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Adaptive laboratory evolution experiments provide a controlled context in which the dynamics of selection and adaptation can be followed in real-time at the single-nucleotide level. And yet this precision introduces hundreds of degrees-of-freedom as genetic changes accrue in parallel lineages over generations. On short timescales, physiological constraints have been leveraged to provide a coarse-grained view of bacterial gene expression characterized by a small set of phenomenological parameters. Here, we ask whether this same framework, operating at a level between genotype and fitness, informs physiological changes that occur on evolutionary timescales. Using a strain adapted to growth in glucose minimal medium, we find that the proteome is substantially remodeled over 40 000 generations. The most striking change is an apparent increase in enzyme efficiency, particularly in the enzymes of lower-glycolysis. We propose that deletion of metabolic flux-sensing regulation early in the adaptation results in increased enzyme saturation and can account for the observed proteome remodeling.

Neural progenitor cells within the cerebral cortex undergo a characteristic switch between symmetric self-renewing cell divisions early in development and asymmetric neurogenic divisions later. Yet, the mechanisms controlling this transition remain unclear. Previous work has shown that early but not late neural progenitor cells (NPCs) endogenously express the autism-linked transcription factor Foxp1, and both loss and gain of Foxp1 function can alter NPC activity and fate choices. Here, we show that premature loss of Foxp1 upregulates transcriptional programs regulating angiogenesis, glycolysis, and cellular responses to hypoxia. These changes coincide with a premature destabilization of HIF-1α, an elevation in HIF-1α target genes, including Vegfa in NPCs, and precocious vascular network development. In vitro experiments demonstrate that stabilization of HIF-1α in Foxp1-deficient NPCs rescues the premature differentiation phenotype and restores NPC maintenance. Our data indicate that the endogenous decline in Foxp1 expression activates the HIF-1α transcriptional program leading to changes in the tissue environment adjacent to NPCs, which, in turn, might alter their self-renewal and neurogenic capacities.

In Alzheimer's disease (AD), dysfunctional mitochondrial metabolism is associated with synaptic loss, the major pathological correlate of cognitive decline. Mechanistic insight for this relationship, however, is still lacking. Here, comparing isogenic wild-type and AD mutant human induced pluripotent stem cell (hiPSC)-derived cerebrocortical neurons (hiN), evidence is found for compromised mitochondrial energy in AD using the Seahorse platform to analyze glycolysis and oxidative phosphorylation (OXPHOS). Isotope-labeled metabolic flux experiments revealed a major block in activity in the tricarboxylic acid (TCA) cycle at the α-ketoglutarate dehydrogenase (αKGDH)/succinyl coenzyme-A synthetase step, metabolizing α-ketoglutarate to succinate. Associated with this block, aberrant protein S-nitrosylation of αKGDH subunits inhibited their enzyme function. This aberrant S-nitrosylation is documented not only in AD-hiN but also in postmortem human AD brains versus controls, as assessed by two separate unbiased mass spectrometry platforms using both SNOTRAP identification of S-nitrosothiols and chemoselective-enrichment of S-nitrosoproteins. Treatment with dimethyl succinate, a cell-permeable derivative of a TCA substrate downstream to the block, resulted in partial rescue of mitochondrial bioenergetic function as well as reversal of synapse loss in AD-hiN. These findings have therapeutic implications that rescue of mitochondrial energy metabolism can ameliorate synaptic loss in hiPSC-based models of AD.

Understanding the dynamics of biological systems in evolving environments is a challenge due to their scale and complexity. Here, we present a computational framework for the timescale decomposition of biochemical reaction networks to distill essential patterns from their intricate dynamics. This approach identifies timescale hierarchies, concentration pools, and coherent structures from time-series data, providing a system-level description of reaction networks at physiologically important timescales. We apply this technique to kinetic models of hypothetical and biological pathways, validating it by reproducing analytically characterized or previously known concentration pools of these pathways. Moreover, by analyzing the timescale hierarchy of the glycolytic pathway, we elucidate the connections between the stoichiometric and dissipative structures of reaction networks and the temporal organization of coherent structures. Specifically, we show that glycolysis is a cofactor-driven pathway, the slowest dynamics of which are described by a balance between high-energy phosphate bond and redox trafficking. Overall, this approach provides more biologically interpretable characterizations of network dynamics than large-scale kinetic models, thus facilitating model reduction and personalized medicine applications. IMPORTANCE Complex interactions within interconnected biochemical reaction networks enable cellular responses to a wide range of unpredictable environmental perturbations. Understanding how biological functions arise from these intricate interactions has been a long-standing problem in biology. Here, we introduce a computational approach to dissect complex biological systems dynamics in evolving environments. This approach characterizes the timescale hierarchies of complex reaction networks, offering a system-level understanding at physiologically relevant timescales. Analyzing various hypothetical and biological pathways, we show how stoichiometric properties shape the way energy is dissipated throughout reaction networks. Notably, we establish that glycolysis operates as a cofactor-driven pathway, where the slowest dynamics are governed by a balance between high-energy phosphate bonds and redox trafficking. This approach enhances our understanding of network dynamics and facilitates the development of reduced-order kinetic models with biologically interpretable components.

The high incidence of epithelial malignancies in HIV-1 infected individuals is associated with co-infection with oncogenic viruses, such as high-risk human papillomaviruses (HR HPVs), mostly HPV16. The molecular mechanisms underlying the HIV-1-associated increase in epithelial malignancies are not fully understood. A collaboration between HIV-1 and HR HPVs in the malignant transformation of epithelial cells has long been anticipated. Here, we delineated the effects of HIV-1 reverse transcriptase on the in vitro and in vivo properties of HPV16-infected cervical cancer cells. A human cervical carcinoma cell line infected with HPV16 (Ca Ski) was made to express HIV-1 reverse transcriptase (RT) by lentiviral transduction. The levels of the mRNA of the E6 isoforms and of the factors characteristic to the epithelial/mesenchymal transition were assessed by real-time RT-PCR. The parameters of glycolysis and mitochondrial respiration were determined using Seahorse technology. RT expressing Ca Ski subclones were assessed for the capacity to form tumors in nude mice. RT expression increased the expression of the E6*I isoform, modulated the expression of E-CADHERIN and VIMENTIN, indicating the presence of a hybrid epithelial/mesenchymal phenotype, enhanced glycolysis, and inhibited mitochondrial respiration. In addition, the expression of RT induced phenotypic alterations impacting cell motility, clonogenic activity, and the capacity of Ca Ski cells to form tumors in nude mice. These findings suggest that HIV-RT, a multifunctional protein, affects HPV16-induced oncogenesis, which is achieved through modulation of the expression of the E6 oncoprotein. These results highlight a complex interplay between HIV antigens and HPV oncoproteins potentiating the malignant transformation of epithelial cells.

Hematopoietic stem cells (HSCs) exhibit significant functional and metabolic alterations within the lung cancer microenvironment, contributing to tumor progression and immune evasion by increasing differentiation into myeloid-derived suppressor cells (MDSCs). Our aim is to analyze the metabolic transition of HSCs from glycolysis to oxidative phosphorylation (OXPHOS) in lung cancer and determine its effects on HSC functionality. Using a murine Lewis Lung Carcinoma lung cancer model, we conducted metabolic profiling of long-term and short-term HSCs, as well as multipotent progenitors, comparing their metabolic states in normal and cancer conditions. We measured glucose uptake using 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino]-2-Deoxyglucose (2-NBDG) and assessed levels of lactate, acetyl-coenzyme A, and ATP. Mitochondrial functionality was evaluated through flow cytometry, alongside the impact of the glucose metabolism inhibitor 2-DG on HSC differentiation and mitochondrial activity. HSCs under lung cancer conditions showed increased glucose uptake and lactate production, with an associated rise in OXPHOS activity, marking a metabolic shift. Treatment with 2-DG led to decreased T-HSCs and MDSCs and an increased red blood cell count, highlighting its potential to influence metabolic and differentiation pathways in HSCs. This study provides novel insights into the metabolic reprogramming of HSCs in lung cancer, emphasizing the critical shift from glycolysis to OXPHOS and its implications for the therapeutic targeting of cancer-related metabolic pathways. [ABSTRACT FROM AUTHOR]

Background: Diabetic atherosclerosis is one of the main causes of morbidity and mortality worldwide, but its therapeutic options are limited. Liraglutide (LIR), a synthetic analog of GLP-1 approved as an anti-obesity drug by the FDA, has been reported as a promising drug for diabetic atherosclerosis. However, the main problem with LIR is its use that requires regular parenteral injections, which necessitates the improvement of drug delivery for increased efficiency and minimization of injection numbers. Results: The objective of our present study was to prepare and characterize nanoparticles (BSA@LIR-PMF) for targeted drug delivery using LIR-encapsulated platelet membrane fragments (PMF) coated bovine serum albumin (BSA). We used various methods to characterize the prepared nanoparticles and evaluated their efficiency on diabetes-induced atherosclerosis in vitro and in vivo. The results showed that the nanoparticles were spherical and had good stability and uniform size with intact membrane protein structure. The loading and encapsulation rates (LR and ER) of BSA@LIR-PMF were respectively 7.96% and 85.56%, while the cumulative release rate was around 77.06% after 24 h. Besides, we also examined the impact of BSA@LIR-PMF on the proliferation, migration, phagocytosis, reactive oxygen species (ROS) levels, oxidative phosphorylation, glycolysis, lactate and ATP levels, and lipid deposition in the aortas. The results indicated that BSA@LIR-PMF could effectively inhibit ox-LDL-stimulated abnormal cell proliferation and migration, reduce the level of ROS and lactate concentration, and enhance the level of ATP, thereby improving oxidative phosphorylation in ox-LDL-treated cells. Conclusion: BSA@LIR-PMF significantly inhibited diabetes-induced atherosclerosis. It was anticipated that the BSA@LIR-PMF nanoparticles might be used for treating diabetes-associated cardiovascular complications. [ABSTRACT FROM AUTHOR]

The microenvironment mediated by the microglia (MG) M1/M2 phenotypic switch plays a decisive role in the neuronal fate and cognitive function of Alzheimer's disease (AD). However, the impact of metabolic reprogramming on microglial polarization and its underlying mechanism remains elusive. This study reveals that cordycepin improved cognitive function and memory in APP/PS1 mice, as well as attenuated neuronal damage by triggering MG‐M2 polarization and metabolic reprogramming characterized by increased OXPHOS and glycolysis, rather than directly protecting neurons. Simultaneously, cordycepin partially alleviates mitochondrial damage in microglia induced by inhibitors of OXPHOS and glycolysis, further promoting MG‐M2 transformation and increasing neuronal survival. Through confirmation of cordycepin distribution in the microglial mitochondria via mitochondrial isolation followed by HPLC‐MS/MS techniques, HKII and PDK2 are further identified as potential targets of cordycepin. By investigating the effects of HKII and PDK2 inhibitors, the mechanism through which cordycepin targeted HKII to elevate ECAR levels in the glycolysis pathway while targeting PDK2 to enhance OCR levels in PDH‐mediated OXPHOS pathway, thereby inducing MG‐M2 polarization, promoting neuronal survival and exerting an anti‐AD role is elucidated. [ABSTRACT FROM AUTHOR]

Current therapeutics of endometriosis focus on hormonal disruption of endometriotic lesions (ectopic endometrium, EcE). Recent findings show higher glycolysis utilization in EcE, suggesting non-hormonal strategy for disease treatment that addresses cellular metabolism. Identifying metabolically altered cell types in EcE is important for targeted metabolic drug therapy without affecting eutopic endometrium (EuE). Here, using single-cell RNA-sequencing, we examine twelve metabolic pathways in paired samples of EuE and EcE from women with confirmed endometriosis. We detect nine major cell types in both EuE and EcE. Metabolic pathways are most differentially regulated in perivascular, stromal, and endothelial cells, with the highest changes in AMPK signaling, HIF-1 signaling, glutathione metabolism, oxidative phosphorylation, and glycolysis. We identify transcriptomic co-activation of glycolytic and oxidative metabolism in perivascular and stromal cells of EcE, indicating a critical role of metabolic reprogramming in maintaining endometriotic lesion growth. Perivascular cells, involved in endometrial stroma repair and angiogenesis, may be potential targets for non-hormonal treatment of endometriosis. Single-cell transcriptomics reveals altered metabolism in ectopic and eutopic endometrium. These findings suggest a critical role of metabolic reprogramming in endometriotic lesion growth and survival, with perivascular cells being key contributors. [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]

Background: Influenza virus is one of the most common pathogens that cause viral pneumonia. During pneumonia, host immune inflammation regulation involves microbiota in the intestine and glycolysis in the lung tissues. In the clinical guidelines for pneumonia treatment in China, Ma Xing Shi Gan Decoction (MXSG) is a commonly prescribed traditional Chinese medicine formulation with significant efficacy, however, it remains unclear whether its specific mechanism of action is related to the regulation of intestinal microbiota structure and lung tissue glycolysis. Objective: This study aimed to investigate the mechanism of action of MXSG in an animal model of influenza virus-induced pneumonia. Specifically, we aimed to elucidate how MXSG modulates intestinal microbiota structure and lung tissue glycolysis to exert its therapeutic effects on pneumonia. Methods: We established a mouse model of influenza virus-induced pneumoni, and treated with MXSG. We observed changes in inflammatory cytokine levels and conducted 16S rRNA gene sequencing to assess the intestinal microbiota structure and function. Additionally, targeted metabolomics was performed to analyze lung tissue glycolytic metabolites, and Western blot and enzyme-linked immunosorbent assays were performed to assess glycolysis-related enzymes, lipopolysaccharides (LPSs), HIF-1a, and macrophage surface markers. Correlation analysis was conducted between the LPS and omics results to elucidate the relationship between intestinal microbiota and lung tissue glycolysis in pneumonia animals under the intervention of Ma Xing Shi Gan Decoction. Results: MXSG reduced the abundance of Gram-negative bacteria in the intestines, such as Proteobacteria and Helicobacter, leading to reduced LPS content in the serum and lungs. This intervention also suppressed HIF-1a activity and lung tissue glycolysis metabolism, decreased the number of M1-type macrophages, and increased the number of M2-type macrophages, effectively alleviating lung damage caused by influenza virus-induced pneumonia. Conclusion: MXSG can alleviate glycolysis in lung tissue, suppress M1-type macrophage activation, promote M2-type macrophage activation, and mitigate inflammation in lung tissue. This therapeutic effect appears to be mediated by modulating gut microbiota and reducing endogenous LPS production in the intestines. This study demonstrates the therapeutic effects of MXSG on pneumonia and explores its potential mechanism, thus providing data support for the use of traditional Chinese medicine in the treatment of respiratory infectious diseases. [ABSTRACT FROM AUTHOR]

Disrupted lipid metabolism is a characteristic of gliomas. This study utilizes an ultrastructural approach to characterize the prevalence and distribution of lipids within gliomas. This study made use of tissue from IDH1 wild type (IDH1-wt) glioblastoma (n = 18) and IDH1 mutant (IDH1-mt) astrocytoma (n = 12) tumors. We uncover a prevalent and intriguing surplus of lipids. The bulk of the lipids manifested as sizable cytoplasmic inclusions and extracellular deposits in the tumor microenvironment (TME); in some tumors the lipids were stored in the classical membraneless spheroidal lipid droplets (LDs). Frequently, lipids accumulated inside mitochondria, suggesting possible dysfunction of the beta-oxidation pathway. Additionally, the tumor vasculature have lipid deposits in their lumen and vessel walls; this lipid could have shifted in from the tumor microenvironment or have been produced by the vessel-invading tumor cells. Lipid excess in gliomas stems from disrupted beta-oxidation and dysfunctional oxidative phosphorylation pathways. The implications of this lipid-driven environment include structural support for the tumor cells and protection against immune responses, non-lipophilic drugs, and free radicals. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis. Here, a macrophage infection model was used to unravel the role of the histone deacetylase sirtuin 6 (SIRT6) in Mtb‐triggered regulation of the innate immune response. Mtb infection downregulated microRNA‐26a and upregulated its target SIRT6. SIRT6 suppressed glycolysis and expression of HIF‐1α‐dependent glycolytic genes during infection. In addition, SIRT6 regulated the levels of intracellular succinate which controls stabilization of HIF‐1α, as well as the release of interleukin (IL)‐1β. Furthermore, SIRT6 inhibited inducible nitric oxide synthase (iNOS) and proinflammatory IL‐6 but augmented anti‐inflammatory arginase expression. The miR‐26a/SIRT6/HIF‐1α axis therefore regulates glycolysis and macrophage immune responses during Mtb infection. Our findings link SIRT6 to rewiring of macrophage signaling pathways facilitating dampening of the antibacterial immune response. [ABSTRACT FROM AUTHOR]

The immune system requires a high energy expenditure to resist pathogen invasion. Macrophages undergo metabolic reprogramming to meet these energy requirements and immunologic activity and polarize to M1-type macrophages. Understanding the metabolic pathway switching in large yellow croaker (Larimichthys crocea) macrophages in response to lipopolysaccharide (LPS) stimulation and whether this switching affects immunity is helpful in explaining the stronger immunity of hypoxia-tolerant L. crocea. In this study, transcript levels of glycolytic pathway genes (Glut1 and Pdk1), mRNA levels or enzyme activities of glycolytic enzymes [hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), and lactate dehydrogenase A (LDHA)], aerobic respiratory enzymes [pyruvate dehydrogenase (PDH), isocitrate dehydrogenase (IDH), and succinate dehydrogenase (SDH)], metabolites [lactic acid (LA) and adenosine triphosphate (ATP)], levels of bactericidal products [reactive oxygen species (ROS) and nitric oxide (NO)], and transcripts and level changes of inflammatory factors [IL1β, TNFα, and interferon (IFN) γ] were detected in LPSstimulated L. crocea head kidney macrophages. We showed that glycolysis was significantly induced, the tricarboxylic acid (TCA) cycle was inhibited, and metabolic reprogramming occurred, showing the Warburg effect when immune cells were activated. To determine the potential regulatory mechanism behind these changes, LcHIF-1α was detected and found to be significantly induced and transferred to the nucleus after LPS stimulation. LcHif-1a interference led to a significant reduction in glycolytic pathway gene transcript expression, enzyme activity, metabolites, bactericidal substances, and inflammatory factor levels; a significant increase in the aerobic respiration enzymes; and decreased migration, invasion, and phagocytosis. Further ultrastructural observation by electron microscopy showed that fewer microspheres contained phagocytes and that more cells were damaged after LcHif-1α interference. LcHif-1α overexpression L. crocea head kidney macrophages showed the opposite trend, and promoter activities of Ldha and Il1β were significantly enhanced after LcHif-1α overexpression in HEK293T cells. Our data showed that LcHIF-1α acted as a metabolic switch in L. crocea macrophages and was important in polarization. Hypoxia-tolerant L. crocea head kidney showed a stronger Warburg effect and inhibited the TCA cycle, higher metabolites, and bactericidal substance levels. These results collectively revealed that LcHif-1α may promote the functional activities of head kidney macrophages in protecting hypoxia-tolerant L. crocea from Aeromonas hydrophila infection. [ABSTRACT FROM AUTHOR]

Cell adhesion to the extracellular matrix and its natural outcome of cell spreading, along with the maintenance of barrier activity, are essential behaviors of epithelial cells, including retinal pigment epithelium (RPE). Disruptions in these characteristics can result in severe vision-threatening diseases such as diabetic macular edema and age-related macular degeneration. However, the precise mechanisms underlying how RPE cells regulate their barrier integrity and cell spreading are not fully understood. This study aims to elucidate the relative importance of upper glycolytic components in governing these cellular behaviors of RPE cells. Electric Cell-Substrate Impedance Sensing (ECIS) technology was utilized to assess in real-time the effects of targeting various upper glycolytic enzymes on RPE barrier function and cell spreading by measuring cell resistance and capacitance, respectively. Specific inhibitors used included WZB117 for Glut1 inhibition, Lonidamine for Hexokinase inhibition, PFK158 for PFKFB3/PFK axis inhibition, and TDZD-8 for Aldolase inhibition. Additionally, the viability of RPE cells was evaluated using a lactate dehydrogenase (LDH) cytotoxicity assay. The most significant decrease in electrical resistance and increase in capacitance of RPE cells were observed due to dose-dependent inhibition of Glut1 using WZB117, as well as Aldolase inhibition with TDZD-8. LDH level analysis at 24–72 h post-treatment with WZB117 (1 and 10 μM) or TDZD-8 (1 μM) showed no significant difference compared to the control, indicating that the disruption of RPE functionality was not attributed to cell death. Lastly, inhibition of other upper glycolytic components, including PFKFB3/PFK with PFK158 or Hexokinase with Lonidamine, did not significantly affect RPE cell behavior. This study provides insights into the varied roles of upper glycolytic components in regulating the functionality of RPE cells. Specifically, it highlights the critical roles of Glut1 and Aldolase in preserving barrier integrity and promoting RPE cell adhesion and spreading. Such understanding will guide the development of safe interventions to treat RPE cell dysfunction in various retinal disorders. [ABSTRACT FROM AUTHOR]

Cancer cells exhibit a unique metabolic preference for the glycolytic pathway over oxidative phosphorylation for maintaining the tumor microenvironment. Lactate dehydrogenase A (LDHA) is a key enzyme that facilitates glycolysis by converting pyruvate to lactate and has been shown to be upregulated in multiple cancers due to the hypoxic tumor microenvironment. Diclofenac (DCF), a nonsteroidal anti‐inflammatory drug, has been shown to exhibit anticancer effects by interfering with the glucose metabolism pathway. However, the specific targets of this drug remain unknown. Using in silico, biochemical, and biophysical studies, we show that DCF binds to LDHA adjacent to the substrate binding site and inhibits its activity in a dose‐dependent and allosteric manner in HeLa cells. Thus, DCF inhibits the hypoxic microenvironment and induces apoptosis‐mediated cell death. DCF failed to induce cytotoxicity in HeLa cells when LDHA was knocked down, confirming that DCF exerts its antimitotic effects via LDHA inhibition. DCF‐induced LDHA inhibition alters pyruvate, lactate, NAD+, and ATP production in cells, and this could be a possible mechanism through which DCF inhibits glucose uptake in cancer cells. DCF‐induced ATP deprivation leads to mitochondria‐mediated oxidative stress, which results in DNA damage, lipid peroxidation, and apoptosis‐mediated cell death. Reduction in intracellular ATP levels additionally activates the sensor kinase, adenosine monophosphate‐activated protein kinase (AMPK), which further downregulates phosphorylated ribosomal S6 kinase (p‐S6K), leading to apoptosis‐mediated cell death. We find that in LDHA knocked down cells, intracellular ATP levels were depleted, resulting in the inhibition of p‐S6K, suggesting the involvement of DCF‐induced LDHA inhibition in the activation of the AMPK/S6K signaling pathway. [ABSTRACT FROM AUTHOR]

A disturbed balance between excitation and inhibition (E/I balance) is increasingly recognized as a key driver of neurodegeneration in multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. To understand how chronic hyperexcitability contributes to neuronal loss in MS, we transcriptionally profiled neurons from mice lacking inhibitory metabotropic glutamate signaling with shifted E/I balance and increased vulnerability to inflammation-induced neurodegeneration. This revealed a prominent induction of the nuclear receptor NR4A2 in neurons. Mechanistically, NR4A2 increased susceptibility to excitotoxicity by stimulating continuous VGF secretion leading to glycolysis-dependent neuronal cell death. Extending these findings to people with MS (pwMS), we observed increased VGF levels in serum and brain biopsies. Notably, neuron-specific deletion of Vgf in a mouse model of MS ameliorated neurodegeneration. These findings underscore the detrimental effect of a persistent metabolic shift driven by excitatory activity as a fundamental mechanism in inflammation-induced neurodegeneration. [ABSTRACT FROM AUTHOR]

Glycolysis is a major determinant of pulmonary artery smooth muscle cell (PASMC) proliferation in pulmonary hypertension (PH). Circular RNAs (circRNAs) are powerful regulators of glycolysis in multiple diseases; however, the role of circRNAs in glycolysis in PH has been poorly characterized. The aim of this study was to uncover the regulatory mechanism of a new circRNA, circNAP1L4, in human pulmonary artery smooth muscle cell (HPASMC) proliferation through the host protein NAP1L4 to regulate the super‐enhancer‐driven glycolysis gene hexokinase II (HK II). CircNAP1L4 was downregulated in hypoxic HPASMCs and plasma of PH patients. Functionally, circNAP1L4 overexpression inhibited glycolysis and proliferation in hypoxic HPASMCs. Mechanistically, circNAP1L4 directly bound to its host protein NAP1L4 and affected the ability of NAP1L4 to move into the nucleus to regulate the epigenomic signals of the super‐enhancer of HK II. Intriguingly, circNAP1L4 overexpression inhibited the proliferation but not the migration of human pulmonary arterial endothelial cells (HPAECs) cocultured with HPASMCs. Furthermore, pre‐mRNA‐processing‐splicing Factor 8 (PRP8) was found to regulate the production ratio of circNAP1L4 and linear NAP1L4. In vivo, targeting circNAP1L4 alleviates SU5416 combined with hypoxia (SuHx)‐induced PH. Overall, these findings reveal a new circRNA that inhibits PASMC proliferation and serves as a therapeutic target for PH. [ABSTRACT FROM AUTHOR]

Background: One of major challenges in breast tumor therapy is the existence of breast cancer stem cells (BCSCs). BCSCs are a small subpopulation of tumor cells that exhibit characteristics of stem cells. BCSCs are responsible for progression, recurrence, chemoresistance and metastasis of breast cancer. Ca2+ signalling plays an important role in diverse processes in cancer development. However, the role of Ca2+ signalling in BCSCs is still poorly understood. Methods: A highly effective 3D soft fibrin gel system was used to enrich BCSC-like cells from ER+ breast cancer lines MCF7 and MDA-MB-415. We then investigated the role of two Ca2+-permeable ion channels Orai1 and Orai3 in the growth and stemness of BCSC-like cells in vitro, and tumorigenicity in female NOD/SCID mice in vivo. Results: Orai1 RNA silencing and pharmacological inhibition reduced the growth of BCSC-like cells in tumor spheroids, decreased the expression levels of BCSC markers, and reduced the growth of tumor xenografts in NOD/SCID mice. Orai3 RNA silencing also had similar inhibitory effect on the growth and stemness of BCSC-like cells in vitro, and tumor xenograft growth in vivo. Mechanistically, Orai1 and SPCA2 mediate store-operated Ca2+ entry. Knockdown of Orai1 or SPCA2 inhibited glycolysis pathway, whereas knockdown of Orai3 or STIM1 had no effect on glycolysis. Conclusion: We found that Orai1 interacts with SPCA2 to mediate store-independent Ca2+ entry, subsequently promoting the growth and tumorigenicity of BCSC-like cells via glycolysis pathway. In contrast, Orai3 and STIM1 mediate store-operated Ca2+ entry, promoting the growth and tumorigenicity of BCSC-like cells via a glycolysis-independent pathway. Together, our study uncovered a well-orchestrated mechanism through which two Ca2+ entry pathways act through distinct signalling axes to finely control the growth and tumorigenicity of BCSCs. [ABSTRACT FROM AUTHOR]

Cancer cells acquire metabolic advantages over their normal counterparts regarding the use of nutrients for sustained cell proliferation and cell survival in the tumor microenvironment. Notable among the metabolic traits in cancer cells is the Warburg effect, which is a reprogrammed form of glycolysis that favors the rapid generation of ATP from glucose and the production of biological macromolecules by diverting glucose into various metabolic intermediates. Meanwhile, mannose, which is the C‐2 epimer of glucose, has the ability to dampen the Warburg effect, resulting in slow‐cycling cancer cells that are highly susceptible to chemotherapy. This anticancer effect of mannose appears when its catabolism is compromised in cancer cells. Moreover, de novo synthesis of mannose within cancer cells has also been identified as a potential target for enhancing chemosensitivity through targeting glycosylation pathways. The underlying mechanisms by which alterations in mannose metabolism induce cancer cell vulnerability are just beginning to emerge. This review summarizes the current state of our knowledge of mannose metabolism and provides insights into its manipulation as a potential anticancer strategy. [ABSTRACT FROM AUTHOR]

Background: The escalating global burden of diabetes and its associated cognitive impairment underscores the urgency for effective interventions. Bergenin shows promise in regulating glucose metabolism, mitigating inflammation, and improving cognitive function. Zebrafish models offer a unique platform for assessing drug efficacy and exploring pharmacological mechanisms, complemented by subsequent investigations in cell and rat models. Methods: The experimental subjects included zebrafish larvae (CZ98:Tg (mpeg1: EGFP)ihb20Tg/+), adult zebrafish (immersed in 2% glucose), BV2 cell line (50 mM glucose + 10 μm Aβ1-42), and a streptozotocin (STZ) bilateral intracerebroventricular injection rat model. Bergenin's effects on the toxicity, behavior, and cognitive function of zebrafish larvae and adults were evaluated. The Morris water maze assessed cognitive function in rats. Neuronal histopathological changes were evaluated using HE and Nissl staining. qPCR and Western blot detected the expression of glycolysis enzymes, inflammatory factors, and Bergenin's regulation of PPAR/NF-κB pathway in these three models. Results: 1) In zebrafish larvae, Bergenin interventions significantly reduced glucose levels and increased survival rates while decreasing teratogenicity rates. Microglial cell fluorescence in the brain notably decreased, and altered swimming behavior tended to normalize. 2) In adult zebrafish, Bergenin administration reduced BMI and blood glucose levels, altered swimming behavior to slower speeds and more regular trajectories, enhanced recognition ability, decreased brain glucose and lactate levels, weakened glycolytic enzyme activities, improved pathological changes in the telencephalon and gills, reduced expression of pro-inflammatory cytokines, decreased ins expression and increased expression of irs1, irs2a, and irs2b, suggesting a reduction in insulin resistance. It also altered the expression of pparg and rela. 3) In BV2 cell line, Bergenin significantly reduced the protein expression of glycolytic enzymes (GLUT1, HK2, PKFKB3, and PKM2), lowered IL-1β, IL-6, and TNF-α mRNA expression, elevated PPAR-γ protein expression, and decreased P-NF-κB-p65 protein expression. 4) In the rat model, Bergenin improves learning and memory abilities in STZ-induced rats, mitigates neuronal damage in the hippocampal region, and reduces the expression of inflammatory factors IL-1β, IL-6, and TNF-α. Bergenin decreases brain glucose and lactate levels, as well as glycolytic enzyme activity. Furthermore, Bergenin increases PPARγ expression and decreases p-NF-κB p65/NF-κB p65 expression in the hippocampus. Conclusion: Bergenin intervenes through the PPAR-γ/NF-κB pathway, redirecting glucose metabolism, alleviating inflammation, and preventing high glucoseinduced neuronal damage. [ABSTRACT FROM AUTHOR]

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The recent birth of the immunometabolism field has comprehensively demonstrated how the rewiring of intracellular metabolism is critical for supporting the effector functions of many immune cell types, such as myeloid cells. Among all, the transcriptional regulation mediated by Hypoxia-Inducible Factors (HIFs) and Nuclear factor erythroid 2-related factor 2 (NRF2) have been consistently shown to play critical roles in regulating the glycolytic metabolism, redox homeostasis and inflammatory responses of macrophages (Mjs). Although both of these transcription factors were first discovered back in the 1990s, new advances in understanding their function and regulations have been continuously made in the context of immunometabolism. Therefore, this review attempts to summarize the traditionally and newly identified functions of these transcription factors, including their roles in orchestrating the key events that take place during glycolytic reprogramming in activated myeloid cells, as well as their roles in mediating Mj inflammatory responses in various bacterial infection models. [ABSTRACT FROM AUTHOR]

Astrocytes control brain activity via both metabolic processes and gliotransmission, but the physiological links between these functions are scantly known. Here we show that endogenous activation of astrocyte type-1 cannabinoid (CB1) receptors determines a shift of glycolysis towards the lactate-dependent production of d-serine, thereby gating synaptic and cognitive functions in male mice. Mutant mice lacking the CB1 receptor gene in astrocytes (GFAP-CB1-KO) are impaired in novel object recognition (NOR) memory. This phenotype is rescued by the gliotransmitter d-serine, by its precursor l-serine, and also by lactate and 3,5-DHBA, an agonist of the lactate receptor HCAR1. Such lactate-dependent effect is abolished when the astrocyte-specific phosphorylated-pathway (PP), which diverts glycolysis towards l-serine synthesis, is blocked. Consistently, lactate and 3,5-DHBA promoted the co-agonist binding site occupancy of CA1 post-synaptic NMDA receptors in hippocampal slices in a PP-dependent manner. Thus, a tight cross-talk between astrocytic energy metabolism and gliotransmission determines synaptic and cognitive processes. The molecular interplay between metabolic and synaptic functions of astrocytes is underexplored. Here, the authors show that astrocyte cannabinoid type-1 receptors integrate lactate and D-serine signaling to promote NMDA receptor-dependent cognition. [ABSTRACT FROM AUTHOR]

Metabolic rewiring during the proliferation-to-quiescence transition is poorly understood. Here, using a model of contact inhibition-induced quiescence, we conducted 13C-metabolic flux analysis in proliferating (P) and quiescent (Q) mouse embryonic fibroblasts (MEFs) to investigate this process. Q cells exhibit reduced glycolysis but increased TCA cycle flux and mitochondrial respiration. Reduced glycolytic flux in Q cells correlates with reduced glycolytic enzyme expression mediated by yes-associated protein (YAP) inhibition. The increased TCA cycle activity and respiration in Q cells is mediated by induced mitochondrial pyruvate carrier (MPC) expression, rendering them vulnerable to MPC inhibition. The malate-to-pyruvate flux, which generates NADPH, is markedly reduced by modulating malic enzyme 1 (ME1) dimerization in Q cells. Conversely, the malate dehydrogenase 1 (MDH1)-mediated oxaloacetate-to-malate flux is reversed and elevated in Q cells, driven by high mitochondrial-derived malate levels, reduced cytosolic oxaloacetate, elevated MDH1 levels, and a high cytoplasmic NAD+/NADH ratio. Transcriptomic analysis revealed large number of genes are induced in Q cells, many of which are associated with the extracellular matrix (ECM), while YAP-dependent and cell cycle-related genes are repressed. The results suggest that high TCA cycle flux and respiration in Q cells are required to generate ATP and amino acids to maintain de-novo ECM protein synthesis and secretion. Metabolic changes happening when cells enter quiescence are poorly understood. Here, the authors report that quiescent cells exhibit reduced glycolysis mediated by YAP inhibition and increased mitochondrial activity mediated by pyruvate carrier induced expression. [ABSTRACT FROM AUTHOR]

Immunometabolism has been an emerging hotspot in the fields of tumors, obesity, and atherosclerosis in recent decades, yet few studies have investigated its connection with rheumatoid arthritis (RA). In principle, intracellular metabolic pathways upstream regulated by nutrients and growth factors control the effector functions of immune cells. Dynamic communication and hypermetabolic lesions of immune cells within the inflammatory synovial microenvironment contributes to the development and progression of RA. Hence, targeting metabolic pathways within immune subpopulations and pathological cells may represent novel therapeutic strategies for RA. Natural products constitute a great potential treasury for the research and development of novel drugs targeting RA. Here, we aimed to delineate an atlas of glycolysis, lipid metabolism, amino acid biosynthesis, and nucleotide metabolism in the synovial microenvironment of RA that affect the pathological processes of synovial cells. Meanwhile, therapeutic potentials and pharmacological mechanisms of natural products that are demonstrated to inhibit related key enzymes in the metabolic pathways or reverse the metabolic microenvironment and communication signals were discussed and highlighted. [ABSTRACT FROM AUTHOR]

Although rapid progression and a poor prognosis in influenza A virus (IAV) infection–induced acute exacerbation of chronic obstructive pulmonary disease (AECOPD) are frequently associated with metabolic energy disorders, the underlying mechanisms and rescue strategies remain unknown. We herein demonstrated that the level of resting energy expenditure increased significantly in IAV‐induced AECOPD patients and that cellular energy exhaustion emerged earlier and more significantly in IAV‐infected primary COPD bronchial epithelial (pDHBE) cells. The differentially expressed genes were enriched in the oxidative phosphorylation (OXPHOS) pathway; additionally, we consistently uncovered much earlier ATP exhaustion, more severe mitochondrial structural destruction and dysfunction, and OXPHOS impairment in IAV‐inoculated pDHBE cells, and these changes were rescued by melatonin. The level of OMA1‐dependent cleavage of OPA1 in the mitochondrial inner membrane and the shift in energy metabolism from OXPHOS to glycolysis were significantly increased in IAV‐infected pDHBE cells; however, these changes were rescued by OMA1‐siRNA or melatonin further treatment. Collectively, our data revealed that melatonin rescued IAV–induced cellular energy exhaustion via OMA1‐OPA1‐S to improve the clinical prognosis in COPD. This treatment may serve as a potential therapeutic agent for patients in which AECOPD is induced by IAV. [ABSTRACT FROM AUTHOR]

In this study, we investigated the role of hypoxia in the development of chronic inflammatory bowel disease (IBD), focusing on its impact on the HIF-1α signaling pathway through the upregulation of lipocalin 2 (LCN2). Using a murine model of colitis induced by sodium dextran sulfate (DSS) under hypoxic conditions, transcriptome sequencing revealed LCN2 as a key gene involved in hypoxia-mediated exacerbation of colitis. Bioinformatics analysis highlighted the involvement of crucial pathways, including HIF-1α and glycolysis, in the inflammatory process. Immune infiltration analysis demonstrated the polarization of M1 macrophages in response to hypoxic stimulation. In vitro studies using RAW264.7 cells further elucidated the exacerbation of inflammation and its impact on M1 macrophage polarization under hypoxic conditions. LCN2 knockout cells reversed hypoxia-induced inflammatory responses, and the HIF-1α pathway activator dimethyloxaloylglycine (DMOG) confirmed LCN2's role in mediating inflammation via the HIF-1α-induced glycolysis pathway. In a DSS-induced colitis mouse model, oral administration of LCN2-silencing lentivirus and DMOG under hypoxic conditions validated the exacerbation of colitis. Evaluation of colonic tissues revealed altered macrophage polarization, increased levels of inflammatory factors, and activation of the HIF-1α and glycolysis pathways. In conclusion, our findings suggest that hypoxia exacerbates colitis by modulating the HIF-1α pathway through LCN2, influencing M1 macrophage polarization in glycolysis. This study contributes to a better understanding of the mechanisms underlying IBD, providing potential therapeutic targets for intervention. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming is one of the significant characteristics of malignant tumor development. It provides the tumor with sufficient energy and materials. During the process by which tumor cells acquire metabolic reprogramming, epigenetic changes play a crucial role. N6-methyladenosine (m6A) in mRNA is the most common post-transcriptional modification of mRNA. It regulates the transcription, maturation, translation, and degradation of mRNA. Studies have shown that m6A helps promote the metabolic reprogramming of tumor cells. However, the complete mechanism still requires further research. METTL3 is a key enzyme for m6A methylation that catalyzes m6A progression by forming complexes with other proteins, such as METTL14 and WTAP. Notably, the critical role of METTL3 in the metabolic transition of gastrointestinal tumors has not been given due attention. This article summarizes the specific pathways through which METTL3 affects the reprogramming of cellular glucose metabolism in gastrointestinal tumors. We aimed to clarify the importance of METTL3 in the energy reprogramming of gastrointestinal tumors. [ABSTRACT FROM AUTHOR]

Hypoxia is a critical factor contributing to a poor prognosis and challenging glioma therapy. Previous studies have indicated that hypoxia drives M2 polarization of macrophages and promotes cancer progression in various solid tumors. However, the more complex and diverse mechanisms underlying this process remain to be elucidated. Here, we aimed to examine the functions of hypoxia in gliomas and preliminarily investigate the underlying mechanisms of M2 macrophage polarization caused by hypoxia. We found that hypoxia significantly enhances the malignant phenotypes of U87 and U251 cells by regulating glycolysis. In addition, hypoxia mediated accumulation of the glycolysis product [lactic acid (LA)], which is subsequently absorbed by macrophages to induce its M2 polarization, and this process is reverted by both the glycolysis inhibitor and silenced monocarboxylate transporter (MCT-1) in macrophages, indicating that M2 macrophage polarization is associated with the promotion of glycolysis by hypoxia. Interestingly, we also found that hypoxia mediated LA accumulation in glioma cells upon uptake by macrophages upregulates H3K18La expression and promotes tumor necrosis factor superfamily member 9 (TNFSF9) expression in a histone-lactylation-dependent manner based on the results of chromatin immunoprecipitation sequencing (ChIP seq) enrichment analysis. Subsequent in vitro and in vivo experiments further indicated that TNFSF9 facilitated glioma progression. Mechanistically, hypoxia-mediated LA accumulation in glioma cells is taken up by macrophages and then induces its M2 macrophage polarization by regulating TNFSF9 expression via MCT-1/H3K18La signaling, thus facilitating the malignant progression of gliomas. NEW & NOTEWORTHY: Our study revealed that hypoxia induces the production of LA accumulation through glycolysis in glioma cells, which is subsequently absorbed by macrophages and leads to its M2 polarization via the MCT-1/H3K18La/TNFSF9 axis, ultimately significantly promoting the malignant progression of glioma cells. These findings are novel and noteworthy as they provide insights into the connection between energy metabolism and epigenetics in gliomas. [ABSTRACT FROM AUTHOR]

Fructose bisphosphate aldolases (FBAs) catalyze the reversible cleavage of fructose 1,6‐bisphosphate into dihydroxyacetone phosphate and glyceraldehyde 3‐phosphate. We analyzed two previously uncharacterized cytosolic Arabidopsis FBAs, AtFBA4 and AtFBA5. Based on a recent report, we examined the interaction of AtFBA4 with calmodulin (CaM)‐like protein 11 (AtCML11). AtFBA4 did not bind AtCML11; however, we found that CaM bound AtFBA5 in a Ca2+‐dependent manner with high specificity and affinity (KD ~ 190 nm) and enhanced its stability. AtFBA4 and AtFBA5 exhibited Michaelis–Menten kinetics with Km and Vmax values of 180 μm and 4.9 U·mg−1 for AtFBA4, and 6.0 μm and 0.30 U·mg−1 for AtFBA5, respectively. The flavonoid morin inhibited both isozymes. Our study suggests that Ca2+ signaling and flavanols may influence plant glycolysis/gluconeogenesis. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is a difficult-to-cure disease with high worldwide incidence and mortality. Among the many changes observed in cancer cells and patient samples is altered glycosylation, a commonly observed modification of biomolecules such as proteins. These glycan structures can dictate protein function, and dysregulation of glycosylation can contribute to tumor migration and metastasis. Thus, manipulation of glycosylation states may be a novel approach to cancer treatment. One target of the well-known tumor suppressor p53 is FUCA1, encoding alpha-L-fucosidase, which plays a role in glycosylation, although the exact mechanism linking FUCA1 to cancer is unclear. Investigation into these glycosylation processes and the mechanisms linking the p53-FUCA1 axis to cancer development may provide new insights into this disease and suggest new drug targets for cancer therapies. Cancer is a difficult-to-cure disease with high worldwide incidence and mortality, in large part due to drug resistance and disease relapse. Glycosylation, which is a common modification of cellular biomolecules, was discovered decades ago and has been of interest in cancer research due to its ability to influence cellular function and to promote carcinogenesis. A variety of glycosylation types and structures regulate the function of biomolecules and are potential targets for investigating and treating cancer. The link between glycosylation and carcinogenesis has been more recently revealed by the role of p53 in energy metabolism, including the p53 target gene alpha-L-fucosidase 1 (FUCA1), which plays an essential role in fucosylation. In this review, we summarize roles of glycan structures and glycosylation-related enzymes to cancer development. The interplay between glycosylation and tumor microenvironmental factors is also discussed, together with involvement of glycosylation in well-characterized cancer-promoting mechanisms, such as the epidermal growth factor receptor (EGFR), phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and p53-mediated pathways. Glycan structures also modulate cell–matrix interactions, cell–cell adhesion as well as cell migration and settlement, dysfunction of which can contribute to cancer. Thus, further investigation of the mechanistic relationships among glycosylation, related enzymes and cancer progression may provide insights into potential novel cancer treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: NSCLC is one of the most life-threatening forms of oncological diseases. Although targeted and immunotherapy treatments have improved NSCLC prognosis, the chance of surviving is still limited for many patients. Therefore, further efforts are required to improve NSCLC care. AdipoRon is emerging as an antineoplastic molecule in the treatment of different cancers, but its potential in NSCLC is yet to be explored. Herein, we demonstrated that AdipoRon strongly impairs viability, growth and stemness in NSCLC cells. We also recorded higher glucose consumption and lactate accumulation as a result of AdipoRon treatment. Remarkably, the employment of glycolytic-interfering agents enhanced its antiproliferative features. A signaling pathways analysis revealed a marked AMPK phosphorylation, while, in contrast, its abrogation by Compound-C significantly counteracted AdipoRon effectiveness. Altogether, these findings emphasize AdipoRon's anticancer feature even in NSCLC, supporting its endorsement as a future candidate in cancer and NSCLC therapy. Despite the countless therapeutic advances achieved over the years, non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. To this primacy contribute both non-oncogene addicted and advanced NSCLCs, in which conventional therapies are only partially effective. The adiponectin receptor agonist AdipoRon has revealed antiproliferative action in different cancers, including osteosarcoma and pancreatic cancer. Herein, we investigated its potential anticancer role in NSCLC for the first time. We proved that AdipoRon strongly inhibits viability, growth and colony formation in H1299 and A549 NSCLC cells, mainly through a slowdown in cell cycle progression. Along with the biological behaviors, a metabolic switching was observed after AdipoRon administration in NSCLC cells, consisting of higher glucose consumption and lactate accumulation. Remarkably, both 2-Deoxy Glucose and Oxamate glycolytic-interfering agents greatly enhanced AdipoRon's antiproliferative features. As a master regulator of cell metabolism, AMP-activated protein kinase (AMPK) was activated by AdipoRon. Notably, the ablation of AdipoRon-induced AMPK phosphorylation by Compound-C significantly counteracted its effectiveness. However, the engagement of other pathways should be investigated afterwards. With a focus on NSCLC, our findings further support the ability of AdipoRon in acting as an anticancer molecule, driving its endorsement as a future candidate in NSCLC therapy. [ABSTRACT FROM AUTHOR]

In most species studied, energy deficits inhibit female reproductive behavior, but the location and nature of energy sensors and how they affect behavior are unknown. Progress has been facilitated by using Drosophila melanogaster, a species in which reproduction and food availability are closely linked. Adult males and females were either fed or food deprived (FD) and then tested in an arena with a fed, opposite-sex conspecific with no food in the testing arena. Only FD females (not FD males) significantly decreased their copulation rate and increased their copulation latency, and the effects of FD were prevented in females fed either yeast alone or glucose alone, but not sucralose alone, cholesterol alone, or amino acids alone. It is well-known that high-fat diets inhibit copulation rate in this species, and the effects of FD on copulation rate were mimicked by treatment with an inhibitor of glucose but not free fatty acid oxidation. The availability of oxidizable glucose was a necessary condition for copulation rate in females fed either yeast alone or fed a nutritive fly medium, which suggests that the critical component of yeast for female copulation rate is oxidizable glucose. Thus, female copulation rate in D. melanogaster is sensitive to the availability of oxidizable metabolic fuels, particularly the availability of oxidizable glucose or substrates/byproducts of glycolysis. NEW & NOTEWORTHY Copulation rate was decreased in food-deprived female but not in male adults when tested without food in the testing arena. Copulation rate was 1) maintained by feeding glucose alone, yeast alone, nutritive medium lacking yeast, but not sucralose, amino acids, or cholesterol alone; 2) decreased by inhibition of glycolysis in females fed either nutritive medium or yeast alone; and 3) not affected by inhibition of fatty acid oxidation. Thus, female copulation rate was linked to glycolytic status. [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]

Inflammatory bowel diseases (IBDs) are prevalent and debilitating diseases with limited clinical treatment strategies. Mesenchymal stem cell (MSCs) are pluripotent stem cells with self-renewal capability and multiple immunomodulatory effects, which make them a promising therapeutic approach for IBDs. Thus, optimization of MSCs regimes is crucial for their further clinical application. Wogonin, a flavonoid-like compound with extensive immunomodulatory and adjuvant effects, has been investigated as a potential pretreatment for MSCs in IBD treatment. In this study, we employed the DSS-induced acute colitis mouse model to compare the therapeutic effectiveness of MSCs in pretreated with or without wogonin and further explore the underlying mechanism. Compared to untreated MSCs, MSCwogonin (pretreated with wogonin) showed greater effectiveness in the treatment of colitis. Further experiments revealed that wogonin treatment activated the AKT signaling pathway, resulting in higher cellular glycolysis. Inhibition of AKT phosphorylation by perifosine not only decreased glycolysis but impaired the therapeutic efficiency of MSCwogonin. Consistent with these results, qPCR data indicated that wogonin treatment induced the expression of immunomodulatory molecules IL-10, IDO, and AGR1, which were reduced by perifosine. Together, our data demonstrated that wogonin preconditioning strategy further augmented the therapeutic efficacy of MSCs via promoting glycolysis, which should be a promising strategy for optimizing MSCs therapy in IBDs. [ABSTRACT FROM AUTHOR]

M1/M2 macrophage polarization plays an important role in regulating the balance of the microenvironment within tissues. Moreover, macrophage polarization involves the reprogramming of metabolism, such as glucose and lipid metabolism. Transcriptional coactivator B‐cell lymphoma‐3 (Bcl‐3) is an atypical member of the IκB family that controls inflammatory factor levels in macrophages by regulating nuclear factor kappa B pathway activation. However, the relationship between Bcl‐3 and macrophage polarization and metabolism remains unclear. In this study, we show that the knockdown of Bcl‐3 in macrophages can regulate glycolysis‐related gene expression by promoting the activation of the nuclear factor kappa B pathway. Furthermore, the loss of Bcl‐3 was able to promote the interferon gamma/lipopolysaccharide‐induced M1 macrophage polarization by accelerating glycolysis. Taken together, these results suggest that Bcl‐3 may be a candidate gene for regulating M1 polarization in macrophages. [ABSTRACT FROM AUTHOR]

Senescent cells accumulate in various organs with ageing, and its accumulation induces chronic inflammation and age-related physiological dysfunctions. Several remodelling of intracellular environments have been identified in senescent cells, including enlargement of cell/nuclear size and intracellular acidification. Although these alterations of intracellular environments were reported to be involved in the unique characteristics of senescent cells, the contribution of intracellular acidification to senescence-associated cellular phenotypes is poorly understood. Here, we identified that the upregulation of TXNIP and its paralog ARRDC4 as a hallmark of intracellular acidification in addition to KGA-type GLS1. These genes were also upregulated in response to senescence-associated intracellular acidification. Neutralization of the intracellular acidic environment ameliorated not only senescence-related upregulation of TXNIP , ARRDC4 and KGA but also inflammation-related genes, possibly through suppression of PDK-dependent anaerobic glycolysis. Furthermore, we found that expression of the intracellular acidification-induced genes, TXNIP and ARRDC4 , correlated with inflammatory gene expression in heterogeneous senescent cell population in vitro and even in vivo , implying that the contribution of intracellular pH to senescence-associated cellular features, such as SASP. [ABSTRACT FROM AUTHOR]

Cells configure their metabolism in a synchronized and timely manner to meet their energy demands throughout development and adulthood. Transitions of developmental stages are coupled to metabolic shifts, such that glycolysis is highly active during cell proliferation, whereas oxidative phosphorylation prevails in postmitotic states. In the cerebellum, metabolic transitions are remarkable given its protracted developmental timelines. Such distinctive feature, along with its high neuronal density and metabolic demands, make the cerebellum highly vulnerable to metabolic insults. Despite the expansion of metabolomic approaches to uncover biological mechanisms, little is known about the role of metabolism on cerebellar development and maintenance. To illuminate the intricate connections between metabolism, physiology, and cerebellar disorders, we examined here the impact of metabolism on cerebellar growth, maturation, and adulthood through the lens of inborn errors of metabolism. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy for gastric cancer remains a challenge due to its limited efficacy. Metabolic reprogramming toward glycolysis has emerged as a promising avenue for enhancing the sensitivity of tumors to immunotherapy. Pyruvate dehydrogenase kinases (PDKs) play pivotal roles in regulating glycolysis. The importance of PDKs in the context of gastric cancer immunotherapy and their potential as therapeutic targets have not been fully explored. Methods: PDK and PD-L1 expression was analyzed using data from the GSE66229 and The Cancer Genome Atlas (TCGA) cohorts. Additionally, the Immune Checkpoint Blockade Therapy Atlas (ICBatlas) database was utilized to assess PDK expression in an immune checkpoint blockade (ICB) therapy group. Subsequently, the upregulation of PD-L1 and the enhancement of anticancer effects achieved by targeting PDK were validated through in vivo and in vitro assays. The impact of PDK on histone acetylation was investigated using ChIP‒qPCR to detect changes in histone acetylation levels. Results: Our analysis revealed a notable negative correlation between PD-L1 and PDK expression. Downregulation of PDK led to a significant increase in PD-L1 expression. PDK inhibition increased histone acetylation levels by promoting acetyl-CoA generation. The augmentation of acetyl-CoA production and concurrent inhibition of histone deacetylation were found to upregulate PD-L1 expression in gastric cancer cells. Additionally, we observed a significant increase in the anticancer effect of PD-L1 antibodies following treatment with a PDK inhibitor. Conclusions: Downregulation of PDK in gastric cancer cells leads to an increase in PD-L1 expression levels, thus potentially improving the efficacy of PD-L1 immune checkpoint blockade therapy. [ABSTRACT FROM AUTHOR]

Exploring cellular responses necessitates studying real‐time metabolic pathway kinetics, considering the adaptable nature of cells. Glycolysis and glutaminolysis are interconnected pathways fundamental to driving cellular metabolism, generating both energy and essential biosynthetic molecules. While prior studies explored glycolysis tracking, this research focuses on monitoring the kinetics of the glutaminolysis pathway by evaluating the effect of glutamine availability on glycolytic kinetics and by investigating the impact of a stimulator (oligomycin) and inhibitor (2DG) on the glycolytic flux in the presence of glutamine. Additionally, we adapted a rate equation model to provide improved understanding of the pathway kinetics. The experimental and simulated results indicate a significant reduction in extracellular lactate production in the presence of glutamine, reflecting a shift from glycolysis towards oxidative phosphorylation, due to the additional contribution of glutamine to energy production through the ETC (electron transport chain), reducing the glycolytic load. Oligomycin, an ETC inhibitor, increases lactate production to the original glycolytic level, despite the presence of glutamine. Nevertheless, its mechanism is influenced by the presence of glutamine, as predicted by the model. Conversely, 2DG notably reduces lactate production, affirming its glycolytic origin. The gradual increase in lactate production under the influence of 2DG implies increased activation of glutaminolysis as an alternative energy source. The model also simulates the varying metabolic responses under varying carbon/modulator concentrations. In conclusion, the kinetic model described here contributes to the understanding of changes in intracellular metabolites and their interrelationships in a way which would be challenging to obtain solely through kinetic assays. [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]

The efficacy of transarterial chemoembolization (TACE) has been limited by insufficient embolization and a high incidence of tumor recurrence. Herein, we identified that aberrant metabolic reprogramming and immunosuppression contribute to TACE refractoriness and Rhein, as a potential glycolytic metabolism inhibitor and immunoactivation inducer, was optimized to sensitize tumors to TACE therapy. To achieve efficient embolization, we developed an oil‐in‐water lipiodol embolic emulsion by stabilizing the self‐assembled Rhein nanogel. The assembled Rhein exhibited a nanofiber network, and its integration enhanced the mechanical stability and viscoelasticity of the lipiodol embolic agent. With the synergistic advantages of solid and liquid embolic agents, this carrier‐free Pickering emulsion exhibits efficient embolization and sustained drug release in models of unilateral renal artery embolization, rabbit ear tumor embolization, rabbit orthotopic liver cancer, and rat orthotopic liver cancer. Compared to conventional three‐way catheter mixing methods, multimodal imaging corroborates a marked enhancement in local drug retention and tumor suppression. Importantly, the incorporation of Rhein‐mediated synergistic immunoembolization in this strategy achieved efficient embolization while robustly activating anti‐tumor immune responses, including inducing immunogenic cell death, dendritic cell activation, and major histocompatibility complex class I presentation to CD8+ T cells for tumor killing. Together, these findings reveal a novel strategy for the application of self‐assembled Rhein nanofiber‐stabilized lipiodol emulsion to control metabolic signaling and immunoactivation in TACE. [ABSTRACT FROM AUTHOR]

mTORC1/2 dual inhibitors may be more effective than mTORC1 inhibitor rapamycin. However, their metabolic impacts on colon cancer cells remain unexplored. We conducted a comparative analysis of the anti-proliferative effects of rapamycin and the novel OSI-027 in colon cancer cells HCT-116, evaluating their metabolic influences through ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Our results demonstrate that OSI-027 more effectively inhibits colon cancer cell proliferation than rapamycin. Additionally, we identified nearly 600 metabolites from the spectra, revealing significant differences in metabolic patterns between cells treated with OSI-027 and rapamycin. Through VIP value screening, we pinpointed crucial metabolites contributing to these distinctions. For inhibiting glycolysis and reducing glucose consumption, OSI-027 was likely to be more potent than rapamycin. For amino acids metabolism, although OSI-027 has a broad effect as rapamycin, their effects in degrees were not exactly the same. These findings address the knowledge gap regarding mTORC1/2 dual inhibitors and lay a foundation for their further development and research. [ABSTRACT FROM AUTHOR]

Copyright of Science & Technology of Food Industry is the property of Science & Technology of Food Industry Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: The RNA N6-methyladenosine (m6A) modification has become an essential hotspot in epigenetic modulation. Serine–arginine protein kinase 1 (SRPK1) is associated with the pathogenesis of various cancers. However, the m6A modification of SRPK1 and its association with the mechanism of in lung adenocarcinoma (LUAD) remains unclear. Methods: Western blotting and polymerase chain reaction (PCR) analyses were carried out to identify gene and protein expression. m6A epitranscriptomic microarray was utilized to the assess m6A profile. Loss and gain-of-function assays were carried out elucidate the impact of METTL3 and SRPK1 on LUAD glycolysis and tumorigenesis. RNA immunoprecipitation (RIP), m6A RNA immunoprecipitation (MeRIP), and RNA stability tests were employed to elucidate the SRPK1's METTL3-mediated m6A modification mechanism in LUAD. Metabolic quantification and co-immunoprecipitation assays were applied to investigate the molecular mechanism by which SRPK1 mediates LUAD metabolism. Results: The epitranscriptomic microarray assay revealed that SRPK1 could be hypermethylated and upregulated in LUAD. The main transmethylase METTL3 was upregulated and induced the aberrant high m6A levels of SRPK1. Mechanistically, SRPK1's m6A sites were directly methylated by METTL3, which also stabilized SRPK1 in an IGF2BP2-dependent manner. Methylated SRPK1 subsequently promoted LUAD progression through enhancing glycolysis. Further metabolic quantification, co-immunoprecipitation and western blot assays revealed that SRPK1 interacts with hnRNPA1, an important modulator of PKM splicing, and thus facilitates glycolysis by upregulating PKM2 in LUAD. Nevertheless, METTL3 inhibitor STM2457 can reverse the above effects in vitro and in vivo by suppressing SRPK1 and glycolysis in LUAD. Conclusion: It was revealed that in LUAD, aberrantly expressed METTL3 upregulated SRPK1 levels via an m6A-IGF2BP2-dependent mechanism. METTL3-induced SRPK1 fostered LUAD cell proliferation by enhancing glycolysis, and the small-molecule inhibitor STM2457 of METTL3 could be an alternative novel therapeutic strategy for individuals with LUAD. [ABSTRACT FROM AUTHOR]

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Glycolysis is a shared feature in various cancers including lung adenocarcinoma (LUAD). Testis Expressed 19 (TEX19) is correlated with cancer progression. But its effect on LUAD remains an unanswered question. The focus of our study was primarily to investigate how TEX19 works exactly in LUAD. We first downloaded mRNA data from TCGA-LUAD and performed differential expression analysis. Then, we performed a Kaplan–Meier analysis to analyze the relationship between mRNA expression and patients' prognoses. hTFtarget database was utilized for the prediction of upstream transcription factors of mRNA. Next, qRT-PCR was employed for detecting TEX19 and Forkhead box A1 (FOXA1) expression. Western blot was adopted to detect the expression of glycolysis-related proteins. We also used CCK-8, colony formation, and flow cytometry assays to detect cell viability, proliferation, and apoptosis. Seahorse XF Extracellular Flux Analyzers were introduced to analyze extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Detection kits were used to detect pyruvate, lactate, citric acid, and malic acid. TEX19 was highly expressed in LUAD tissues. Real-time quantitative PCR (qRT-PCR) assay showed that TEX19 was significantly overexpressed in LUAD cell lines compared with normal bronchial epithelial cells BEAS-2B. Knockdown of TEX19 remarkably inhibited cell activity and proliferation, and promoted cell apoptosis, TEX19 was enriched in the glycolytic pathway. Meanwhile, the knockdown of TEX19 significantly hampered the contents of pyruvate, lactate, citric acid, and malic acid. The bioinformatics analysis, dual luciferase reporter experiment, and chromatin immunoprecipitation (ChIP) assay showed that FOXA1 was bound with TEX19. FOXA1 had a high expression level in LUAD. The rescue assay demonstrated that FOXA1, by activating TEX19 expression, enhanced glycolysis and proliferation and inhibited apoptosis of LUAD cells. In summary, FOXA1 promoted glycolysis and proliferation of LUAD cells by activating TEX19. This result can provide a theoretical basis for future research on LUAD. [ABSTRACT FROM AUTHOR]

MARCH5 is a ring-finger E3 ubiquitin ligase located in the outer membrane of mitochondria. A previous study has reported that MARCH5 was up-regulated and contributed to the migration and invasion of OC cells by serving as a competing endogenous RNA. However, as a mitochondrial localized E3 ubiquitin ligase, the function of MARCH5 in mitochondrial-associated metabolism reprogramming in human cancers remains largely unexplored, including OC. We first assessed the glycolysis effect of MARCH5 in OC both in vitro and in vivo. Then we analyzed the effect of MARCH5 knockdown or overexpression on respiratory activity by evaluating oxygen consumption rate, activities of OXPHOS complexes and production of ATP in OC cells with MARCH5. Co-immunoprecipitation, western-blot, and in vitro and vivo experiments were performed to investigate the molecular mechanisms underlying MARCH5-enhanced aerobic glycolysis s in OC. In this study, we demonstrate that the abnormal upregulation of MARCH5 is accompanied by significantly increased aerobic glycolysis in OC. Mechanistically, MARCH5 promotes aerobic glycolysis via ubiquitinating and degrading mitochondrial pyruvate carrier 1 (MPC1), which mediates the transport of cytosolic pyruvate into mitochondria by localizing on mitochondria outer membrane. In line with this, MPC1 expression is significantly decreased and its downregulation is closely correlated with unfavorable survival. Furthermore, in vitro and in vivo assays revealed that MARCH5 upregulation-enhanced aerobic glycolysis played a critical role in the proliferation and metastasis of OC cells. Taken together, we identify a MARCH5-regulated aerobic glycolysis mechanism by degradation of MPC1, and provide a rationale for therapeutic targeting of aerobic glycolysis via MARCH5-MPC1 axis inhibition. [ABSTRACT FROM AUTHOR]

Pyruvate kinase M2 (PKM2) is a key rate-limiting enzyme in glycolysis. It is well known that PKM2 plays a vital role in the proliferation of tumor cells. However, PKM2 can also exert its biological functions by mediating multiple signaling pathways in neurological diseases, such as Alzheimer's disease (AD), cognitive dysfunction, ischemic stroke, post-stroke depression, cerebral small-vessel disease, hypoxic-ischemic encephalopathy, traumatic brain injury, spinal cord injury, Parkinson's disease (PD), epilepsy, neuropathic pain, and autoimmune diseases. In these diseases, PKM2 can exert various biological functions, including regulation of glycolysis, inflammatory responses, apoptosis, proliferation of cells, oxidative stress, mitochondrial dysfunction, or pathological autoimmune responses. Moreover, the complexity of PKM2's biological characteristics determines the diversity of its biological functions. However, the role of PKM2 is not entirely the same in different diseases or cells, which is related to its oligomerization, subcellular localization, and post-translational modifications. This article will focus on the biological characteristics of PKM2, the regulation of PKM2 expression, and the biological role of PKM2 in neurological diseases. With this review, we hope to have a better understanding of the molecular mechanisms of PKM2, which may help researchers develop therapeutic strategies in clinic. [ABSTRACT FROM AUTHOR]