glycolysis and mitochondria, facilitated the effects of a cancer theranostic system. [ABSTRACT FROM AUTHOR]

Altered aerobic glycolysis is the robust mechanism to support cancer cell survival and proliferation beyond the maintenance of cellular energy metabolism. Several investigators portrayed the important role of deregulated glycolysis in different cancers, including breast cancer. Breast cancer is the most ubiquitous form of cancer and the primary cause of cancer death in women worldwide. Breast cancer with increased glycolytic flux is hampered to eradicate with current therapies and can result in tumor recurrence. In spite of the low order efficiency of ATP production, cancer cells are highly addicted to glycolysis. The glycolytic dependency of cancer cells provides potential therapeutic strategies to preferentially kill cancer cells by inhibiting glycolysis using antiglycolytic agents. The present review emphasizes the most recent research on the implication of glycolytic enzymes, including glucose transporters (GLUTs), hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), lactate dehydrogenase-A (LDHA), associated signalling pathways and transcription factors, as well as the antiglycolytic agents that target key glycolytic enzymes in breast cancer. The potential activity of glycolytic inhibitors impinges cancer prevalence and cellular resistance to conventional drugs even under worse physiological conditions such as hypoxia. As a single agent or in combination with other chemotherapeutic drugs, it provides the feasibility of new therapeutic modalities against a wide spectrum of human cancers. • Glycolytic components are major drivers of metabolic discrepancies in breast cancer. • Each breast cancer subtype exhibits unique metabolic phenotype traits. • Transcription factors and signalling pathways robustly alter the metabolic phenotype of breast cancer. • The potential antiglycolytic agents provide conclusive benefits in the treatment modalities against breast cancer. [ABSTRACT FROM AUTHOR]

Cancer cells rely on aerobic glycolysis and DNA repair signals to drive tumor growth and develop drug resistance. Yet, fine-tuning aerobic glycolysis with the assist of nanotechnology, for example, dampening lactate dehydrogenase (LDH) for cancer cell metabolic reprograming remains to be investigated. Here we focus on anaplastic thyroid cancer (ATC) as an extremely malignant cancer with the high expression of LDH, and develop a pH-responsive and nucleus-targeting platinum nanocluster (Pt@TAT/sPEG) to simultaneously targets LDH and exacerbates DNA damage. Pt@TAT/sPEG effectively disrupts LDH activity, reducing lactate production and ATP levels, and meanwhile induces ROS production, DNA damage, and apoptosis in ATC tumor cells. We found Pt@TAT/sPEG also blocks nucleotide excision repair pathway and achieves effective tumor cell killing. In an orthotopic ATC xenograft model, Pt@TAT/sPEG demonstrates superior tumor growth suppression compared to Pt@sPEG and cisplatin. This nanostrategy offers a feasible approach to simultaneously inhibit glycolysis and DNA repair for metabolic reprogramming and enhanced tumor chemotherapy. Pt@TAT/sPEG simultaneously modulates both glucose metabolism and DNA damage repair for metabolic reprogramming and enhanced tumor chemotherapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Osteoblasts rely on glucose as their primary energy source both for differentiation and to maintain function. Oxidative phosphorylation (OXPHOS) predominantly facilitates osteoclast differentiation, while glycolysis is the primary energy source for bone resorption by osteoclasts. Bone releases a series of endocrine factors to regulate systemic energy homeostasis. Disturbances in bone metabolism resulting from osteoporosis lead to imbalances in energy metabolism, further expediting the advance of osteoporosis. The bone serves as an energy reservoir and actively engages in whole-body energy metabolism. Numerous studies have determined fuel requirements and bioenergetic properties of bone under physiological conditions as well as the dysregulation of energy metabolism associated with bone metabolic diseases. Here, we review the main sources of energy in bone cells and their regulation, as well as the endocrine role of the bone in systemic energy homeostasis. Moreover, we discuss metabolic changes that occur as a result of osteoporosis. Exploration in this area will contribute to an enhanced comprehension of bone energy metabolism, presenting novel possibilities to address metabolic diseases. [ABSTRACT FROM AUTHOR]

The heart utilizes glucose and its metabolites as both energy sources and building blocks for cardiac growth and survival under both physiological and pathophysiological conditions. YAP/TAZ, transcriptional co-activators of the Hippo pathway, are key regulators of cell proliferation, survival, and metabolism in many cell types. Increasing lines of evidence suggest that the Hippo-YAP/TAZ signaling pathway is involved in the regulation of both physiological and pathophysiological processes in the heart. In particular, YAP/TAZ play a critical role in mediating aerobic glycolysis, the Warburg effect, in cardiomyocytes. Here, we summarize what is currently known about YAP/TAZ signaling in the heart by focusing on the regulation of glucose metabolism and its functional significance. [Display omitted] • The heart utilizes glucose as a source of energy and building blocks via glycolysis and the auxiliary pathways. • YAP/TAZ play an important role in the regulation of physiological and pathophysiological processes in the heart. • YAP/TAZ control glucose metabolism under some physiological and pathophysiological conditions in the heart. [ABSTRACT FROM AUTHOR]

Methicillin-resistant Staphylococcus aureus (MRSA) is the primary pathogenic agent responsible for epidermal wound infection and suppuration, seriously threatening the life and health of human beings. To address this fundamental challenge, we propose a heterojunction nanocomposite (Ca-CN/MnS) comprised of Ca-doped g-C 3 N 4 and MnS for the therapy of MRSA-accompanied wounds. The Ca doping leads to a reduction in both the bandgap and the singlet state S 1 –triplet state T 2 energy gap (Δ E ST). The Ca doping also facilitates the two-photon excitation, thus remarkably promoting the separation and transfer of 808 nm near-infrared (NIR) light–triggered electron–hole pairs together with the built-in electric field. Thereby, the production of reactive oxygen species and heat are substantially augmented nearby the nanocomposite under 808 nm NIR light irradiation. Consequently, an impressive photocatalytic MRSA bactericidal efficiency of 99.98 ± 0.02 % is achieved following exposure to NIR light for 20 min. The introduction of biologically functional elements (Ca and Mn) can up-regulate proteins such as pyruvate kinase (PKM), L-lactate dehydrogenase (LDHA), and calcium/calmodulin-dependent protein kinase (CAMKII), trigger the glycolysis and calcium signaling pathway, promote cell proliferation, cellular metabolism, and angiogenesis, thereby expediting the wound-healing process. This heterojunction nanocomposite, with its precise charge-transfer pathway, represents a highly effective bactericidal and bioactive system for treating multidrug-resistant bacterial infections and accelerating tissue repair. Due to the bacterial resistance, developing an antibiotic-free and highly effective bactericidal strategy to treat bacteria-infected wounds is critical. We have designed a heterojunction consisting of calcium doped g-C 3 N 4 and MnS (Ca-CN/MnS) that can rapidly kill methicillin-resistant Staphylococcus aureus (MRSA) without damaging normal tissue through a synergistic effect of two-photon stimulated photothermal and photodynamic therapy. In addition, the release of trace amounts of biofunctional elements Mn and Ca triggers glycolysis and calcium signaling pathways that promote cellular metabolism and cell proliferation, contributing to tissue repair and wound healing. [Display omitted] [ABSTRACT FROM AUTHOR]

Ischemia Stroke (IS) is an acute neurological condition with high morbidity, disability, and mortality due to a severe reduction in local cerebral blood flow to the brain and blockage of oxygen and glucose supply. Oxidative stress induced by IS predisposes neurons to ferroptosis. TP53-induced glycolysis and apoptosis regulator (TIGAR) inhibits the intracellular glycolytic pathway to increase pentose phosphate pathway (PPP) flux, promotes NADPH production and thus generates reduced glutathione (GSH) to scavenge reactive oxygen species (ROS), and thus shows strong antioxidant effects to ameliorate cerebral ischemia/reperfusion injury. However, in the current study, prolonged ischemia impaired the PPP, and TIGAR was unable to produce NADPH but was still able to reduce neuronal ferroptosis and attenuate ischemic brain injury. Ferroptosis is a form of cell death caused by free radical-driven lipid peroxidation, and the vast majority of ROS leading to oxidative stress are generated by mitochondrial succinate dehydrogenase (SDH) driving reverse electron transfer (RET) via the mitochondrial electron transport chain. Overexpression of TIGAR significantly inhibited hypoxia-induced enhancement of SDH activity, and TIGAR deficiency further enhanced SDH activity. We also found that the inhibitory effect of TIGAR on SDH activity was related to its mitochondrial translocation under hypoxic conditions. TIGAR may inhibit SDH activity by mediating post-translational modifications (acetylation and succinylation) of SDH A through interaction with SDH A. SDH activity inhibition reduces neuronal ferroptosis by decreasing ROS production, eliminating MitoROS levels and attenuating lipid peroxide accumulation. Notably, TIGAR-mediated inhibition of SDH activity and ferroptosis was not dependent on the PPP-NADPH-GPX4 pathways. In conclusion, mitochondrial translocation of TIGAR in prolonged ischemia is an important pathway to reduce neuronal ferroptosis and provide sustainable antioxidant defense for the brain under prolonged ischemia, further complementing the mechanism of TIGAR resistance to oxidative stress induced by IS. [Display omitted] • TIGAR resists ferroptosis in prolonged ischemia by inhibiting mitochondrial succinate dehydrogenase (SDH) activity. • The inhibitory effect of TIGAR on SDH activity is independent of its Fru-2, 6-BPase activity. • SDH activity inhibition reduces neuronal ferroptosis by decreasing ROS productionand attenuating lipid peroxide accumulation. [ABSTRACT FROM AUTHOR]

Modulating the metabolism of cancer cells, immune cells, or both is a promising strategy to potentiate cancer immunotherapy in the nutrient-competitive tumor microenvironment. Glutamine has emerged as an ideal target as cancer cells highly rely on glutamine for replenishing the tricarboxylic acid cycle in the process of aerobic glycolysis. However, non-specific glutamine restriction may induce adverse effects in unconcerned tissues and therefore glutamine inhibitors have achieved limited success in the clinic so far. Here we report the synthesis and evaluation of a redox-responsive prodrug of 6-Diazo-5-oxo-L-norleucine (redox-DON) for tumor-targeted glutamine inhibition. When applied to treat mice bearing subcutaneous CT26 mouse colon carcinoma, redox-DON exhibited equivalent antitumor efficacy but a greatly improved safety profile, particularly, in spleen and gastrointestinal tract, as compared to the state-of-the-art DON prodrug, JHU083. Furthermore, redox-DON synergized with checkpoint blockade antibodies leading to durable cures in tumor-bearing mice. Our results suggest that redox-DON is a safe and effective therapeutic for tumor-targeted glutamine inhibition showing promise for enhanced metabolic modulatory immunotherapy. The approach of reversible chemical modification may be generalized to other metabolic modulatory drugs that suffer from overt toxicity. [Display omitted] [ABSTRACT FROM AUTHOR]

Androgen receptor (AR) is one of the key targets for the treatment of castration-resistant prostate cancer (CRPC). Current endocrine therapy can greatly improve patients with CRPC. However, with the change of pathogenic mechanism, acquired resistance often leads to the failure of treatment. Studies have shown that tanshinone IIA (TS-IIA) and its derivatives have significant antitumor activity, and have certain AR-targeting effects, but the mechanism is unknown. In this study, the TS-IIA analog TB3 was found to significantly inhibit the growth of CRPC in vitro and in vivo. Molecular docking, cellular thermal shift assay, and cycloheximide experiments confirmed that AR was the target of TB3 and promoted the degradation of AR. Furthermore, TB3 can significantly inhibit glycolysis metabolism by targeting the AR/PKM2 axis. The addition of pyruvic acid could significantly alleviate the inhibitory effect of TB3 on CRPC cells. Besides, the knockdown of AR or PKM2 also could reverse the effect of TB3 on CRPC cells. Taken together, our study suggests that TS-IIA derivative TB3 inhibits glycolysis to prevent the CRPC process by targeting the AR/PKM2 axis. [ABSTRACT FROM AUTHOR]

Zinc is required for many critical processes, including intermediary metabolism. In Saccharomyces cerevisiae, the Zap1 activator regulates the transcription of ~ 80 genes in response to Zn supply. Some Zap1-regulated genes are Zn transporters that maintain Zn homeostasis, while others mediate adaptive responses that enhance fitness. One adaptive response gene encodes the 2-cysteine peroxiredoxin Tsa1, which is critical to Zn-deficient (ZnD) growth. Depending on its redox state, Tsa1 can function as a peroxidase, a protein chaperone, or a regulatory redox sensor. In a screen for possible Tsa1 regulatory targets, we identified a mutation (cdc19S492A) that partially suppressed the tsa1Δ growth defect. The cdc19S492A mutation reduced activity of its protein product, pyruvate kinase isozyme 1 (Pyk1), implicating Tsa1 in adapting glycolysis to ZnD conditions. Glycolysis requires activity of the Zn-dependent enzyme fructose-bisphosphate aldolase 1, which was substantially decreased in ZnD cells. We hypothesized that in ZnD tsa1Δ cells, the loss of a compensatory Tsa1 regulatory function causes depletion of glycolytic intermediates and restricts dependent amino acid synthesis pathways, and that the decreased activity of Pyk1S492A counteracted this depletion by slowing the irreversible conversion of phosphoenolpyruvate to pyruvate. In support of this model, supplementing ZnD tsa1Δ cells with aromatic amino acids improved their growth. Phosphoenolpyruvate supplementation, in contrast, had a much greater effect on growth rate of WT and tsa1Δ ZnD cells, indicating that inefficient glycolysis is a major factor limiting yeast growth. Surprisingly however, this restriction was not primarily due to low fructosebisphosphate aldolase 1 activity, but instead occurs earlier in glycolysis. [ABSTRACT FROM AUTHOR]

Although tyrosol is a quorum-sensing molecule of Candida species, it has antifungal activity at supraphysiological concentrations. Here, we studied the effect of tyrosol on the physiology and genome-wide transcription of Aspergillus nidulans to gain insight into the background of the antifungal activity of this compound. Tyrosol efficiently reduced germination of conidia and the growth on various carbon sources at a concentration of 35 mM. The growth inhibition was fungistatic rather than fungicide on glucose and was accompanied with downregulation of 2199 genes related to e.g. mitotic cell cycle, glycolysis, nitrate and sulphate assimilation, chitin biosynthesis, and upregulation of 2250 genes involved in e.g. lipid catabolism, amino acid degradation and lactose utilization. Tyrosol treatment also upregulated genes encoding glutathione-S-transferases (GSTs), increased specific GST activities and the glutathione (GSH) content of the cells, suggesting that A. nidulans can detoxify tyrosol in a GSH-dependent manner even though this process was weak. Tyrosol did not induce oxidative stress in this species, but upregulated "response to nutrient levels", "regulation of nitrogen utilization", "carbon catabolite activation of transcription" and "autophagy" genes. Tyrosol may have disturbed the regulation and orchestration of cellular metabolism, leading to impaired use of nutrients, which resulted in growth reduction. • Tyrosol had strong growth inhibitory effect against Aspergillus nidulans. • Tyrosol upregulated glutathione dependent detoxification processes. • Tyrosol treatment did not cause oxidative stress but upregulated autophagy genes. • According to RNAseq data tyrosol disturbed nutrient sensing and utilization. [ABSTRACT FROM AUTHOR]

Due to insufficient and defective vascularization, the tumor microenvironment is often nutrient-depleted. LDHA has been demonstrated to play a tumor-promoting role by facilitating the glycolytic process. However, whether and how LDHA regulates cell survival in the nutrient-deficient tumor microenvironment is still unclear. Here, we sought to investigate the role and mechanism of LDHA in regulating cell survival and proliferation under energy stress conditions. Our results showed that the aerobic glycolysis levels, cell survival and proliferation of cervical cancer cells decreased significantly after inhibition of LDHA under normal culture condition while LDHA deficiency greatly inhibited glucose starvation-induced ferroptosis and promoted cell proliferation and tumor formation under energy stress conditions. Mechanistic studies suggested that glucose metabolism shifted from aerobic glycolysis to mitochondrial OXPHOS under energy stress conditions and LDHA knockdown increased accumulation of pyruvate in the cytosol, which entered the mitochondria and upregulated the level of oxaloacetate by phosphoenolpyruvate carboxylase (PC). Importantly, the increase in oxaloacetate production after absence of LDHA remarkably activated AMP-activated protein kinase (AMPK), which increased mitochondrial biogenesis and mitophagy, promoted mitochondrial homeostasis, thereby decreasing ROS level. Moreover, repression of lipogenesis by activation of AMPK led to elevated levels of reduced nicotinamide adenine dinucleotide phosphate (NADPH), which effectively resisted ROS-induced cell ferroptosis and enhanced cell survival under energy stress conditions. These results suggested that LDHA played an opposing role in survival and proliferation of cervical cancer cells under energy stress conditions, and inhibition of LDHA may not be a suitable treatment strategy for cervical cancer. [Display omitted] • Knockdown of LDHA promotes survival and proliferation of cervical cancer cells under energy stress conditions. • Knockdown of LDHA directly alters the metabolic phenotype of cervical cancer cells under energy stress conditions. • Knockdown of LDHA activates AMPK signal under energy stress conditions. [ABSTRACT FROM AUTHOR]

Trace metal zinc is involved in key processes of solid tumors by its antioxidant properties, while the role of zinc at the onset of esophageal squamous cell carcinoma (ESCC) remains controversial. This study aimed to determine whether zinc is associated with the ESCC and underlying molecular events involving malignant progression. Based on a case-control study, we found serum and urine zinc were decreased and correlated with ESCC progression. Thus, an in vitro model for zinc deficiency (ZD) was established, and we found that ZD contributed to the proliferation, migration, and invasion of EC109 cells. Untargeted metabolomics identified 59 upregulated metabolites and 6 downregulated metabolites, among which glycolysis and ferroptosis-related oxidation of chain fatty acids might play crucial steps in ZD-treated molecular events. Interestingly, ZD disrupted redox homeostasis and enhanced cytosolic Fe2+ of EC109 cells, while lipid peroxidation, the key marker of ferroptosis occurrence, was decreased after ZD treatment. The mechanism underlying these changes may involve ZD-enhanced ESCC glycolysis and lactate production, which confer ferroptosis resistance by inhibiting of p -AMPK and leading to the upregulation of SREBP1 and SCD1 to enhance the production of anti -ferroptosis monounsaturated fatty acids. [Display omitted] • Zinc element is decreased in the serum and urine of ESCC. • Zinc deficiency enhances ESCC glycolysis. • Zinc deficiency disrupts redox homeostasis and elevates Fe2+ in EC109 cells. • Zinc deficiency enhances ESCC ferroptosis resistance by upregulating lactate production. [ABSTRACT FROM AUTHOR]

Physical exercise is established as an important factor of health and generally is recommended for its positive effects on several tissues, organs, and systems. These positive effects come from metabolic adaptations that also include oxidative eustress, in which physical activity increases ROS production and antioxidant mechanisms, although this depends on the intensity of the exercise. Muscle metabolism through mechanisms such as aerobic and anaerobic glycolysis, tricarboxylic acid cycle, and oxidative lipid metabolism can produce metabolites and co-factors which directly impact the epigenetic machinery. In this review, we clearly reinforce the evidence that exercise regulates several epigenetic mechanisms and explain how these mechanisms can be regulated by metabolic products and co-factors produced during exercise. In fact, recent evidence has demonstrated the importance of epigenetics in the gene expression changes implicated in metabolic adaptation after exercise. Importantly, intermediates of the metabolism generated by continuous, acute, moderate, or strenuous exercise control the activity of epigenetic enzymes, therefore turning on or turning off the gene expression of specific programs which can lead to physiological adaptations after exercise. [Display omitted] • Epigenetic mechanisms depend on changes in the levels of metabolites, which are modified during physical exercise. • Exercise produces free radical species which impact epigenetic regulation. • Physical exercise modulates the epigenetic machinery, and this control is influenced by the intensity and duration of the exercise. [ABSTRACT FROM AUTHOR]

Changes to our environment have led to the emergence of human pathogens such as chikungunya virus. Chikungunya virus infection is today a major public health concern. It is a debilitating chronic disease impeding patients' mobility, affecting millions of people. Disease development relies on skeletal muscle infection. The importance of skeletal muscle in chikungunya virus infection led to the hypothesis that it could serve as a viral reservoir and could participate to virus persistence. Here we questioned the interconnection between skeletal muscle cells metabolism, their differentiation stage and the infectivity of the chikungunya virus. We infected human skeletal muscle stem cells at different stages of differentiation with chikungunya virus to study the impact of their metabolism on virus production and inversely the impact of virus on cell metabolism. We observed that chikungunya virus infectivity is cell differentiation and metabolism-dependent. Chikungunya virus interferes with the cellular metabolism in quiescent undifferentiated and proliferative muscle cells. Moreover, activation of chikungunya infected quiescent muscle stem cells, induces their proliferation, increases glycolysis and amplifies virus production. Therefore, our results showed that Chikungunya virus infectivity and the antiviral response of skeletal muscle cells relies on their energetic metabolism and their differentiation stage. Then, muscle stem cells could serve as viral reservoir producing virus after their activation. • CHIKV human skeletal muscle cells infection relies on their energetic metabolism. • CHIKV human myoblasts infection augments their glycolysis. • Human satellite cells activation boosts their glycolysis inducing CHIKV production. • Human satellite cells could serve as CHIKV reservoir. [ABSTRACT FROM AUTHOR]

This study investigated the effects of two types of resistance exercise with active and inactive recovery on lipolysis and glycolysis in healthy young men. Twelve healthy males (Mean ± SD; age, 25.5 ± 3.1 years; Body mass index, 24.2 ± 2.0 kg/m2) performed traditional resistance exercise (TRE) at 80% of 1RM (3 sets of 6 repetitions) with 2 min passive recovery, and an interval resistance exercise (IRE) trial at 60% of 1RM (3 sets of 6 repetitions) followed by active recovery (1 set of 6 repetitions at 20% of 1RM). Three blood samples were taken before and immediately after exercise, and after one-hour recovery and were analyzed to measure glucose, insulin, non-esterified free fatty acid (NEFA), and glycerol concentration. Statistical analyses of the data revealed a main significant effect of resistance exercise and a significant (P < 0.05) interaction for insulin and glucose concentrations. IRE and subsequent recovery caused a further decrease in insulin concentration compared to TRE. Glycerol concentration increased in response to resistance exercise and decreased significantly (P < 0.05) during the recovery period, whereas, the concentration of NEFA increased significantly during the recovery period (P < 0.05) and these changes were not significantly different between the two protocols. We conclude, that IRE leads to more reductions in insulin concentrations during exercise and recovery than TRE, and that although NEFA and glycerol change following resistance exercise, lipolysis is not related to the exercise type when the exercise volume is constant. [ABSTRACT FROM AUTHOR]

[Display omitted] • Deep eutectic solvent-catalyzed glycolysis of post-consumer PET is proposed. • ChCl–Zn(OAc) 2 affords complete conversion of PET with high BHET selectivity. • Degradation mechanism of PET glycolysis is examined through DFT calculations. • Machine learning is applied to construct a predictive model for PET glycolysis. To achieve a sustainable and circular economy, developing effective plastic recycling methods is essential. Despite advances in the chemical recycling of plastic waste, modern industries require highly efficient and sustainable solutions to address environmental problems. In this study, we propose an efficient glycolysis strategy for post-consumer polyethylene terephthalate (PET) using deep eutectic solvents (DESs) to produce bis(2-hydroxyethyl) terephthalate (BHET) with high selectivity. Choline chloride (ChCl)- and urea-based DESs were synthesized using various metal salts and were tested for the glycolysis of PET waste; ChCl–Zn(OAc) 2 exhibited the best performance. The DES-containing solvent system afforded a complete PET conversion, producing BHET at a high yield (91.6%) under optimal reaction conditions. The degradation mechanism of PET and its interaction with DESs were systematically investigated using density functional theory-based calculations. Furthermore, an intuitive machine learning model was developed to predict the PET conversion and BHET selectivity for different DES compositions. Our findings demonstrate that the DES-catalyzed glycolysis of post-consumer PET could enable the development of a sustainable chemical recycling process, providing insights to identify the new design of DESs for plastic decomposition. [ABSTRACT FROM AUTHOR]

Activated platelets promote tumor progression and metastasis through active interactions with cancer cells, especially in promoting epithelial-mesenchymal transition (EMT) of tumor cells and shedding tumor cells into the blood. Blocking platelet-tumor cell interactions can be a potential strategy to inhibit tumor metastasis. Platelet activation requires energy produced from aerobic glycolysis. Based on this, we propose a platelet suppression strategy by reprogramming glucose metabolism of platelets, which has an advantage over conventional antiplatelet treatment that has a risk of serious hemorrhage. We develop a biomimetic delivery system using platelet membrane-hybridized liposomes (PM-Lipo) for codelivery of quercetin and shikonin to simultaneously inhibit lactate transporter MCT-4 and a glycolytic enzyme PKM2 for achieving metabolic reprogramming of platelets and suppressing platelet activation. Notably, PM-Lipo can also inhibit glycolysis in cancer cells, which actually takes "two-birds-one-stone" action. Consequently, the platelet-tumor cell interactions are inhibited. Moreover, PM-Lipo can bind with circulating tumor cells and reduce their seeding in the premetastatic microenvironment. The in vivo studies further demonstrated that PM-Lipo can effectively suppress primary tumor growth and reduce lung metastasis without affecting inherited functions of platelets. Reprogramming glycolysis of platelets can remodel the tumor immune microenvironment, including suppression of Treg and stimulation of CTLs. After i.v. injection, PM-Lipo arrives at the tumor site and acts on platelets and tumor cells. By reprogramming glycolysis in both of them, PM-Lipo inhibits platelet activation and tumor cell proliferation, blocks tumor-platelet interaction, and suppresses tumor metastasis. Additionally, PM-Lipo can bind with circulating tumor cells and reduce their seeding in pre-metastatic niche. [Display omitted] [ABSTRACT FROM AUTHOR]

Metabolic heterogeneity and the tumor immunosuppressive microenvironment (TIME) of triple-negative breast cancer (TNBC) hinder therapeutic effectiveness. Although emerging metabolic therapy and immunotherapy show promise, they are limited by off-target effects and immune escape. Here, a redox-activatable, sequentially-releasing nanoparticle (AMANC@M) for tumor-targeted delivery of anticancer agents and CRISPR/Cas9 has been developed. AMANC@M can reverse the TIME through dual metabolic inhibition, thereby enhancing TNBC therapy. AMANC@M demonstrates excellent biosafety and targets tumors precisely through biomimetic hybrid membrane-mediated homologous homing and the enhanced permeability and retention (EPR) effect. Once internalized into tumor cells, the CRISPR/Cas9 system ("energy nanolock") is released through glutathione (GSH) cleavage and effectively knocks down the expression of lactate dehydrogenase A (LDHA) to suppress glycolysis. After peeling off of the gene editing shell, a newly synthesized targeted drug, CPI-Z2 ("nutrihijacker" and "energy nanolock"), is released in a controlled manner to block the mitochondrial tricarboxylic acid (TCA) cycle. Nitric oxide (NO) produced from loaded L-arginine enhances the efficiency of CPI-Z2 and reduces drug resistance. Combined with NO therapy, both blockades of nutrients and energy production transform the hypoxia and acidic TIME into an immunocompetent tumor microenvironment (TME) for tumor elimination. Furthermore, AMANC@M offers capabilities for photothermal (PT) therapy and provides clear imaging through PT, photoacoustic (PA), or computed tomography (CT) signals in tumor tissue. Thus, this study provides a new and promising sequentially stimuli-responsive targeting strategy for nanoparticle development, making it a potential treatment candidate for TNBC and other tumors. [Display omitted] • A targeted, redox-activatable, sequentially-releasing strategy is proposed. • Regulation of glycolysis and TCA cycle with nutrihijacker and energy nanolock. • The NPs activate cytotoxic T lymphocytes by inhibiting metabolism to reverse TIME. • The NPs allow multimodal cancer treatment guided by PT/PA/CT multimodal imaging. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is a progressive disease with vascular remodeling as a critical structural alteration. We have previously shown that metabolic reprogramming is an early initiating mechanism in animal models of PH. This metabolic dysregulation has been linked to remodeling the mitochondrial network to favor fission. However, whether the mitochondrial fission/fusion balance underlies the metabolic reprogramming found early in PH development is unknown. Utilizing a rat early model of PH, in conjunction with cultured pulmonary endothelial cells (PECs), we utilized metabolic flux assays, Seahorse Bioassays, measurements of electron transport chain (ETC) complex activity, fluorescent microscopy, and molecular approaches to investigate the link between the disruption of mitochondrial dynamics and the early metabolic changes that occur in PH. We observed increased fusion mediators, including Mfn1, Mfn2, and Opa1, and unchanged fission mediators, including Drp1 and Fis1, in a two-week monocrotaline-induced PH animal model (early-stage PH). We were able to establish a connection between increases in fusion mediator Mfn1 and metabolic reprogramming. Using an adenoviral expression system to enhance Mfn1 levels in pulmonary endothelial cells and utilizing 13C-glucose labeled substrate, we found increased production of 13C lactate and decreased TCA cycle metabolites, revealing a Warburg phenotype. The use of a 13C 5 -glutamine substrate showed evidence that hyperfusion also induces oxidative carboxylation. The increase in glycolysis was linked to increased hypoxia-inducible factor 1α (HIF-1α) protein levels secondary to the disruption of cellular bioenergetics and higher levels of mitochondrial reactive oxygen species (mt-ROS). The elevation in mt-ROS correlated with attenuated ETC complexes I and III activities. Utilizing a mitochondrial-targeted antioxidant to suppress mt-ROS, limited HIF-1α protein levels, which reduced cellular glycolysis and reestablished mitochondrial membrane potential. Our data connects mitochondrial fusion-mediated mt-ROS to the Warburg phenotype in early-stage PH development. [Display omitted] • Fission/fusion balance disruption is critical for metabolic reprogramming in PH. • Mitofusin1 (Mfn1) overexpression produced metabolic remodeling in endothelial cells. • Mfn1 mediated metabolic remodeling disrupted bioenergetics and increased glycolysis. • Mfn1 increased mitochondrial ROS and HIF-1α, and disrupted ETC complexes I and III. • Mitochondrial targeted ROS scavenger T-SSP decreased Mfn1 mediated ROS. [ABSTRACT FROM AUTHOR]

[Display omitted] • Paradigm shift from reactive to 3P medicine in essential in cancer management. • Natural substances are characterized by potent anticancer effects in primary and secondary care. • Working hypothesis proposes HIF-1α pathways to target by flavonoids against cancer resistance. • Clinically relevant example: individuals with the Flammer (FS) syndrome phenotype. • Economy relevant innovation is cost-effective prevention of the health-to-disease transition. Cancer management faces multiple obstacles, including resistance to current therapeutic approaches. In the face of challenging microenvironments, cancer cells adapt metabolically to maintain their supply of energy and precursor molecules for biosynthesis and thus sustain rapid proliferation and tumor growth. Among the various metabolic adaptations observed in cancer cells, the altered glucose metabolism is the most widely studied. The aberrant glycolytic modification in cancer cells has been associated with rapid cell division, tumor growth, cancer progression, and drug resistance. The higher rates of glycolysis in cancer cells, as a hallmark of cancer progression, is modulated by the transcription factor hypoxia inducible factor 1 alpha (HIF-1α), a downstream target of the PI3K/Akt signaling, the most deregulated pathway in cancer. We provide a detailed overview of current, primarily experimental, evidence on the potential effectiveness of flavonoids to combat aberrant glycolysis-induced resistance of cancer cells to conventional and targeted therapies. The manuscript focuses primarily on flavonoids reducing cancer resistance via affecting PI3K/Akt, HIF-1α (as the transcription factor critical for glucose metabolism of cancer cells that is regulated by PI3K/Akt pathway), and key glycolytic mediators downstream of PI3K/Akt/HIF-1α signaling (glucose transporters and key glycolytic enzymes). The working hypothesis of the manuscript proposes HIF-1α – the transcription factor critical for glucose metabolism of cancer cells regulated by PI3K/Akt pathway as an attractive target for application of flavonoids to mitigate cancer resistance. Phytochemicals represent a source of promising substances for cancer management applicable to primary, secondary, and tertiary care. However, accurate patient stratification and individualized patient profiling represent crucial steps in the paradigm shift from reactive to predictive, preventive, and personalized medicine (PPPM / 3PM). The article is focused on targeting molecular patterns by natural substances and provides evidence-based recommendations for the 3PM relevant implementation. [ABSTRACT FROM AUTHOR]

Background: The heart has metabolic flexibility, which is influenced by fed/fasting states, and pathologies such as myocardial ischemia and hypertrophic cardiomyopathy (HCM). Hyperpolarized (HP) 13C-pyruvate MRI is a promising new tool for non-invasive quantification of myocardial glycolytic and Krebs cycle flux. However, human studies of HP 13C-MRI have yet to demonstrate regional quantification of metabolism, which is important in regional ischemia and HCM patients with asymmetric septal/apical hypertrophy. Methods: We developed and applied methods for whole-heart imaging of 13C-pyruvate, 13C-lactate and 13C-bicarbonate, following intravenous administration of [1-13C]-pyruvate. The image acquisition used an autonomous scanning method including bolus tracking, real-time magnetic field calibrations and metabolite-specific imaging. For quantification of metabolism, we evaluated 13C metabolite images, ratio metrics, and pharmacokinetic modeling to provide measurements of myocardial lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH) mediated metabolic conversion in 5 healthy volunteers (fasting & 30 min following oral glucose load). Results: We demonstrate whole heart coverage for dynamic measurement of pyruvate-to-lactate conversion via LDH and pyruvate-to-bicarbonate conversion via PDH at a resolution of 6 × 6 × 21 mm3 (13C-pyruvate) and 12 × 12 × 21 mm3 (13C-lactate, 13C-bicarbonate). 13C-pyruvate and 13C-lactate were detected simultaneously in the RV blood pool, immediately after intravenous injection, reflecting LDH activity in blood. In healthy volunteers, myocardial 13C-pyruvate-SNR, 13C-lactate-SNR, 13C-bicarbonate-SNR, 13C-lactate/pyruvate ratio, 13C-pyruvate-to-lactate conversion rate, kPL, and 13C-pyruvate-to-bicarbonate conversion rate, kPB, all had statistically significant increases following oral glucose challenge. kPB, reflecting PDH activity and pyruvate entering the Krebs Cycle, had the highest correlation with blood glucose levels and was statistically significant. Conclusions: We demonstrate first-in-human regional quantifications of cardiac metabolism by HP 13C-pyruvate MRI that aims to reflect LDH and PDH activity. [ABSTRACT FROM AUTHOR]

Proliferating cells have increased mitochondrial activity relative to quiescent cells. Metabolic pathways in mitochondria are saturated in proliferating cells exhibiting the Warburg effect. Mitochondrial activity is constrained by the flux of NAD+ turnover in proliferating cells. The Warburg effect occurs in proliferating cells because glycolysis outpaces the maximum rate of glucose oxidation. A long-standing question in cancer biology has been why oxygenated tumors ferment the majority of glucose they consume to lactate rather than oxidizing it in their mitochondria, a phenomenon known as the 'Warburg effect.' An abundance of evidence shows not only that most cancer cells have fully functional mitochondria but also that mitochondrial activity is important to proliferation. It is therefore difficult to rationalize the metabolic benefit of cancer cells switching from respiration to fermentation. An emerging perspective is that rather than mitochondrial metabolism being suppressed in tumors, as is often suggested, mitochondrial activity increases to the level of saturation. As such, the Warburg effect becomes a signature of excess glucose being released as lactate due to mitochondrial overload. [ABSTRACT FROM AUTHOR]

Maximal accumulated oxygen deficit (MAOD) is a gold standard measure of anaerobic capacity. The purpose of this study was to evaluate an alternative measure that avoids the contentious assumptions and the time-consuming procedures of the MAOD method. Twenty-seven women (mean ± SD, age, 22 ± 1 y, height 165 ± 7 cm, weight 63.4 ± 9.7 kg) and 25 men (22 ± 1 y, 179 ± 6 cm, 80.8 ± 14.8 kg) performed running and cycling tests that resulted in exhaustion after ∼5 min. In each test, anaerobic capacity was determined as MAOD and as the sum of the phosphocreatine (PCr) and glycolytic contributions, which were determined from the post-exercise oxygen uptake curve and blood lactate concentration, respectively. The sum, " PCr + glycolysis ", was compared to MAOD using analysis of variance. There was no difference (P = 0.64) between MAOD and PCr + glycolysis (no main effect of method in the analysis of variance). Values were 78 ± 7 mL·kg−1 and 75 ± 8 mL·kg−1 in running (effect size for paired means = 0.8) and 59 ± 6 mL·kg−1 and 61 ± 8 mL·kg−1 in cycling (effect size for paired means = –0.7). Values were greater (P < 0.01) in running (significant effect of mode) with effect sizes of 4.6 for MAOD and 2.9 for PCr + glycolysis. There was no interaction effect involving sex. It is concluded that PCr + glycolysis provides a valid measure of anaerobic capacity that avoids difficulties associated with the MAOD method and is suitable for running as well as for cycling exercise and for recreationally-active, moderately fit men as well as for women. [ABSTRACT FROM AUTHOR]

Formaldehyde (FA) exposure has been positively correlated with many diseases including various types of cancers. However, the mechanisms of FA-related carcinogenesis are still unclear. Tumor-associated macrophages (TAMs) are the most abundant immune cells in tumor microenvironment, which is a heterogeneous population consist of both pro-inflammatory (M1) and immunosuppressive (M2) cells. TAMs are deeply involved in tumor development and progression. Our previous studies demonstrated that FA enhanced M1 polarization of macrophages through induction of HIF-1α-mediated glycolysis. To examine if TAM polarizations are also potentiated by FA, BALB/c nude mice were inoculated with A549 cells to develop subcutaneous tumors and exposed to 2.0 mg/m3 FA for 14 days. Significant increases of both M1 and M2 polarizations of TAMs were observed in tumor tissues of FA-exposed mice. After confirmation of the potentiation effects in RAW264.7 and THP-1-derived in vitro TAM models, FA at 25 and 50 μM was found to enhance TAM immunosuppressive functions and glycolytic metabolism. In addition, FA-induced glycolysis in TAMs was reversed by a specific HIF-1α inhibitor PX-478 at 5 μM, and suppression of glycolytic metabolism with a glucose analog 2-DG at 1 mM also alleviated FA-potentiated TAM functions, which indicated that FA induced TAM polarizations through the upregulation of HIF-1α-mediated glycolysis. These results illustrated a potential carcinogenic mechanism of FA through metabolic disturbance of tumor immunity, which could be utilized to develop preventative or therapeutic agents for FA-induced carcinogenesis and immune disorders. [Display omitted] • FA potentiated both M1 and M2 polarizations of TAMs in vivo and in vitro. • FA reinforced TAM functions and glycolytic metabolism. • HIF-1α mediated FA-induced TAM polarizations and glycolysis. • Suppression of glycolysis alleviated FA-potentiated TAM functions. [ABSTRACT FROM AUTHOR]

The definitive number of Sertoli cells (SCs), achieved during the proliferative periods, defines the spermatogenic capacity in adulthood. It is recognized that FSH is the main mitogen targeting SC and that it exerts its action, at least partly, through the activation of the PI3K/Akt/mTORC1 pathway. mTORC1 controls a large number of cellular functions, including glycolysis and cell proliferation. Interestingly, recent evidence revealed that the glycolytic flux might modulate mTORC1 activity and, consequently, cell cycle progression. Although mature SC metabolism has been thoroughly studied, several aspects of metabolism regulation in proliferating SC are still to be elucidated. The objective of this study was to explore whether aerobic glycolysis is regulated by FSH through mTORC1 pathway in proliferating SC, and to assess the involvement of glycolysis in the regulation of SC proliferation. The present study was carried out utilizing 8-day-old rat SC cultures. The results obtained show that FSH enhances glycolytic flux through the induction of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and lactate dehydrogenase A (LDHA) in an mTORC1 dependent manner. In addition, PFKFB3 and LDH inhibitors prevent FSH from activating mTORC1 and stimulating SC proliferation and glycolysis, presumably through mTORC1 pathway inhibition. In summary, FSH simultaneously regulates SC proliferation and glycolysis in an mTORC1 dependent manner, and glycolysis seems to cooperate with FSH in the stimulation of both cellular functions through the modulation of the same signalling pathway. Therefore, a positive feedback between the mTORC1 pathway and glycolysis triggered by FSH is hypothesized. A schematic model of the cooperative role of glycolysis in the regulation of Sertoli cell proliferation by FSH through the mTORC1 signalling pathway. FSH upregulates glycolysis and proliferation in an mTORC1-dependent manner by inducing PFKFB3, LDHA, CCND1 and CCND2 expression due to enhanced c-Myc transcriptional activity (red pathway). Simultaneously, the higher glycolytic flux promoted by FSH might lead to the activation of the mTORC1 signalling pathway, which is involved in the upregulation of PFKFB3, LDHA, CCND1 and CCND2 expression trough c-Myc (blue pathway). [Display omitted] • FSH regulates Sertoli cell proliferation and aerobic glycolysis trough mTORC1. • Glycolysis cooperates with FSH in stimulating proliferation and glycolytic flux. • mTORC1 and glycolysis under FSH stimulation might constitute a virtuous cycle. [ABSTRACT FROM AUTHOR]