Glycolysis-related Genes Research Articles

Study on Carbohydrate Metabolism in Adult Zebrafish (Danio rerio).

Excessive carbohydrate intake leads to metabolic disorders in fish. However, few literatures have reported the appropriate carbohydrate level for zebrafish, and the metabolic response to dietary carbohydrate remains largely unknown in zebrafish. This study assessed the responses of zebrafish and zebrafish liver cell line (ZFL) to different carbohydrate levels. In vivo results showed that ≥30% dietary dextrin levels significantly increased the plasma glucose content, activated the expression of hepatic glycolysis-related genes, and inhibited the expression of hepatic gluconeogenesis-related genes in zebrafish. Oil red O staining, triglyceride content, and Hematoxylin-Eosin staining results showed that dietary dextrin levels of ≥30% significantly increased lipid accumulation and liver damage, as well as processes related to glycolipid metabolism and inflammation in zebrafish. In ZFL, the transcription factor sterol regulatory element binding protein-1c signal intensity, 4,4-difluoro-1,3,5,7,8-pentamethyl-4-bora-3a,4a-diaza-s-indacene (BODIPY 493/503) signal intensity, and triglyceride content were also significantly increased when incubated in high glucose, along with abnormal glycolipid metabolism and increased inflammation-related genes. In conclusion, we demonstrated that the maximum dietary carbohydrate level in adult zebrafish should be less than 30%. Excess dietary carbohydrates (30%-50%) caused hepatic steatosis and damage to zebrafish, similar to that seen in aquaculture species. Thus, this study assessed responses to different carbohydrate levels in zebrafish and illustrated that zebrafish is an optimal model for investigating glucose metabolism in some aquatic animals.

Glycometabolic reprogramming in cementoblasts: A vital target for enhancing cell mineralization.

Cementum, a constituent part of periodontal tissues, has important adaptive and reparative functions. It serves to attach the tooth to alveolar bone and acts as a barrier delimit epithelial growth and bacteria evasion. A dynamic and highly responsive cementum is essential for maintaining occlusal relationships and the integrity of the root surface. It is a thin layer of mineralized tissue mainly produced by cementoblasts. Cementoblasts are osteoblast-like cells essential for the restoration of periodontal tissues. In recent years, glucose metabolism has been found to be critical in bone remodeling and osteoblast differentiation. However, the glucose metabolism of cementoblasts remains incompletely understood. First, immunohistochemistry staining and in vivo tracing with 18 F-fluorodeoxyglucose (18 F-FDG) revealed significantly higher glucose metabolism in cementum formation. To test the bioenergetic pathways of cementoblast differentiation, we compared the bioenergetic profiles of mineralized and unmineralized cementoblasts. As a result, we observed a significant increase in the consumption of glucose and production of lactate, coupled with the higher expression of glycolysis-related genes. However, the expression of oxidative phosphorylation-related genes was downregulated. The verified results were consistent with the RNA sequencing results. Likewise, targeted energy metabolomics shows that the levels of glycolytic metabolites were significantly higher in the mineralized cementoblasts. Seahorse assays identified an increase in glycolytic flux and reduced oxygen consumption during cementoblast mineralization. Apart from that, we also found that lactate dehydrogenase A (LDHA), a key glycolysis enzyme, positively regulates the mineralization of cementoblasts. In summary, cementoblasts mainly utilized glycolysis rather than oxidative phosphorylation during the mineralization process.

Comparative analysis of different rice substrates for solid-state fermentation by a citrinin-free Monascus purpureus mutant strain with high pigment production

Monascus pigment (MP) is a safe and natural microbial coloring agent. MP and red yeast rice (RYR) play an important role in the food industry. In this study, a citrinin-free Monascus puprureus MS-12 with high MP production was generated using dual mutagenesis of atmospheric and room-temperature plasma and heavy ion beam irradiation. The fermentation characteristics of eight rice substrates for solid-state fermentation (SSF) were compared to produce a premium RYR. Indica rice was the optimal fermentation substrate (MP = 4526 U/g in RYR), followed by japonica rice (MP = 3556 U/g). The MP value was <1000 U/g using other substrates (red, brown and black rice) for fermentation. RT-qPCR results demonstrated that the expression levels of MP synthesis- and the glycolysis-related genes of the mutant strain were upregulated compared with those of the parental strain, with MpigA exhibiting a 1.70-fold increase, while the relative expression levels of citrinin synthesis-related genes were downregulated; citE was downregulated 7.84-fold. In comparison to M. purpureus MS-12 mRNA levels using indica rice as the fermentation substrate during SSF, genes for MP, citrinin biosynthesis, and glycolysis resulted in the downregulation of other substrates. Our results show that colored and glutinous rice are unsuitable for RYR preparation via SSF. The maximum MP value was obtained using indical rice as the fermentation substrate, resulting from the upregulated expression levels of the pigment biosynthesis gene cluster and glycolytic pathway.

Calcitriol suppresses gastric cancer progression and cisplatin resistance by inhibiting glycolysis and M2 macrophage polarization through inhibition of mTOR activation.

The tumor microenvironment (TME) plays a critical role in tumor progression, with macrophages and tumor cells interacting within the TME, influencing cancer development. Despite the known anticancer properties of calcitriol, its role in the TME remains uncertain. This study aimed to explore the effects of calcitriol on macrophages and cancer cells in the TME and its impact on gastric cancer cell proliferation and cisplatin resistance. In vitro TME models were established using conditioned medium from gastric cancer cells (CCM) and macrophages (MCM) treated with or without calcitriol. The results revealed that calcitriol treatment suppressed the expression of glycolysis-related genes and proteins (GLUT1, HKII, LDHA) in MCM-induced gastric cancer cells, leading to increased cancer cell apoptosis and reduced viability, along with decreased Cyclin D1 gene expression. Moreover, calcitriol treatment inhibited mTOR activation in MCM-induced gastric cancer cells. Additionally, calcitriol hindered CCM-induced M2 macrophage polarization by reducing CD206 expression and increasing TNFα gene expression in THP1-derived macrophages, attenuating cisplatin resistance. These findings suggest that calcitriol may impede gastric cancer progression by targeting glycolysis and M2 macrophage polarization through the regulation of mTOR activation in the TME.

GLUT1 Mediates the Metabolic Reprogramming and Inflammation of CCR2$^+$ Monocytes/Macrophages from Patients with DCM.

Macrophages expressing CC chemokine receptor 2 (CCR2) possess characteristics and performance akin to M1 polarized macrophages, which promote inflammation. Advanced heart failure (HF) patients with higher abundance of CCR2+ macrophages are more likely to experience adverse remodeling. The precise mechanism of CCR2+ macrophages in how they affect the progression of dilated cardiomyopathy remains unknown. Cardiac biopsy samples from dilated cardiomyopathy patients (DCM) were used for immunohistochemistry and immunofluorescence staining. PCR is employed to identify the IL-1β, IL-6, TNF-α, TGF-β, MMP2, MMP9, PKM1, PKM1, GLUT1, GLUT2, GLUT3, GLUT4, PDK1, PFKFB3, PFK1 and HK2 mRNA expression of CCR2+ monocytes/macrophages from the peripheral blood of DCM patients. Seahorse was used to evaluate the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of CCR2+ monocytes/macrophages. 2-DG was used to simulate a lack of glucose. Lentivirus containing GLUT1 inhibitory sequence was used to knockdown GLUT1 gene expression of CCR2+ monocytes/macrophages. Western Blot and immunofluorescence staining was used to evaluate the expression of NLRP3. Immunostaining results of cardiac biopsy tissue from dilated cardiomyopathy (DCM) patients demonstrated that the progression to HF was associated with an increase in the number of CCR2+ macrophages. PCR results demonstrated that CCR2 monocytes and macrophages derived from the blood of DCM patients expressed elevated levels of inflammatory factors and up regulation of glycolysis related genes. In addition, OCR and glucose uptake experiments confirmed that increased glucose uptake of these cells was associated with greater inflammation and correlated with a worsening of cardiac function. limiting the glucose supply to CCR2+ monocytes and macrophages, or suppressing the activity of glucose transporter 1 (GLUT1) could reduce inflammation levels. These results suggest that CCR2+ monocytes and macrophages rely on metabolic reprogramming to trigger inflammatory response and contribute to myocardial injury and the progression of DCM.

Elevated expression of glycolytic genes as a prominent feature of early-onset preeclampsia: insights from integrative transcriptomic analysis.

Introduction: Preeclampsia (PE), a notable pregnancy-related disorder, leads to 40,000+ maternal deaths yearly. Recent research shows PE divides into early-onset (EOPE) and late-onset (LOPE) subtypes, each with distinct clinical features and outcomes. However, the molecular characteristics of various subtypes are currently subject to debate and are not consistent. Methods: We integrated transcriptomic expression data from a total of 372 placental samples across 8 publicly available databases via combat algorithm. Then, a variety of strategies including Random Forest Recursive Feature Elimination (RF-RFE), differential analysis, oposSOM, and Weighted Correlation Network Analysis were employed to identify the characteristic genes of the EOPE and LOPE subtypes. Finally, we conducted in vitro experiments on the key gene HK2 in HTR8/SVneo cells to explore its function. Results: Our results revealed a complex classification of PE placental samples, wherein EOPE manifests as a highly homogeneous sample group characterized by hypoxia and HIF1A activation. Among the core features is the upregulation of glycolysis-related genes, particularly HK2, in the placenta-an observation corroborated by independent validation data and single-cell data. Building on the pronounced correlation between HK2 and EOPE, we conducted in vitro experiments to assess the potential functional impact of HK2 on trophoblast cells. Additionally, the LOPE samples exhibit strong heterogeneity and lack distinct features, suggesting a complex molecular makeup for this subtype. Unsupervised clustering analysis indicates that LOPE likely comprises at least two distinct subtypes, linked to cell-environment interaction and cytokine and protein modification functionalities. Discussion: In summary, these findings elucidate potential mechanistic differences between the two PE subtypes, lend support to the hypothesis of classifying PE based on gestational weeks, and emphasize the potential significant role of glycolysis-related genes, especially HK2 in EOPE.

Epstein-Barr Virus Promotes Oral Squamous Cell Carcinoma Stemness through the Warburg Effect.

Epstein-Barr virus (EBV) is associated with various human malignancies. An association between EBV infection and oral squamous cell carcinoma (OSCC) has recently been reported. We established EBV-positive OSCC cells and demonstrated that EBV infection promoted OSCC progression. However, the mechanisms by which EBV promotes OSCC progression remain poorly understood. Therefore, we performed metabolic analyses of EBV-positive OSCC cells and established a xenograft model to investigate the viral contribution to OSCC progression. Here, we demonstrated that EBV infection induced mitochondrial stress by reducing the number of mitochondrial DNA (mtDNA) copies. Microarray data from EBV-positive OSCC cells showed altered expression of glycolysis-related genes, particularly the upregulation of key genes involved in the Warburg effect, including LDHA, GLUT1, and PDK1. Furthermore, lactate production and LDH activity were elevated in EBV-positive OSCC cells. EBV infection significantly upregulated the expression levels of cancer stem cell (CSC) markers such as CD44 and CD133 in the xenograft model. In this model, tumor growth was significantly increased in EBV-positive SCC25 cells compared with that in uninfected cells. Furthermore, tumorigenicity increased after serial passages of EBV-positive SCC25 tumors. This study revealed the oncogenic role of EBV in OSCC progression by inducing the Warburg effect and cancer stemness.

Abstract 040: Evidence Of Increased Glycolysis In Renal Cortex Of High Salt Fed Sprague Dawley Rats

To determine whole kidney O 2 and substance metabolism in an unanesthetized state, arterial (A), renal venous (Vr) blood and urine (U) were analyzed together with measurements of renal blood flow (RBF), blood pressure (BP) and GFR in conscious freely moving male SD rats. RBF and BP were measured continuously (24/7) via chronically implanted ultrasonic flow probe and A-line respectively. A and Vr blood through chronically implanted catheters and urine (U) were sampled intermittently when rats were fed a 0.4% NaCl (LS) diet and on days 7, 14, and 21 after switching to a 4.0% NaCl (HS) diet (HS7, HS14, HS21). A and Vr O 2 contents were determined by radiometer and a global metabolomic analysis was performed at the JAX Laboratory (LC-MS-MS). GFR was determined in another group of rats by transcutaneous detection of the attenuation of i.v. injected FITC sinistrin. Cortical (Cx) and outer medullary (OM) tissues were obtained from the other group of rats and underwent metabolomic and mRNAseq analyses (Novogene). From another group of rats, glomeruli (Glo), proximal tubules (PT) and non-PT were isolated for RT-PCR. BP and RBF slightly increased by HS3 (P&lt;0.05) and were sustained at these levels. O 2 extraction rose progressively from 0.10 ± 0.01 at LS to 0.14 ± 0.01 at HS21 (P&lt;0.05). GFR increased from 0.64 to 0.83 mL/min/100 g (P&lt;0.05) at HS7 and sustained. Na + reabsorption and O 2 consumption were positively correlated. Clear distinctions were observed in a sparse partial least squares discriminant analysis of tissue metabolomics among LS, HS14, and HS21. The mRNAseq analysis found that the HS diet resulted in the activation of immune system-related genes in both Cx and OM and the downregulation of genes related to the TCA cycle and metabolism of amino acids and fatty acids in Cx only. In contrast, glycolysis-related genes including hexokinase ( Hk ) and pyruvate kinase ( Pkm ) were upregulated in Cx. Metabolic fluxes (A-Vr-U) showed the increased release of lactate and pyruvate from the kidney when fed HS. Increased mRNA expression of Hk and Pkm in HS21 was observed only in PT but not in Glo and non-PT. In summary, SD rats fed a HS diet underwent changes in RBF, O 2 extraction, and utilization of substrates with evidence of increased glycolysis.

Identification of an optimized glycolytic-related risk signature for predicting the prognosis in breast cancer using integrated bioinformatic analysis.

Aberrant metabolic disorders and significant glycolytic alterations in tumor tissues and cells are hallmarks of breast cancer (BC) progression. This study aims to elucidate the key biomarkers and pathways mediating abnormal glycolysis in breast cancer using bioinformatics analysis. Differential genes expression analysis, gene ontology analysis, Kyoto encyclopedia of genes and genomes analysis, gene set enrichment analyses, and correlation analysis were performed to explore the expression and prognostic implications of glycolysis-related genes. We effectively integrated 4 genes to construct a prognostic model of shorter survival in the high-risk versus low-risk group. The prognostic model showed promising predictive value and may be an integral part of the prognosis of BC. The survival analysis and receiver operating characteristic curves suggested that the signature showed a good predictive performance in both the The Cancer Genome Atlas training set and 2 gene expression omnibus validation sets. Multivariable analysis demonstrated that the 4-gene signature had an independent prognostic value. Furthermore, all calibration curves exhibited robust validity in prognostic prediction. We established an optimized 4-gene signature to clarify the connection between glycolysis and BC, and offered an attractive platform for risk stratification and prognosis predication of BC patients.

Acute cigarette smoke exposure leads to higher viral infection in human bronchial epithelial cultures by altering interferon, glycolysis and GDF15-related pathways

BackgroundAcute exacerbations of chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD), are frequently associated with rhinovirus (RV) infections. Despite these associations, the pathogenesis of virus-induced exacerbations is incompletely understood. We aimed to investigate effects of cigarette smoke (CS), a primary risk factor for COPD, on RV infection in airway epithelium and identify novel mechanisms related to these effects.MethodsPrimary bronchial epithelial cells (PBEC) from COPD patients and controls were differentiated by culture at the air–liquid interface (ALI) and exposed to CS and RV-A16. Bulk RNA sequencing was performed using samples collected at 6 and 24 h post infection (hpi), and viral load, mediator and l-lactate levels were measured at 6, 24 and 48hpi. To further delineate the effect of CS on RV-A16 infection, we performed growth differentiation factor 15 (GDF15) knockdown, l-lactate and interferon pre-treatment in ALI-PBEC. We performed deconvolution analysis to predict changes in the cell composition of ALI-PBEC after the various exposures. Finally, we compared transcriptional responses of ALI-PBEC to those in nasal epithelium after human RV-A16 challenge.ResultsCS exposure impaired antiviral responses at 6hpi and increased viral replication at 24 and 48hpi in ALI-PBEC. At 24hpi, CS exposure enhanced expression of RV-A16-induced epithelial interferons, inflammation-related genes and CXCL8. CS exposure increased expression of oxidative stress-related genes, of GDF15, and decreased mitochondrial membrane potential. GDF15 knockdown experiments suggested involvement of this pathway in the CS-induced increase in viral replication. Expression of glycolysis-related genes and l-lactate production were increased by CS exposure, and was demonstrated to contribute to higher viral replication. No major differences were demonstrated between COPD and non-COPD-derived cultures. However, cellular deconvolution analysis predicted higher secretory cells in COPD-derived cultures at baseline.ConclusionAltogether, our findings demonstrate that CS exposure leads to higher viral infection in human bronchial epithelium by altering not only interferon responses, but likely also through a switch to glycolysis, and via GDF15-related pathways.

Construction of lncRNA/Pseudogene-miRNA Network Based on In Silico Approaches for Glycolysis Pathway to Identify Prostate Adenocarcinoma-Related Potential Biomarkers.

LncRNAs, pseudogenes, and miRNAs participate a fundamental function in tumorigenesis, metabolism, and invasion of cancer cells, although their regulation of tumor glycolysis in prostate adenocarcinoma (PRAD) is thoroughly not well studied. In this study, we applied transcriptomic, proteomic, and medical information to identify glycolysis-related key genes and modules associated with PRAD. Then, the glycolysis-related lncRNA/lncRNAs/pseudogenes-miRNA-mRNA network was constructed. Analysis of DNA methylation status and expression data determined a DNA methylation-dysregulated three-DE-mRNAs signature for predicting diagnosis, ANGPTL4, GNE, and HSPA in PRAD patients and healthy control. Several lncRNAs/pseudogenes, significantly correlated with the overall survival PVT1, CA5BP1, MIRLET7BHG, SNHG12, and ZNF37BP and disease-free survival status, MALAT1, GUSBP11, MIRLET7BHG, and SNHG1, of patients with PRAD were determined. The methylation profile of DE-lncRNA/pseudogenes was significantly proper for predicting PRAD prognostic model. The transcription level of 6 DE-mRNA ANGPTL4, QSOX1, BIK, CLDN3, DDIT4, and TFF3 was correlated with cancer-related fibroblast infiltration in PRAD. The mutated form of 7 mRNAs, COL5A1, IDH1, HK2, DDIT4, GNE, and QSOX1, was associated with PRAD. In addition to the glycolysis pathway, DE-RNAs play regulatory roles on several pathways, including DNA damage, RTK, cell cycle, RAS/MAPK, TSC/mTOR and PI3K/AKT, AR hormone, and EMT. Overall, our study improves our knowledge of the relation between lncRNAs/pseudogenes and miRNA related to glycolysis and PRAD pathogenesis.

Resveratrol Ameliorates Imiquimod-Induced Psoriasis-Like Mouse Model via Reducing Macrophage Infiltration and Inhibiting Glycolysis.

Resveratrol (Res) is a natural polyphenol with anti-inflammatory and immunomodulatory effects. Alterations in metabolic pathways have been studied in psoriasis. This study is aimed to further explore the potential molecular mechanism of psoriasis improvement by Res. Imiquimod (IMQ)-induced psoriasis-like mouse model was established to observe the effects of Res. NanoString nCounter Metabolic Pathways Panel was used to analyze the changed mRNA and qRT-PCR was used for validation. Flow cytometry was used to analyze immune cell subsets in skin lesions. In vitro, we observed the effects of Res on R848-stimulated macrophages glycolysis and inflammation. Res reduced the proliferation of keratinocytes and the secretion of inflammatory cytokines in IMQ-induced psoriasis-like mouse model. Psoriasis model skin lesions were in a state of hypoxia, with upregulated glycolysis and downregulated AMPK activity. Res inhibited the levels of hypoxia-related genes (hif1α, hif3α) and glycolysis-related genes (hk1, ldha), meanwhile increased the levels of AMPK genes (prkaa1, prkaa2). Flow cytometry analysis revealed that Res decreased the infiltration of macrophages in psoriasis-like lesions. In addition, Res decreased the secretion of macrophage-associated pro-inflammatory cytokines (IL-23, TNF-α, IL-1β). In vitro, Res diminished the secretion of IL-23, TNF-α, IL-1β, and lactate by R848-stimulated macrophages and activated AMPK. This study suggested that Res diminished psoriasis symptoms by inhibiting macrophages infiltration and inhibiting glycolysis, which providing novel insights into the underlying mechanisms of therapeutic action of Res in the treatment of psoriasis.

Transcriptomics and metabolomics reveal the molecular and metabolic adaptation to heat stress in Manila clam Ruditapes philippinarum

Temperature is an important environmental factor affecting metabolism, growth and life activities of marine bivalves. To reveal the molecular and metabolic responses to heat stress, comparative transcriptomics and metabolomics were performed in the commercially important bivalve, Manila clam Ruditapes philippinarum. Comparative transcriptomics revealed a total of 3980 differential genes (DEGs) mainly involved in energy metabolism, protein processing, glycerolphospholipid metabolism, inoxidizability and anti-apoptosis. Comparative metabolomic analysis identified 293 differential metabolites (DEMs) in the heat-stressed clams, including Acetyl-CoA, Beta-D-Glucose, phosphatidylcholine and free amino acids. For the heat-stress clams, they showed the significantly increased enzyme activities of AKP and ACP, as well as antioxidant-related enzyme activities (SOD and CAT) and oxidative damage substance (MDA). The changes in gene expression of glycolysis-related genes (GLUT1, GLK, HK1 and GPI6) and metabolites (Beta-D-Glucose and Acetyl-CoA) reflect the adjusted energy metabolism in the heat-stressed clams. The protein processing in endoplasmic reticulum may play the important roles in the stability of cell membrane structure during heat adaptation. The increased contents of glycerophospholipid (PC) may be essential to maintain the stability and permeability of cell membrane in the heat-stressed clams. Molecular chaperones (HSP70 and HSP90) may participate in the degradation of misfolded proteins to maintain cell homeostasis during the heat stress. To defense the heat stress, clams also initiate the protection and defense mechanisms by activating antioxidant system, innate immune system and anti-apoptotic system. These findings will shed new lights on molecular and metabolic adaptation to heat stress in the intertidal mollusks in a warming climate at the global scale.

Glycolysis induces Th2 cell infiltration and significantly affects prognosis and immunotherapy response to lung adenocarcinoma.

Glycolysis has a major role in cancer progression and can affect the tumor immune microenvironment, while its specific role in lung adenocarcinoma (LUAD) remains poorly studied. We obtained publicly available data from The Cancer Genome Atlas and Gene Expression Omnibus databases and used R software to analyze the specific role of glycolysis in LUAD. The Single Sample Gene Set Enrichment Analysis (ssGSEA) indicated a correlation between glycolysis and unfavorable clinical outcome, as well as a repression effect on the immunotherapy response of LUAD patients. Pathway enrichment analysis revealed a significant enrichment of MYC targets, epithelial-mesenchymal transition (EMT), hypoxia, G2M checkpoint, and mTORC1 signaling pathways in patients with higher activity of glycolysis. Immune infiltration analysis showed a higher infiltration of M0 and M1 macrophages in patients with elevated activity of glycolysis. Moreover, we developed a prognosis model based on six glycolysis-related genes, including DLGAP5, TOP2A, KIF20A, OIP5, HJURP, and ANLN. Both the training and validation cohorts demonstrated the high efficiency of prognostic prediction in this model, which identified that patients with high risk may have a poorer prognosis and lower sensitivity to immunotherapy. Additionally, we also found that Th2 cell infiltration may predict poorer survival and resistance to immunotherapy. The study indicated that glycolysis is significantly associated with poor prognosis in patients with LUAD and immunotherapy resistance, which might be partly dependent on the Th2 cell infiltration. Additionally, the signature comprised of six genes related to glycolysis showed promising predictive value for LUAD prognosis.

Metabolic Responses of Normal Rat Kidneys to a High Salt Intake.

In this study, novel methods were developed, which allowed continuous (24/7) measurement of arterial blood pressure and renal blood flow in freely moving rats and the intermittent collection of arterial and renal venous blood to estimate kidney metabolic fluxes of O2 and metabolites. Specifically, the study determined the effects of a high salt (HS; 4.0% NaCl) diet upon whole kidney O2 consumption and arterial and renal venous plasma metabolomic profiles of normal Sprague-Dawley rats. A separate group of rats was studied to determine changes in the cortex and outer medulla tissue metabolomic and mRNAseq profiles before and following the switch from a 0.4% to 4.0% NaCl diet. In addition, targeted mRNA expression analysis of cortical segments was performed. Significant changes in the metabolomic and transcriptomic profiles occurred with feeding of the HS diet. A progressive increase of kidney O2 consumption was found despite a reduction in expression of most of the mRNA encoding enzymes of TCA cycle. A novel finding was the increased expression of glycolysis-related genes in Cx and isolated proximal tubular segments in response to an HS diet, consistent with increased release of pyruvate and lactate from the kidney to the renal venous blood. Data suggests that aerobic glycolysis (eg, Warburg effect) may contribute to energy production under these circumstances. The study provides evidence that kidney metabolism responds to an HS diet enabling enhanced energy production while protecting from oxidative stress and injury. Metabolomic and transcriptomic analysis of kidneys of Sprague-Dawley rats fed a high salt diet.

Why is Babesia not killed by artemisinin like Plasmodium?

Babesia spp. are intraerythrocytic apicomplexans that digest and utilize red blood cells in a similar way to intraerythrocytic Plasmodium spp., but unlike the latter, are not sensitive to artemisinin. A comparison of Babesia and Plasmodium genomes revealed that Babesia genomes, which are smaller than those of Plasmodium, lack numerous genes, and especially haem synthesis-related genes, that are found in the latter. Single-cell sequencing analysis showed that the different treatment groups of Babesia microti with expressed pentose phosphate pathway-related, DNA replication-related, antioxidation-related, glycolysis-related, and glutathione-related genes were not as sensitive to artemether as Plasmodium yoelii 17XNL. In particular, pentose phosphate pathway-related, DNA replication-related, and glutathione-related genes, which were actively expressed in P. yoelii 17XNL, were not actively expressed in B. microti. Supplying iron in vivo can promote the reproduction of B. microti. These results suggest that Babesia spp. lack a similar mechanism to that of malaria parasites through which the haem or iron in hemoglobin is utilized, and that this likely leads to their insensitivity to artemisinin.Graphical

Multi-omic analysis of glycolytic signatures: exploring the predictive significance of heterogeneity and stemness in immunotherapy response and outcomes in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is a global health challenge with complex pathophysiology, characterized by high mortality rates and poor early detection due to significant tumor heterogeneity. Stemness significantly contributes to the heterogeneity of HCC tumors, and glycolysis is crucial for maintaining stemness. However, the predictive significance of glycolysis-related metabolic genes (GMGs) in HCC remains unknown. Therefore, this study aimed to identify critical GMGs and establish a reliable model for HCC prognosis. Methods: GMGs associated with prognosis were identified by evaluating genes with notable expression changes between HCC and normal tissues retrieved from the MsigDB database. Prognostic gene characteristics were established using univariate and multivariate Cox regression studies for prognosis prediction and risk stratification. The "CIBERSORT" and "pRRophetic" R packages were respectively used to evaluate the immunological environment and predict treatment response in HCC subtypes. The HCC stemness score was obtained using the OCLR technique. The precision of drug sensitivity prediction was evaluated using CCK-8 experiments performed on HCC cells. The miagration and invasion ability of HCC cell lines with different riskscores were assessed using Transwell and wound healing assays. Results: The risk model based on 10 gene characteristics showed high prediction accuracy as indicated by the receiver operating characteristic (ROC) curves. Moreover, the two GMG-related subgroups showed considerable variation in the risk of HCC with respect to tumor stemness, immune landscape, and prognostic stratification. The in vitro validation of the model's ability to predict medication response further demonstrated its reliability. Conclusion: Our study highlights the importance of stemness variability and inter-individual variation in determining the HCC risk landscape. The risk model we developed provides HCC patients with a novel method for precision medicine that enables clinical doctors to customize treatment plans based on unique patient characteristics. Our findings have significant implications for tailored immunotherapy and chemotherapy methods, and may pave the way for more personalized and effective treatment strategies for HCC.

A novel glycolysis-related gene signature for predicting the prognosis of multiple myeloma.

Background: Metabolic reprogramming is an important hallmark of cancer. Glycolysis provides the conditions on which multiple myeloma (MM) thrives. Due to MM's great heterogeneity and incurability, risk assessment and treatment choices are still difficult. Method: We constructed a glycolysis-related prognostic model by Least absolute shrinkage and selection operator (LASSO) Cox regression analysis. It was validated in two independent external cohorts, cell lines, and our clinical specimens. The model was also explored for its biological properties, immune microenvironment, and therapeutic response including immunotherapy. Finally, multiple metrics were combined to construct a nomogram to assist in personalized prediction of survival outcomes. Results: A wide range of variants and heterogeneous expression profiles of glycolysis-related genes were observed in MM. The prognostic model behaved well in differentiating between populations with various prognoses and proved to be an independent prognostic factor. This prognostic signature closely coordinated with multiple malignant features such as high-risk clinical features, immune dysfunction, stem cell-like features, cancer-related pathways, which was associated with the survival outcomes of MM. In terms of treatment, the high-risk group showed resistance to conventional drugs such as bortezomib, doxorubicin and immunotherapy. The joint scores generated by the nomogram showed higher clinical benefit than other clinical indicators. The in vitro experiments with cell lines and clinical subjects further provided convincing evidence for our study. Conclusion: We developed and validated the utility of the MM glycolysis-related prognostic model, which provides a new direction for prognosis assessment, treatment options for MM patients.

BPA exposure enhances the metastatic aggression of ovarian cancer through the ERα/AKT/mTOR/HIF-1α signaling axis.

Long-term exposure to bisphenol A (BPA) in humans may promote ovarian cancer development. In present study, the mechanisms by which BPA mediates the aggression metastatic behavior of ovarian cancer were investigated in vitro/in vivo. The results showed that BPA (10μM) significantly promoted the proliferation, migration and invasion of human ovarian cancer cells (ES-2 and OVCAR-3cells); moreover, it promoted ES-2 and OVCAR-3cell glucose uptake, lactic acid release and intracellular ATP synthesis. After administration of 5μg/kg/day BPA, tumor volume was increased compared with that in control group. KEGG and GO enrichment analyses showed that the genes from ES-2cell in 10μM BPA-treated group were enriched mainly in central carbon metabolism and PI3K-AKT signaling pathway. Then, qRT‒PCR and western blotting results showed that BPA (10μM) increased the mRNA and protein expression levels of glycolysis-related genes and mTOR, p-AKT HIF-1α and ERα in vitro/vivo; whereas this effect was reduced after treatment with the ERα inhibitor methyl-piperidino-pyrazole. Furthermore, coimmunoprecipitation and mass spectrometry showed that BPA promoted the direct interaction of ERα with lactate dehydrogenase A. These results show that BPA directly promoted the proliferation, migration and invasion of ovarian cancer cells through the ERα/AKT/mTOR/HIF-1α signaling axis to enhance glycolysis.

Identification of a novel glycolysis-related prognosis risk signature in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a particularly aggressive cluster of breast cancer characterized by significant molecular heterogeneity. Glycolysis is a metabolic pathway that is significantly associated with cancer progression, metastasis, recurrence and chemoresistance. However, the potential roles of glycolysis-related genes in TNBC remain unclear. In the present study, we identified 108 glycolysis-related differentially expressed genes (DEGs) between breast cancer (BRCA) tumor tissues and normal tissues, and we divided patients into two different clusters with significantly distinct molecular characteristics, clinicopathological features, prognosis, immune cell infiltration and mutation burden. We then constructed a 10-gene signature that classified all TNBCs into low- and high-risk groups. The high-risk group had significantly lower survival than the low-risk group, which implied that the risk score was an independent prognostic indicator for TNBC patients. Consequently, we constructed and validated a prognostic nomogram, which accurately predicted individual overall survival (OS) of TNBC. Moreover, the risk score predicted the drug sensitivity of chemotherapeutic agents and immunotherapy for TNBC patients. The present comprehensive analysis of glycolysis-related DEGs in TNBC provides new methods for prognosis prediction and more effective treatment strategies.