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Background: Recent studies have shown that CD32/CD8a/CD28/CD3ζ chimeric receptor cells directly kill breast cancer cells, suggesting the existence of cell surface myeloid FcγR alternative ligands (ALs). Here, we investigated the metabolism, ALs, cytotoxicity, and immunoregulatory functions of CD64/CD28/CD3ζ in colorectal cancer (CRC) and squamous cell carcinoma of the head and neck. Methods: The CD64/CD28/CD3ζ -SFG retroviral vector was used to produce viruses for T-cell transduction. T-cell expansion and differentiation were monitored via flow cytometry. Gene expression was assessed by RNA-seq. Bioenergetics were documented on a Seahorse extracellular flux analyzer. CD64/CD28/CD3ζ polarization was identified via confocal microscopy. Cytotoxicity was determined by MTT assay and bioluminescent imaging, and flow cytometry. Tridimensional antitumor activity of CD64/CD28/CD3ζ T cells was achieved by utilizing HCT116-GFP 3D spheroids via the IncuCyte S3 Live-Cell Analysis system. The intraperitoneal distribution and antitumor activity of NIR-CD64/CD28/CD3ζ and NIR-nontransduced T cells were investigated in CB17-SCID mice bearing subcutaneous FaDu Luc + cells by bioluminescent and fluorescent imaging. IFNγ was assessed by ELISA. Results: Compared to CD16/CD8a/CD28/CD3ζ T cells, CD32/CD8a/CD28/CD3ζ T cells, and non-transduced T cells, CD64/CD28/CD3ζ T cells exhibited the highest levels of cell expansion and persistence capacity. A total of 235 genes linked to cell division and 52 genes related to glycolysis were overexpressed. The glycolytic phenotype was confirmed by functional in vitro studies accompanied by preferential T-cell effector memory differentiation. Interestingly, oxamic acid was found to inhibit CD64-CR T cell proliferation, indicating the involvement of lactate. Upon CD64/CD28/CD3ζ T-cell conjugation with CRC cells, CD64/CD28/CD3ζ cells polarize at immunological synapses, leading to CRC cell death. CD64/CD28/CD3ζ T cells kill SCCHN cells, and in combination with the anti-B7-H3 mAb (376.96) or anti-EGFR mAb, these cells trigger antibody-dependent cellular cytotoxicity (ADCC) in vitro under 2D and 3D conditions. The 376.96 mAb combined with CD64/CD28/CD3ζ T cells had anti-SCCHN activity in vivo. In addition, they induce the upregulation of PD-L1 and HLA-DR expression in cancer cells via IFNγ. PD-L1 positive SCCHN cells in combination with anti-PD-L1 mAb and CD64-CR T cells were killed by ADCC, which enhanced direct cytotoxicity. These findings indicate that the glycolytic phenotype is involved in CD64-CR T cell proliferation/expansion. These cells mediate long-lasting HLA-independent cytotoxicity and ADCC in CRC and SCCHN cells. Conclusions: CD64/CD28/CD3ζ T cells could significantly impact the rational design of personalized studies to treat CRC and SCCHN and the identification of novel FcγR ALs in cancer and healthy cells. [ABSTRACT FROM AUTHOR]

Background: Improving glioma treatment effectiveness requires a thorough understanding of gliomagenesis. Emerging evidences have proved that zinc and ring finger 2 (ZNRF2) contributes to development of various human malignancies. Nevertheless, a comprehensive study of ZNRF2's role in glioma is absent currently. Methods: Utilizing open resources from Chinese Glioma Genome Atlas (CGGA), Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), Connectivity Map (cMap) and other bioinformatic tools, we systematically examined the expression, clinical significance, prognostic value, regulated biological processes, immune infiltration, and potential inhibitors of ZNRF2 in gliomas. Functional experiments were also performed to validate its oncogenic roles in glioblastoma (GBM) cells. Results: Our findings revealed that ZNRF2 expression was elevated in gliomas compared to normal brains, and its higher levels were correlated with increased grades and worse patient prognosis. The immune analysis suggested that immunotherapies targeting immune checkpoint genes could be beneficial for glioma patients with elevated ZNRF2 expression. Endogenous ZNRF2 knockdown impaired GBM cell proliferation, G2/M cell cycle progression and glycolysis, which was revealed by reduced ATP, pyruvic acid, lactic acid levels and less glucose uptake. Finally, we identified methylprednisolone (MP) as a potential ZNRF2 inhibitor and validated its anti-glioma effects in vitro. MP also enhanced the sensitization of GBM cells to temozolomide (TMZ), the primary chemotherapeutic agent for GBM in clinic. Conclusions: Taken together, our study demonstrated ZNRF2 as an essential tumor-promoting factor by favoring GBM cell proliferation and glycolysis. Our findings suggested that ZNRF2 might serve as a novel independent prognostic biomarker and promising therapeutic target for glioma patients. [ABSTRACT FROM AUTHOR]

Background: Sepsis is a potentially fatal condition with a significant risk of death. Acute lung injury (ALI) is a life-threatening complication of sepsis, and the inflammatory response plays a critical role in sepsis-induced ALI. The protective effects of micheliolide (MCL) against renal fibrosis and leukemia have been demonstrated, but the precise underlying mechanisms remain unclear. Methods: In vitro, lipopolysaccharides (LPS) and interferon-gamma (IFN-γ) were used to stimulate RAW264.7 cells and bone marrow-derived macrophages (BMDMs) to investigate the protective effect of MCL on sepsis-induced ALI. Cecal ligation and puncture (CLP) models were constructed in mice to induce ALI in vivo. The expression of inflammatory factors, macrophage polarization markers, and the glycolysis-related enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) were measured in vivo. Mitochondrial function, oxidative stress, and mitochondrial-related proteins were evaluated in vitro. Results: MCL inhibited CLP-induced ALI, as evidenced by improvements in proinflammatory factor levels, lung wet/dry ratios, and histopathological findings. In vitro, MCL treatment significantly suppressed LPS + IFN-γ-induced M1-type polarization of RAW264.7 cells and BMDMs, as well as the production of inflammatory factors and oxidative stress. Mechanistic experiments revealed that MCL suppresses PFKFB3-driven glycolysis to reduce inflammation and activates the mitochondrial unfolded protein response (UPRmt) to alleviate mitochondrial stress. However, the therapeutic effect of MCL was diminished when PFKFB3 was overexpressed in cells. Conclusion: This study is the first to demonstrate that MCL attenuates sepsis-induced ALI by reducing M1-type macrophage polarization. Its therapeutic effect is closely related to the suppression of oxidative stress and PFKFB3-driven glycolysis. [ABSTRACT FROM AUTHOR]

Background: Cancer cells undergo a metabolic shift termed the Warburg effect, transitioning from oxidative phosphorylation to aerobic glycolysis and promoting rapid tumor proliferation. Quinone oxidoreductase (NQO1), a cytosolic flavoprotein, is important for reprogramming cancer cell metabolism. Therefore, NQO1's function in aerobic glycolysis and impact on colorectal cancer (CRC) development and progression was investigated. Methods: The clinical significance of NQO1 was evaluated by analyzing online databases and was substantiated in CRC specimens. NQO1's influence on proliferation, epithelial-mesenchymal transition (EMT), metastasis, apoptosis, and glycolytic pathways in CRC cells was evaluated using in vitro and in vivo experiments. The molecular interactions between NQO1 and microRNA-485-5p (miR-485-5p) were ascertained via quantitative reverse transcription PCR and dual luciferase reporter assays. The molecular mechanisms underlying the miR-485-5p/NQO1 axis and its effects on progression of malignancy and aerobic glycolysis in CRC cell lines were investigated. Results: NQO1 promoted CRC cell proliferation and EMT, augmented their metastatic potential, and suppressed their apoptosis. The NQO1 overexpression-mediated enhancement of glycolytic activity is implicated in the increased proliferation, EMT, and metastatic abilities of, and reduced apoptosis in, CRC cells. Further, miR-485-5p may inhibit the proliferative and invasive traits of CRC cells by directly targeting the 3′ untranslated region of NQO1 mRNA. Conclusions: miR-485-5p/NQO1 signaling axis orchestrates aerobic glycolysis, thereby modulating CRC cell proliferation, metastasis, and apoptosis. Our study provides mechanistic perspectives regarding the role of NQO1 in CRC progression. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PrCa) is a significant health concern, ranking as the second most common cancer in males globally. Genetic factors contribute substantially to PrCa risk, with up to 57% of the risk being attributed to genetic determinants. A major challenge in managing PrCa is the early identification of aggressive cases for targeted treatment, while avoiding unnecessary interventions in slow-progressing cases. Therefore, there is a critical need for genetic biomarkers that can distinguish between aggressive and non-aggressive PrCa cases. Previous research, including our own, has shown that germline variants in ANO7 are associated with aggressive PrCa. However, the function of ANO7 in the prostate remains unknown. Methods: We performed RNA-sequencing (RNA-seq) on RWPE1 cells engineered to express ANO7 protein, alongside the analysis of a single-cell RNA-sequencing (scRNA-seq) dataset and RNA-seq from prostate tissues. Differential gene expression analysis and gene set enrichment analysis (GSEA) were conducted to identify key pathways. Additionally, we assessed oxidative phosphorylation (OXPHOS), glycolysis, and targeted metabolomics. Image analysis of mitochondrial morphology and lipidomics were also performed to provide further insight into the functional role of ANO7 in prostate cells. Results: ANO7 expression resulted in the downregulation of metabolic pathways, particularly genes associated with the MYC pathway and oxidative phosphorylation (OXPHOS) in both prostate tissue and ANO7-expressing cells. Measurements of OXPHOS and glycolysis in the ANO7-expressing cells revealed a metabolic shift towards glycolysis. Targeted metabolomics showed reduced levels of the amino acid aspartate, indicating disrupted mitochondrial function in the ANO7-expressing cells. Image analysis demonstrated altered mitochondrial morphology in these cells. Additionally, ANO7 downregulated genes involved in fatty acid metabolism and induced changes in lipid composition of the cells, characterized by longer acyl chain lengths and increased unsaturation, suggesting a role for ANO7 in regulating lipid metabolism in the prostate. Conclusions: This study provides new insights into the function of ANO7 in prostate cells, highlighting its involvement in metabolic pathways, particularly OXPHOS and lipid metabolism. The findings suggest that ANO7 may act as a key regulator of cellular lipid metabolism and mitochondrial function in the prostate, shedding light on a previously unknown aspect of ANO7's biology. [ABSTRACT FROM AUTHOR]

Initially, it was believed that glycolysis and DNA damage repair (DDR) were two distinct biological processes that independently regulate tumor progression. The former metabolic reprogramming rapidly generates energy and generous intermediate metabolites, supporting the synthetic metabolism and proliferation of tumor cells. While the DDR plays a pivotal role in preserving genomic stability, thus resisting cellular senescence and cell death under both physiological and radio-chemotherapy conditions. Recently, an increasing number of studies have shown closely correlation between these two biological processes, and then promoting tumor progression. For instance, lactic acid, the product of glycolysis, maintains an acidic tumor microenvironment that not only fosters cell proliferation and invasion but also facilitates DDR by enhancing AKT activity. Here, we provide a comprehensive overview of the enzymes and metabolites involved in glycolysis, along with the primary methods for DDR. Meanwhile, this review explores existing knowledge of glycolysis enzymes and metabolites in regulating DDR. Moreover, considering the significant roles of glycolysis and DDR in tumor development and radio-chemotherapy resistance, the present review discusses effective direct or indirect therapeutic strategies targeted to glycolysis and DDR. [ABSTRACT FROM AUTHOR]

Background: Triggering receptor expressed on myeloid cells 2 (TREM2), a surface receptor predominantly expressed on myeloid cells, is a major hub gene in pathology-induced immune signaling. However, its function in hepatocellular carcinoma (HCC) remains controversial. This study aimed to evaluate the role of TREM2 in the tumor microenvironment in the context of HCC progression. Methods: HCC was experimentally induced in wild-type (WT) and Trem2-deficient (Trem2−/−) mice, and clinical sample analysis and in vitro studies on macrophages were conducted. HCC cells were treated with conditioned medium from WT or Trem2−/− macrophages, and their malignant phenotypes and underlying mechanisms were analyzed. Results: TREM2 deficiency reduced liver tumor burden in orthotopic and subcutaneous HCC models by altering CD8+ T cell infiltration. Trem2-deficient macrophages presented increased chemokine secretion. TGF-β1 was found to be positively correlated with TREM2 expression in HCC, and TGF-β blockade reversed TREM2 induction. On the other hand, TREM2+ macrophages were found to be associated with glycolysis and PKM2 expression in HCC cells; this association may be related to the secretion of IL-1β, which enhances the malignant phenotypes of HCC cells. Conclusions: These results reveal that TREM2+ macrophages play a driving role in HCC progression by suppressing CD8+ T cell infiltration and promoting tumor cell glycolysis, providing a new therapeutic target for HCC. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic nephropathy (DN) is a common diabetes-related complication with unclear underlying pathological mechanisms. Although recent studies have linked glycolysis to various pathological states, its role in DN remains largely underexplored. Methods: In this study, the expression patterns of glycolysis-related genes (GRGs) were first analyzed using the GSE30122, GSE30528, and GSE96804 datasets, followed by an evaluation of the immune landscape in DN. An unsupervised consensus clustering of DN samples from the same dataset was conducted based on differentially expressed GRGs. The hub genes associated with DN and glycolysis-related clusters were identified via weighted gene co-expression network analysis (WGCNA) and machine learning algorithms. Finally, the expression patterns of these hub genes were validated using single-cell sequencing data and quantitative real-time polymerase chain reaction (qRT-PCR). Results: Eleven GRGs showed abnormal expression in DN samples, leading to the identification of two distinct glycolysis clusters, each with its own immune profile and functional pathways. The analysis of the GSE142153 dataset showed that these clusters had specific immune characteristics. Furthermore, the Extreme Gradient Boosting (XGB) model was the most effective in diagnosing DN. The five most significant variables, including GATM, PCBD1, F11, HRSP12, and G6PC, were identified as hub genes for further investigation. Single-cell sequencing data showed that the hub genes were predominantly expressed in proximal tubular epithelial cells. In vitro experiments confirmed the expression pattern in NC. Conclusion: Our study provides valuable insights into the molecular mechanisms underlying DN, highlighting the involvement of GRGs and immune cell infiltration. [ABSTRACT FROM AUTHOR]

Bioenergetic therapy based on tumor glucose metabolism is emerging as a promising therapeutic modality. To overcome the poor bioavailability and toxicity of arenobufagin (ArBu), a MOF-derived intelligent nanosystem, ZIAMH, was designed to facilitate energy deprivation by simultaneous interventions of glycolysis, OXPHOS and TCA cycle. Herein, zeolitic imidazolate framework-8 was loaded with ArBu and indocyanine green, encapsulated within metal–phenolic networks for chemodynamic therapy and hyaluronic acid modification for tumor targeting. ZIAMH nanoparticles can release ArBu in the tumor microenvironment for chemtherapy, and ICG enables photothermal therapy under near-infrared laser irradiation. In vitro and in vivo mechanism studies revealed that the ZIAMH nanoplatform downregulated glucose metabolism related genes, resulting in the reduction of energy substances and metabolites in tumors. Additionally, it significantly promoted cell apoptosis by upregulating pro-apoptotic proteins such as Bax, Bax/Bcl-2, cytochrome C. Animal studies have shown that the tumor inhibition efficiency of ZIAMH nanomedicines was three fold higher than that of free drugs. Therefore, this study provides a new strategy for glucose metabolism-mediated bioenergetic therapy and PTT/CDT/CT combined therapy for tumors. [ABSTRACT FROM AUTHOR]

Background: Caffeic acid phenethyl ester (CAPE) is the main bioactive component of poplar type propolis. We previously reported that treatment with caffeic acid phenethyl ester (CAPE) suppressed the cell proliferation, tumor growth, as well as migration and invasion of prostate cancer (PCa) cells via inhibition of signaling pathways of AKT, c-Myc, Wnt and EGFR. We also demonstrated that combined treatment of CAPE and docetaxel altered the genes involved in glycolysis and tricarboxylic acid (TCA) cycle. We therefore suspect that CAPE treatment may interfere glucose metabolism in PCa cells. Methods: Seahorse Bioenergetics platform was applied to analyzed the extra cellular acidification rate (ECAR) and oxygen consumption rate (OCR) of PCa cells under CAPE treatment. UPLC-MSMS with Multiple Reaction Monitoring (MRM), PCR, and western blot were used to analyze the effects of CAPE on metabolites, genes, and proteins involved in glycolysis, TCA cycle and pentose phosphate pathway in PCa cells. Flow cytometry and ELISA were used to determine the level of reactive oxygen species in PCa cells being treated with CAPE. Results: Seahorse Bioenergetics analysis revealed that ECAR, glycolysis, OCR, and ATP production were elevated in C4-2B cells under CAPE treatment. Protein levels of glucose-6-phosphate dehydrogenase (G6PD), phosphogluconate dehydrogenase (PGD), glutaminase (GLS), phospho-AMPK Thr172 as well as abundance of pyruvate, lactate, ribulose-5-phosphate, and sedoheptulose-7-phosphate were increased in CAPE-treated C4-2B cells. ROS level decreased 48 h after treatment with CAPE. Co-treatment of AMPK inhibitor with CAPE exhibited additive growth inhibition on PCa cells. Conclusions: Our study indicated that PCa cells attempted to overcome the CAPE-induced stress by upregulation of glycolysis and G6PD but failed to impede the growth inhibition caused by CAPE. Concurrent treatment of CAPE and inhibitors targeting glycolysis may be effective therapy for advanced PCa. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) is characterized by high mortality and disability rates. Disease-associated microglia (DAM) are a newly discovered subtype of microglia. However, their presence and function in the acute phase of TBI remain unclear. Although glycolysis is important for microglial differentiation, its regulatory role in DAM transformation during the acute phase of TBI is still unclear. In this study, we investigated the functions of DAM-like cells in the acute phase of TBI in mice, as well as the relationship between their transformation and glycolysis. Methods: In this study, a controlled cortical impact model was used to induce TBI in adult male wild-type (WT) C57BL/6 mice and adult male TREM2 knockout mice. Various techniques were used to assess the role of DAM-like cells in TBI and the effects of glycolysis on DAM-like cells, including RT‒qPCR, immunofluorescence assays, behavioural tests, extracellular acidification rate (ECAR) tests, Western blot analysis, cell magnetic sorting and culture, glucose and lactate assays, and flow cytometry. Results: DAM-like cells were observed in the acute phase of TBI in mice, and their transformation depended on TREM2 expression. TREM2 knockout impaired neurological recovery in TBI mice, possibly due in part to their role in clearing debris and secreting VEGFa and BDNF. Moreover, DAM-like cells exhibited significantly increased glycolytic activity. TREM2 regulated the AKT‒mTOR‒HIF-1α pathway and glycolysis in microglia in the acute phase of TBI. The increase in glycolysis in microglia partially contributed to the transformation of DAM-like cells in the acute phase of TBI in mice. Conclusions: Taken together, the results of our study demonstrated that DAM-like cells were present in the acute phase of TBI in mice. TREM2 might influence DAM-like cell transformation by modulating the glycolysis of microglia. Our results provide a new possible pathway for intervening TBI. [ABSTRACT FROM AUTHOR]

Background: The RAR-related orphan receptor alpha (RORA), a circadian clock molecule, is highly associated with anti-oncogenes. In this paper, we defined the precise action and mechanistic basis of RORA in ESCC development under hypoxia. Methods: Expression analysis was conducted by RT-qPCR, western blotting, immunofluorescence (IF), and immunohistochemistry (IHC) assays. The functions of RORA were assessed by detecting its regulatory effects on cell viability, motility, invasion, and tumor growth. DNA pull-down assay and proteomic analysis were employed to identify proteins bound to the RORA promoter. The promoter methylation level of RORA was detected by DNA pyrosequencing. RNA-seq analysis was performed to explore the downstream mechanisms of RORA, and the transcriptional regulation of RORA on SLC2A3 was verified by ChIP-qPCR and dual-luciferase reporter assay. Glycolysis was assessed by detecting the consumption of glucose and the production of lactic acid and ATP. Results: In vitro, RORA was shown to suppress ESCC cell viability, motility, and invasion under hypoxic condition. In vivo, increased RORA expression in mouse xenografts impeded tumor growth. DNMT1 was identified to widely exist in the RORA promoter, increasing DNA methylation and reducing RORA expression in hypoxia-induced KYSE150 ESCC cells. Mechanistically, RORA was found to inactivate the transcription of glucose transporter protein SLC2A3 by interacting with its promoter F1 region. Furthermore, rescue experiments revealed that RORA-mediated suppressive effects on ESCC cell migration and invasion were largely based on its negative regulation of SLC2A3 and glycolysis. Conclusion: DNMT1-driven methylation of RORA promotes ESCC progression largely through affecting SLC2A3 transcription and glycolysis. These findings turn RORA into potential target of anti-cancer therapeutic agents. Highlights: RORA works as a tumor suppressor in ESCC under hypoxia. DNMT1 downregulates RORA by induction of methylation. RORA inactivates SLC2A3 transcription through its promoter F1 region. RORA inactivates SLC2A3 transcription to inhibit ESCC cell glycolysis and metastasis. [ABSTRACT FROM AUTHOR]

Background: Age-related kidney impairment, characterized by tubular epithelial cell senescence and renal fibrosis, poses a significant global public health threat. Although N6-methyladenosine (m6A) methylation is implicated in various pathological processes, its regulatory mechanism in kidney aging remains unclear. Methods: An m6A-mRNA epitranscriptomic microarray was performed to identify genes with abnormal m6A modifications in aged human kidney tissues. Histological, immunohistochemical, and immunofluorescent staining, western blot, and RT-qPCR were employed to examine the biological functions of targeted genes and m6A methyltransferases both in vivo and in vitro. RNA immunoprecipitation, chromatin immunoprecipitation, ribosomal immunoprecipitation, and luciferase reporter assays were used to investigate the specific interactions between m6A methyltransferases, targeted genes, and their downstream signals. Results: Significantly lower m6A modification levels were observed in aged human kidney tissues. GLIS1, identified as a "metabolic remodeling factor," showed significantly reduced protein levels with abnormal m6A modifications. The downregulation of GLIS1 induced cell senescence and renal fibrosis by shifting metabolic remodeling from fatty acid oxidation (FAO) to glycolysis. Additionally, the methylated GLIS1 mRNA was regulated by the abnormal expression of METTL3 and YTHDF1. Silencing METTL3/YTHDF1 weakened the translation of GLIS1 and disrupted the balance between FAO and glycolysis. Conclusions: Our findings suggest that the m6A modification of GLIS1, activated by METTL3 and reduced in a YTHDF1-dependent manner, leads to kidney aging by regulating the metabolic shift from FAO to glycolysis. This mechanism provides a promising therapeutic target for kidney aging. [ABSTRACT FROM AUTHOR]

Backgroud: Recent studies have reported mitochondrial damage and metabolic dysregulation in BPD, but the changes in mitochondrial dynamics and glucose metabolic reprogramming in ATII cells and their regulatory relationship have not been reported. Methods: Neonatal rats in this study were divided into model (FIO2:85%) and control (FIO2: 21%) groups. Lung tissues were extracted at 3, 7, 10 and 14 postnatal days and then conducted HE staining for histopathological observation. We assessed the expression of mitochondria dynamic associated proteins and glycolysis associated enzymes in lung tissues, primary ATII cells and RLE-6TN cells. Double immunofluorescence staining was used to confirm the co-localization of DRP1 and ATII cells. Real-time analyses of ECAR and OCR were performed with primary ATII cells using Seahorse XF96. ATP concentration was measured using an ATP kit. We treated RLE-6TN cells at 85% hyperoxia for 48 h with mitochondrial fission inhibitor Mdivi-1 to verify the role of DRP1 in regulating glucose metabolic reprogramming. Findings: We found that hyperoxia causes ATII cells' mitochondrial morphological change. The expression of DRP1 and p-DRP1 increased in lung tissue and primary ATII cells of neonatal rats exposed to hyperoxia. Glycolysis related enzymes including PFKM, HK2, and LDHA were also increased. Hyperoxia inhibited ATP production in ATII cells. In RLE-6TN cells, we verified that the administration of Mdivi-1 could alleviate the enhancement of aerobic glycolysis and fragmentation of mitochondria caused by hyperoxia. Interpretations: Hyperoxia exposure leads to increased mitochondrial fission in ATII cells and mediates the reprogramming of glucose metabolism via the DRP1 signaling pathway. Inhibiting the activation of DRP1 signaling pathway may be a promising therapeutic target for BPD. [ABSTRACT FROM AUTHOR]

Background: Conventional treatments, including surgery, radiotherapy and chemotherapy, have many limitations in the prognosis of glioma patients. Atorvastatin (ATOR) has a significant inhibitory effect on glioma malignancy. Thus, ATOR may play a key role in the search for new drugs for the effective treatment of gliomas. Methods: U87 cells were treated with different doses of ATOR and transfected. Viability was assessed using MTT, proliferative ability was determined using the colony formation test, Bax and Bcl-2 were identified using Western blot, apoptosis was identified using flow cytometry, and U87 cell migration and invasion were detected using the Transwell assay. Glucose uptake, lactate secretion, and ATP production in U87 cell culture medium were quantified. The positive rates of IFN-γ and TNF-α in CD8T were measured through flow cytometry. Subcutaneous injection of U87 cells was carried out to construct an in vivo mouse model of gliom, followed by HE staining to assess the effects of ATOR and miR-125a-5p on tumor development. Results: ATOR blocked the viability, proliferation, migration, and invasion of U87 cells through the miR-125a-5p/TXLNA axis, and suppressed glycolysis and immune escape of glioma cells. Furthermore, overexpressing miR-125a-5p enhanced the anti-tumor effect of ATOR in vivo. Conclusion: ATOR blocks glioma progression by modulating the miR-125a-5p/TXLNA axis, further demonstrating that ATOR provides an effective therapeutic target for the treatment of glioma. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS), as a common endocrine and metabolic disorder, is often regarded as a primary cause of anovulatory infertility in women. The pathogenesis of PCOS is complex and influenced by multiple factors. Emerging evidence highlights that energy metabolism dysfunction and oxidative stress in granulosa cells (GCs) are pivotal contributors to aberrant follicular development and impaired fertility in PCOS patients. Mitochondrial dysfunction, increased oxidative stress, and disrupted glucose metabolism are frequently observed in individuals with PCOS, collectively leading to compromised oocyte quality. This review delves into the mechanisms linking oxidative stress and energy metabolism abnormalities in PCOS, analyzing their adverse effects on reproductive function. Furthermore, potential therapeutic strategies to mitigate oxidative stress and metabolic disturbances are proposed, providing a theoretical basis for advancing clinical management of PCOS. [ABSTRACT FROM AUTHOR]

Background: Small cell lung cancer (SCLC) is a highly fatal malignancy, the complex tumor microenvironment (TME) is a critical factor affecting SCLC progression. Cancer-associated fibroblasts (CAFs) are crucial components of TME, yet their role in SCLC and the underlying mechanisms during their interaction with SCLC cells remain to be determined. Methods: Microenvironmental cell components were estimated using transcriptome data from SCLC tissue available in public databases, analyzed with bioinformatic algorithms. A co-culture system comprising MRC5 fibroblasts and SCLC cell lines was constructed. RNA sequencing (RNA-seq) was performed on co-cultured and separately cultured MRC5 and H196 cells to identify differentially expressed genes (DEGs) and enriched signaling pathways. Glycolysis and STING signaling in SCLC cells were assessed using glucose uptake assays, qRT-PCR, and Western blot analysis. Immunohistochemical staining of SCLC tissue arrays quantified α-SMA, HLA-DRA and CD8 expression. Results: Non-neuroendocrine (non-NE) SCLC-derived CAFs exhibited more abundance and DEGs than NE SCLC-derived CAFs did, which interact with non-NE SCLC cells can induce the enrichment of glycolysis-related genes, increasement of glucose uptake, upregulation of glycolytic signaling proteins in non-NE SCLC cells and accumulation of lactate in the extracellular environment, confirming CAF-mediated glycolysis promotion. Additionally, glycolysis-induced ATP production activated STING signaling in non-NE SCLC cells, which upregulated T cell chemo-attractants. However, CAF abundance did not correlate with CD8 + T cell numbers in SCLC tissues. Additionally, non-NE SCLC cell-educated CAFs exhibited features of antigen-presenting CAFs (apCAFs), as indicated by the expression of major histocompatibility complex (MHC) molecules. Co-localization of HLA-DRA and α-SMA signals in SCLC tissues confirmed apCAF presence. The apCAFs and CD8 + T cells were co-located in the SCLC stroma, and there was a positive correlation between CAFs and regulatory T cell (Treg) abundance. Conclusion: Our findings suggest that crosstalk between CAFs and non-NE SCLC cells promotes glycolysis in non-NE SCLC cells, thereby increase T cell chemo-attractant expression via activating STING signaling. On the other hand, it promotes the presence of apCAFs, which probably contributes to CD8 + T cell trapping and Treg differentiation. This study emphasizes the pro-tumor function of CAFs in SCLC by promoting glycolysis and impairing T cell function, providing direction for the development of novel therapeutic approaches targeting CAF in SCLC. [ABSTRACT FROM AUTHOR]

Background: Aberrant interplay between epigenetic reprogramming and metabolic rewiring events contributes to bladder cancer progression and metastasis. How the deacetylase Sirtuin-6 (SIRT6) regulates glycolysis and lactate secretion in bladder cancer remains poorly defined. We thus aimed to study the biological functions of SIRT6 in bladder cancer. Methods: Bioinformatic analysis was used to study the prognostic significance of SIRT6/UHRF1 in BLCA. Both in vitro and in vivo assays were used to determine the roles of SIRT6/UHRF1 in BLCA. Deacetylation and ubiquitin assays were performed to uncover the regulations of SIRT6-UHRF1. Measurement of extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) was used to assess glycolytic abilities. Results: Here, we show that protein deacetylase SIRT6 was down-regulated in BLCA, and predicts poor overall survival. SIRT6 deficiency notably enhances BLCA cell proliferation, self-renewal, and migration capacities in vitro and in vivo. Mechanistically, SIRT6 interacts with, deacetylates, and promotes UHRF1 degradation mediated by β-TrCP1. Thus, SIRT6 deficiency leads to stabilized UHRF1 and depends on UHRF1 to accelerate BLCA malignant progression. Furthermore, UHRF1 significantly increased aerobic glycolysis via activating MCT4/HK2 expressions. Down-regulated SIRT6 thus depended on UHRF1 to promote glycolysis and lactate secretion in BLCA. Targeting UHRF1 or MCT4 notably impaired the extracellular lactate accumulations in BLCA. Significantly, a specific small-molecule inhibitor (NSC232003) targeting UHRF1 substantially inhibited SIRT6-deficient BLCA progression. Conclusion: Together, our study uncovered an epigenetic mechanism of the SIRT6/UHRF1 axis in driving BLCA glycolysis and lactate secretion, creating a novel vulnerability for BLCA treatment. [ABSTRACT FROM AUTHOR]

One of the hallmarks of cancer is metabolic reprogramming which controls cellular homeostasis and therapy resistance. Here, we investigated the effect of momordicine-I (M-I), a key bioactive compound from Momordica charantia (bitter melon), on metabolic pathways in human head and neck cancer (HNC) cells and a mouse HNC tumorigenicity model. We found that M-I treatment on HNC cells significantly reduced the expression of key glycolytic molecules, SLC2A1 (GLUT-1), HK1, PFKP, PDK3, PKM, and LDHA at the mRNA and protein levels. We further observed reduced lactate accumulation, suggesting glycolysis was perturbed in M-I treated HNC cells. Metabolomic analyses confirmed a marked reduction in glycolytic and TCA cycle metabolites in M-I-treated cells. M-I treatment significantly downregulated mRNA and protein expression of essential enzymes involved in de novo lipogenesis, including ACLY, ACC1, FASN, SREBP1, and SCD1. Using shotgun lipidomics, we found a significant increase in lysophosphatidylcholine and phosphatidylcholine loss in M-I treated cells. Subsequently, we observed dysregulation of mitochondrial membrane potential and significant reduction of mitochondrial oxygen consumption after M-I treatment. We further observed M-I treatment induced autophagy, activated AMPK and inhibited mTOR and Akt signaling pathways and leading to apoptosis. However, blocking autophagy did not rescue the M-I-mediated alterations in lipogenesis, suggesting an independent mechanism of action. M-I treated mouse HNC MOC2 cell tumors displayed reduced Hk1, Pdk3, Fasn, and Acly expression. In conclusion, our study revealed that M-I inhibits glycolysis, lipid metabolism, induces autophagy in HNC cells and reduces tumor volume in mice. Therefore, M-I-mediated metabolic reprogramming of HNC has the potential for important therapeutic implications. [ABSTRACT FROM AUTHOR]

Background: Clostridium thermocellum is a promising candidate for production of cellulosic biofuels, however, its final product titer is too low for commercial application, and this may be due to thermodynamic limitations in glycolysis. Previous studies in this organism have revealed a metabolic bottleneck at the phosphofructokinase (PFK) reaction in glycolysis. In the wild-type organism, this reaction uses pyrophosphate (PPi) as an energy cofactor, which is thermodynamically less favorable compared to reactions that use ATP as a cofactor. Previously we showed that replacing the PPi-linked PFK reaction with an ATP-linked reaction increased the thermodynamic driving force of glycolysis, but only had a local effect on intracellular metabolite concentrations, and did not affect final ethanol titer. Results: In this study, we substituted PPi-pfk with ATP-pfk, deleted the other PPi-requiring glycolytic gene pyruvate:phosphate dikinase (ppdk), and expressed a soluble pyrophosphatase (PPase) and pyruvate kinase (pyk) genes to engineer PPi-free glycolysis in C. thermocellum. We demonstrated a decrease in the reversibility of the PFK reaction, higher levels of lower glycolysis metabolites, and an increase in ethanol titer by an average of 38% (from 15.1 to 21.0 g/L) by using PPi-free glycolysis. Conclusions: By engineering PPi-free glycolysis in C. thermocellum, we achieved an increase in ethanol production. These results demonstrate that optimizing the thermodynamic landscape through metabolic engineering can enhance product titers. While further increases in ethanol titers are necessary for commercial application, this work represents a significant step toward engineering glycolysis in C. thermocellum to increase ethanol titers. [ABSTRACT FROM AUTHOR]

Background: Recurrent spontaneous abortion (RSA), whose underlying cause has yet to be fully elucidated, is often classified as unexplained recurrent spontaneous abortion (URSA). Promoting the differentiation of CD4+ T cells into Tregs may be the key to prevent URSA. The differentiation of CD4+ T cells was controlled by mTOR, but the regulatory mechanism is still unclear. This study aims to explore the regulatory role of mTOR on CD4+ T cells and evaluate the feasibility of metformin (Met) and 2-Deoxy-D-glucose (2-DG) treatment for URSA. Methods: To elucidate the mechanism of mTOR regulating Th17/Treg, transcriptome sequencing was used to analyze gene differences in clinical decidua tissue, the AMPK, mTOR and glycolytic activity in URSA mice were evaluated by RT-qPCR and WB. In addition, FCM and ELISA were also used to measure the differentiation of CD4+ T cells. Results: Compared to the Control group, significant differences in gene expressions of female pregnancy and Th17 cell differentiation were observed in URSA group. Activation of AMPK and inhibition of glycolysis reduced the abortion rate in URSA mice (p = 0.0013), and inhibited CD4+ T cells differentiation to Th17 cells, which increased Treg/Th17 ratio (p < 0.001) and improved the pregnancy outcomes of URSA mice. Conclusions: Our research had illustrated that AMPK-mTOR pathway regulated glycolysis reprogramming and improved the pregnancy outcomes of URSA. Furthormore, Met and 2-DG promoted the differentiation of CD4+ T cells into Treg cells, providing theoretical basis for clinical prevention of URSA. [ABSTRACT FROM AUTHOR]

Drought, a prevalent abiotic stressor, significantly impacts plant yield and quality. Melatonin (MT), a potent and economical growth regulator, plays a pivotal role in augmenting crop resilience against stress. This study investigated the efficacy of exogenous MT on drought-stressed celery seedlings by comprehensively analyzing phenotypic, physiological, and molecular attributes. The results revealed that exogenous MT mitigated celery seedling damage under drought stress, lowered malondialdehyde (MDA) concentrations, elevated oxidase activities, osmolyte levels, chlorophyll content, and augmented light energy conversion efficiency. Transcriptomic analysis demonstrated that MT could regulate chlorophyll synthesis genes (AgPORA1 and AgDVR2), contributing to heightened photosynthetic potential and increased drought tolerance in celery. Moreover, MT was found to modulate glycolytic pathways, upregulate pyruvate synthesis genes (AgPEP1 and AgPK3), and downregulate degradation genes (AgPDC2 and AgPDHA2), thereby promoting pyruvate accumulation and enhancing peroxidase activity and drought tolerance. The RNA-seq and qRT-PCR analyses demonstrated similar results, showing the same general expression trends. The study elucidates the physiological and molecular mechanisms underlying MT's stress-alleviating effects in celery seedlings, offering insights into MT-based strategies in plant cultivation and breeding for arid environments. [ABSTRACT FROM AUTHOR]

Background: Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor with a poor prognosis, predominantly CA19-9 positive. High CA19-9 levels correlate with increased aggressiveness and worse outcomes. This study employs multi-omics analysis to reveal molecular features and identify therapeutic targets of CA19-9 positive ICC, aiming to support individualized treatment. Methods: Data from seven clinical cohorts, two whole-exome sequencing cohorts, six RNA sequencing/microarray cohorts, one proteomic cohort, 20 single-cell RNA sequencing samples, and one spatial transcriptome sample were analyzed. Key findings were validated on tissue microarrays from 52 ICC samples. Results: CA19-9 positive ICC exhibited poorer OS (median 24.1 v.s. 51.5 months) and RFS (median 11.7 v.s. 28.2 months) compared to negative group (all P < 0.05). Genomic analysis revealed a higher KRAS mutation frequency in the positive group and a greater prevalence of IDH1/2 mutations in the negative group (all P < 0.05). Transcriptomic analysis indicated upregulated glycolysis pathways in CA19-9 positive ICC. Single-cell analysis identified specific glycolysis-related cell subclusters associated with poor prognosis, including Epi_SLC2A1, CAF_VEGFA, and Mph_SPP1. Higher hypoxia in the CA19-9 positive group led to metabolic reprogramming and promoted these cells' formation. These cells formed interactive communities promoting epithelial-mesenchymal transition (EMT) and angiogenesis. Drug sensitivity analysis identified six potential therapeutic drugs. Conclusions: This study systematically elucidated the clinical, genomic, transcriptomic, and immune features of CA19-9 positive ICC. It reveals glycolysis-associated cellular communities and their cancer-promoting mechanisms, enhancing our understanding of ICC and laying the groundwork for individualized therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Cancer cells alter their metabolic phenotypes with nutritional change. Single agent approaches targeting mitochondrial metabolism in cancer have failed due to either dose limiting off target toxicities, or lack of significant efficacy in vivo. To mitigate these clinical challenges, we investigated the potential utility of repurposing FDA approved mitochondrial targeting anthelmintic agents, niclosamide, IMD-0354 and pyrvinium pamoate, to be combined with GLUT1 inhibitor BAY-876 to enhance the inhibitory capacity of the major metabolic phenotypes exhibited by tumors. Methods: To test this, we used breast cancer cell lines MDA-MB-231 and 4T1 which exhibit differing basal metabolic rates of glycolysis and mitochondrial respiration, respectively. Metabolic characterization was carried out using Seahorse XFe96 Bioanalyzer and statistical analysis was carried out via ANOVA. Results: Here, we found that specific responses to mitochondrial and glycolysis targeting agents elicit responses that correlate with tested cell lines basal metabolic rates and fuel preference, highlighting the potential to cater metabolism targeting treatment regimens based on specific tumor nutrient handling. Inhibition of GLUT1 with BAY-876 potently inhibited glycolysis in both MDA-MB-231 and 4T1 cells, and niclosamide and pyrvinium pamoate perturbed mitochondrial respiration that resulted in potent compensatory glycolysis in the cell lines tested. Conclusion: In this regard, combination of BAY-876 with both mitochondrial targeting agents resulted in inhibition of compensatory glycolysis and subsequent metabolic crisis. These studies highlight targeting tumor metabolism as a combination treatment regimen that can be tailored by basal and compensatory metabolic phenotypes. [ABSTRACT FROM AUTHOR]

Targeting mitochondrial metabolism represents a promising approach for cancer treatment. Here, we investigated the mitotoxic potential of the polybrominated diphenyl ether bromoxib, a natural compound isolated from the marine sponge Dysidea family. We could show that bromoxib comprised strong cytotoxicity in different leukemia and lymphoma cell lines (such as HL60, HPBALL, Jurkat, K562, KOPTK1, MOLT4, SUPB15 and Ramos), but also in solid tumor cell lines (such as glioblastoma cell lines SJ-GBM2 and TP365MG). Bromoxib activated the mitochondrial death pathway as evidenced by the rapid translocation of Bax to the mitochondria and the subsequent mitochondrial release of Smac. Accordingly, bromoxib-induced apoptosis was blocked in caspase 9 deficient Jurkat cells and Jurkat cells overexpressing the antiapoptotic protein Bcl-2. In addition, we could show that bromoxib functioned as an uncoupler of the electron transport chain with similar rapid kinetics as CCCP in terms of dissipation of the mitochondrial membrane potential (ΔΨm), processing of the dynamin-like GTPase OPA1 and subsequent fragmentation of mitochondria. Beyond that, bromoxib strongly abrogated ATP production via glycolysis as well as oxidative phosphorylation (OXPHOS) by targeting electron transport chain complexes II, III, and V (ATP-synthase) in Ramos lymphoma cells. Thus, bromoxib's potential to act on both cytosolic glycolysis and mitochondrial respiration renders it a promising agent for the treatment of leukemia and lymphoma. [ABSTRACT FROM AUTHOR]

Background: Sepsis survivors exhibit immune dysregulation that contributes to poor long-term outcomes. Phenotypic and functional alterations within the myeloid compartment are believed to be a contributing factor. Here we dissect the cellular and transcriptional heterogeneity of splenic CD11b+Ly6Chigh myeloid cells that are expanded in mice that survive the cecal ligation and puncture (CLP) murine model of polymicrobial sepsis to better understand the basis of immune dysregulation in sepsis survivors. Methods: Sham or CLP surgeries were performed on C57BL/6J and BALB/c mice. Four weeks later splenic CD11b+Ly6Chigh cells from both groups were isolated for phenotypic (flow cytometry) and functional (phagocytosis and glycolysis) characterization and RNA was obtained for single-cell RNA-seq (scRNA-seq) and subsequent analysis. Results: CD11b+Ly6Chigh cells from sham and CLP surviving mice exhibit phenotypic and functional differences that relate to immune function, some of which are observed in both C57BL/6J and BALB/c strains and others that are not. To dissect disease-specific and strain-specific distinctions within the myeloid compartment, scRNA-seq analysis was performed on CD11b+Ly6Chigh cells from C57BL/6J and BALB/c sham and CLP mice. Uniform Manifold Approximation and Projection from both strains identified 13 distinct clusters of sorted CD11b+Ly6Chigh cells demonstrating significant transcriptional heterogeneity and expressing gene signatures corresponding to classical-monocytes, non-classical monocytes, M1- or M2-like macrophages, dendritic-like cells, monocyte-derived dendritic-like cells, and proliferating monocytic myeloid-derived suppressor cells (M-MDSCs). Frequency plots showed that the percentages of proliferating M-MDSCs (clusters 8, 11 and 12) were increased in CLP mice compared to sham mice in both strains. Pathway and UCell score analysis in CLP mice revealed that cell cycle and glycolytic pathways were upregulated in proliferating M-MDSCs in both strains. Notably, granule protease genes were upregulated in M-MDSCs from CLP mice. ScRNA-seq analyses also showed that phagocytic pathways were upregulated in multiple clusters including the classical monocyte cluster, confirming the increased phagocytic capacity in CD11b+Ly6Chigh cells from CLP mice observed in ex vivo functional assays in C57BL/6J mice. Conclusion: The splenic CD11b+Ly6Chigh myeloid populations expanded in survivors of CLP sepsis correspond to proliferating cells that have an increased metabolic demand and gene signatures consistent with M-MDSCs, a population known to have immunosuppressive capacity. [ABSTRACT FROM AUTHOR]

Background: SARS-CoV-2, a highly contagious coronavirus, is responsible for the global pandemic of COVID-19 in 2019. Currently, it remains uncertain whether SARS-CoV-2 possesses oncogenic or oncolytic potential in influencing tumor progression. Therefore, it is important to evaluate the clinical and functional role of SARS-CoV-2 on tumor progression. Methods: Here, we integrated bioinformatic analysis of COVID-19 RNA-seq data from the GEO database and performed functional studies to explore the regulatory role of SARS-CoV-2 in solid tumor progression, including lung, colon, kidney and liver cancer. Results: Our results demonstrate that infection with SARS-CoV-2 is associated with a decreased expression of genes associated with cancer proliferation and metastasis in lung tissues from patients diagnosed with COVID-19. Several cancer proliferation or metastasis related genes were frequently downregulated in SARS-CoV-2 infected intestinal organoids and human colon carcinoma cells. In vivo and in vitro studies revealed that SARS-CoV-2 nucleocapsid (N) protein inhibits colon and kidney tumor growth and metastasis through the N-terminal (NTD) and the C-terminal domain (CTD). The molecular mechanism indicates that the N protein of SARS-CoV-2 interacts with YBX1, resulting in the recruitment of PKM mRNA into stress granules mediated by G3BP1. This process ultimately destabilizes PKM expression and suppresses glycolysis. Conclusion: Our study reveals a new function of SARS-CoV-2 nucleocapsid protein on tumor progression. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a major global concern. Mesenchymal stem cell-derived exosomes (MSC-EXOs) have demonstrated efficacy as a therapeutic approach for colorectal cancer. However, the precise mechanism by which MSC-EXOs treat colorectal cancer remains unclear. Human umbilical cord (hUC)-MSC-EXOs were isolated and identified. Cell Counting Kit-8 (CCK-8), Transwell, and colony formation assays were used to assess the activity of CRC cells. Glucose consumption, lactic acid production, and extracellular acidification rate (ECAR) were measured to assess glycolytic activity. Cell stemness was assessed using a sphere-formation assay. Furthermore, MSC-exosomal microRNAs (miRNAs) in CRC tissues were analyzed using the EVmiRNA database, and aberrantly expressed miRNAs in CRC cells were obtained from the Gene Expression Omnibus (GEO) database. The binding relationship between miR-486-5p and the never in mitosis gene A-related kinase 2 (NEK2) was predicted using the Starbase database and validated through RNA binding protein immunoprecipitation (RIP) and dual luciferase assays. These results showed that hUC-MSC-EXOs inhibited the proliferation and metastasis of CRC cells. Moreover, glycolysis and stemness abilities of CRC cells also decreased after treatment with hUC-MSC-EXOs. miR-486-5p was found to be enriched in hUC-MSC-EXOs and significantly downregulated in CRC cells. miR-486-5p directly bound to NEK2. Overexpression of NEK2 reversed the inhibitory effect of miR-486-5p on CRC cell glycolysis and stemness. Our study highlights that hUC-MSC-EXO miR-486-5p inhibits glycolysis and cell stemness in CRC by targeting NEK2. This finding offers compelling evidence supporting the potential application of hUC-MSC-EXOs in the treatment of CRC. [ABSTRACT FROM AUTHOR]

Acute myeloid leukaemia (AML) is a highly heterogeneous malignancy, with a poor 5-year overall survival rate of approximately 30%. Consequently, the search for novel therapeutic strategies is ongoing, and the identification of new vulnerabilities could accelerate progress. Oxidative stress and metabolic rewiring are established hallmarks of cancer, and recent evidence suggests that NADPH oxidases may regulate metabolism, potentially linking these two processes. Increasing research highlights the importance of NOX2 in AML, particularly its role in metabolic regulation. In this study, we investigated the effects of simultaneously inhibiting NOX2 and glycolysis in AML cells. Dual inhibition of NOX2 and glycolysis—by targeting hexokinase or lactate dehydrogenase (LDH)—significantly reduced cell proliferation, markedly impaired clonogenic potential, and induced extensive cell death in a broad panel of AML cell lines. Importantly, these findings were further validated in primary bone marrow samples derived from AML patients, where combined inhibition triggered similar potent anti-leukemic effects. Furthermore, the combined inhibition of NOX2 and LDH enhanced the efficacy of cytarabine (AraC), suggesting this approach could boost the effectiveness of conventional therapies. In an in vivo AML model, targeting NOX2 and LDH in myeloid progenitor cells delayed the onset of leukaemia and extended survival. In conclusion, our findings propose a novel therapeutic strategy for AML through the dual targeting of NOX2 and glycolysis. [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 8.29% and 90.39%, 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]

Metabolic reprogramming is a pivotal biological process in which cellular metabolic patterns change to meet the energy demands of increased cell growth and proliferation. In this review, we explore metabolic reprogramming and its impact on fibrotic diseases, providing a detailed overview of the key processes involved in the metabolic reprogramming of renal fibrosis, including fatty acid decomposition and synthesis, glycolysis, and amino acid catabolism. In addition, we report that Chinese medicine ameliorates renal inflammation, oxidative stress, and apoptosis in chronic kidney disease by regulating metabolic processes, thereby inhibiting renal fibrosis. Furthermore, we reveal that multiple targets and signaling pathways contribute to the metabolic regulatory effects of Chinese medicine. In summary, this review aims to elucidate the mechanisms by which Chinese medicine inhibits renal fibrosis through the remodeling of renal cell metabolic processes, with the goal of discovering new therapeutic drugs for treating renal fibrosis. [ABSTRACT FROM AUTHOR]

Background: Succinic acid (SA) is an important bio-based C4 platform chemical with versatile applications, including the production of 1,4-butanediol, tetrahydrofuran, and γ-butyrolactone. The non-conventional yeast Yarrowia lipolytica has garnered substantial interest as a robust cell factory for SA production at low pH. However, the high concentrations of SA, especially under acidic conditions, can impose significant stress on microbial cells, leading to reduced glucose metabolism viability and compromised production performance. Therefore, it is important to develop Y. lipolytica strains with enhanced SA tolerance for industrial-scale SA production. Results: An SA-tolerant Y. lipolytica strain E501 with improved SA production was obtained through adaptive laboratory evolution (ALE). In a 5-L bioreactor, the evolved strain E501 produced 89.62 g/L SA, representing a 7.2% increase over the starting strain Hi-SA2. Genome resequencing and transcriptome analysis identified a mutation in the 26S proteasome regulatory subunit Rpn1, as well as genes involved in transmembrane transport, which may be associated with enhanced SA tolerance. By further fine-tuning the glycolytic pathway flux, the highest SA titer of 112.54 g/L to date at low pH was achieved, with a yield of 0.67 g/g glucose and a productivity of 2.08 g/L/h. Conclusion: This study provided a robust engineered Y. lipolytica strain capable of efficiently producing SA at low pH, thereby reducing the cost of industrial SA fermentation. [ABSTRACT FROM AUTHOR]

Background: The influence of the small Rho GTPase Rif (RHOF) on tumor growth, glycolysis, endothelial–mesenchymal transition (EMT), and the potential mechanism of RHOF in pancreatic cancer (PC) were explored. Methods: RHOF expression in PC tissues and cells was assessed by qRT-PCR and western blotting. The viability, proliferation, apoptosis, migration, and invasion of PC cells were assessed using CCK-8, colony formation, EdU, flow cytometry, scratch, and Transwell assays. The expression of EMT- and glycolysis-related proteins was determined using western blotting. The potential mechanisms of action of RHOF in PC were identified using bioinformatic analysis. The effects of RHOF were assessed in vivo using a xenograft mouse model. Results: PC cell proliferation, migration, and invasion are accelerated by RHOF overexpression, which inhibited apoptosis. RHOF overexpression promoted EMT and glycolysis as evidenced by a decrease in E-cadherin expression and an increase in N-cadherin, Vimentin, HK2, PKM2, and LDHA expression. Bioinformatic analysis indicated that RHOF activated EMT, glycolysis, and Myc targets and that c-Myc could bind to the PKM2 promoter. RHOF overexpression promotes the lactylation and nuclear translocation of Snail1. Silencing Snail1 reversed the promoting effects of RHOF and lactate on cell migration, invasion, and EMT. Moreover, in vivo tumor growth and EMT were inhibited by RHOF silencing. Conclusion: RHOF plays an oncogenic role in PC. c-Myc is upregulated by RHOF and promotes PKM2 transcription. PKM2 further induces glycolysis, and the lactate produced by glycolysis causes the lactylation of Snail1, ultimately promoting EMT. [ABSTRACT FROM AUTHOR]

Background: Pulmonary fibrosis is a serious interstitial lung disease with no viable treatment except for lung transplantation. Glucagon-like peptide-1 receptor (GLP-1R), commonly regarded as an antidiabetic target, exerts antifibrotic effects on various types of organ fibrosis. However, whether GLP-1R modulates the development and progression of pulmonary fibrosis remains unclear. In this study, we investigated the antifibrotic effect of GLP-1R using in vitro and in vivo models of pulmonary fibrosis. Methods: A silica-induced pulmonary fibrosis mouse model was established to evaluate the protective effects of activating GLP-1R with liraglutide in vivo. Primary cultured lung fibroblasts treated with TGF-β1 combined with IL-1β (TGF-β1 + IL-1β) were used to explore the specific effects of liraglutide, MCC950, and 3PO on fibroblast activation in vitro. Cell metabolism assay was performed to determine the glycolytic rate and mitochondrial respiration. RNA sequencing was utilized to analyse the underlying molecular mechanisms by which liraglutide affects fibroblast activation. ChIP‒qPCR was used to evaluate histone lactylation at the promoters of profibrotic genes in TGF-β1 + IL-1β- or exogenous lactate-stimulated lung fibroblasts. Results: Activating GLP-1R with liraglutide attenuated pulmonary inflammation and fibrosis in mice exposed to silica. Pharmacological inhibition of the NLRP3 inflammasome suppressed PFKFB3-driven glycolysis and vice versa, resulting in decreased lactate production in TGF-β1 + IL-1β-stimulated lung fibroblasts. Activating GLP-1R inhibited TGF-β1 + IL-1β-induced fibroblast activation by disrupting the interaction between the NLRP3 inflammasome and PFKFB3-driven glycolysis and subsequently prevented lactate-mediated histone lactylation to reduce pro-fibrotic gene expression. In addition, activating GLP-1R protected mitochondria against the TGF-β1 + IL-1β-induced increase in oxidative phosphorylation in fibroblasts. In exogenous lactate-treated lung fibroblasts, activating GLP-1R not only repressed NLRP3 inflammasome activation but also alleviated p300-mediated histone lactylation. Finally, GLP-1R activation blocked silica-treated macrophage-conditioned media-induced lung fibroblast activation. Conclusions: The antifibrotic effects of GLP-1R activation on pulmonary fibrosis could be attributed to the inhibition of the interaction between NLRP3 inflammasome and PFKFB3-driven glycolysis, and histone lactylation in lung fibroblasts. Thus, GLP-1R is a specific therapeutic target for the treatment of pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Background: The role of ELAVL1 in the progression of various tumors has been demonstrated. Our research aims to investigate how ELAVL1 controls the glycolytic process in nasopharyngeal carcinoma cells through the HMGB3/β-catenin pathway. Methods: The expression of ELAVL1 was detected in clinical tumor samples and nasopharyngeal carcinoma cell lines. A subcutaneous tumor model was established in nude mice to investigate the role of ELAVL1 in tumor progression. The relationship between HMGB3 and ELAVL1 was validated by RNA pull down and RIP assays. TOPFlash/FOPFlash reporter assay was used to detect β-catenin activity. Assay kits were utilized to measure glucose consumption, lactate production, and G6PD activity in nasopharyngeal carcinoma cells. Western blot was conducted to detect the expression of glycolysis-related proteins. The glycolytic capacity was analyzed through extracellular acidification rate (ECAR). Results: In both clinical samples and nasopharyngeal carcinoma cell lines, the expression levels of ELAVL1 mRNA and protein were found to be upregulated. Knockdown of ELAVL1 significantly inhibited the in vivo proliferation of nasopharyngeal carcinoma and suppressed the glycolytic capacity of nasopharyngeal carcinoma cells. ELAVL1 interacts with HMGB3, leading to an increase in the stability of HMGB3 mRNA. Overexpression of HMGB3 elevated the reduced β-catenin activity caused by sh-ELAVL1 and reversed the inhibitory effect of sh-ELAVL1 on cellular glycolytic capacity. Treatment with β-catenin inhibitor (FH535) effectively suppressed the promotion of glycolytic capacity induced by HMGB3 overexpression. Conclusions: ELAVL1 promotes glycolysis in nasopharyngeal carcinoma cells by interacting with HMGB3 to stabilize HMGB3 mRNA, thereby activating β-catenin pathway. Therefore, targeting the ELAVL1-HMGB3-β-catenin axis has the potential to be a novel approach for treating nasopharyngeal carcinoma. Highlights: ELAVL1 promotes glycolysis in nasopharyngeal carcinoma cells. ELAVL1 interacts with HMGB3, thereby activating β-catenin pathway. HMGB3 is involved in ELAVL1-mediated glycolysis in nasopharyngeal carcinoma cells. HMGB3 promotes glycolysis by activating β-catenin pathway in nasopharyngeal carcinoma cells. [ABSTRACT FROM AUTHOR]

The heterogeneous nuclear ribonucleoprotein C (HNRNPC) plays a crucial role in tumorigenesis, yet its role in papillary thyroid carcinoma (PTC) remains elusive. Herein, we elucidated the function and molecular mechanism of HNRNPC in PTC tumorigenesis and progression. Our study unveiled a significant upregulation of HNRNPC in PTC, and knockdown of HNRNPC markedly inhibited the proliferation, invasion, and metastasis of BCPAP cells. Furthermore, HNRNPC modulated PKM alternative splicing in BCPAP cells primarily through m6A modification. Additionally, by upregulating PKM2 expression, HNRNPC promoted aerobic glycolysis in BCPAP cells, thereby facilitating malignant progression in PTC. In summary, our findings demonstrate that HNRNPC regulates PKM alternative splicing through m6A methylation modification and promotes the proliferation, invasion and metastasis of PTC through glucose metabolism pathways mediated by PKM2. These discoveries provide new biomarkers for screening and diagnosing PTC patients and offer novel therapeutic targets for personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Background: N4-Acetylcytidine (ac4C), a highly conserved post-transcriptional mechanism, plays a pivotal role in RNA modification and tumor progression. However, the molecular mechanism by which ac4C modification mediates tumor immunosuppression remains elusive in triple-negative breast cancer (TNBC). Methods: NAT10 expression was analyzed in TNBC samples in the level of mRNA and protein, and compared with the corresponding normal tissues. ac4C modification levels also measured in the TNBC samples. The effects of NAT10 on immune microenvironment and tumor metabolism were investigated. NAT10-mediated ac4C and its downstream regulatory mechanisms were determined in vitro and in vivo. The combination therapy of targeting NAT10 in TNBC was further explored. Results: The results revealed that the loss of NAT10 inhibited TNBC development and promoted T cell activation. Mechanistically, NAT10 upregulated JunB expression by increasing ac4C modification levels on its mRNA. Moreover, JunB further up-regulated LDHA expression and facilitated glycolysis. By deeply digging, remodelin, a NAT10 inhibitor, elevated the surface expression of CTLA-4 on T cells. The combination of remodelin and CTLA-4 mAb can further activate T cells and inhibite tumor progression. Conclusion: Taken together, our study demonstrated that the NAT10-ac4C-JunB-LDHA pathway increases glycolysis levels and creates an immunosuppressive tumor microenvironment (TME). Consequently, targeting this pathway may assist in the identification of novel therapeutic strategies to improve the efficacy of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease characterized by complex metabolic rewiring that enables growth in changing nutrient availability and oxygen conditions. Transcriptome-based prognostic PDAC tumor subtypes, known as 'basal-like' and 'classical' subtypes are associated with differences in metabolic gene expression including genes involved in glycolysis. Tumor subtype-specific metabolism phenotypes may provide new targets for treatment development in PDAC, but their functional relevance has not been fully elucidated. We aimed to investigate differences in metabolic profiles and transcriptomes in tumor models derived from patients with basal-like and classical tumors. Methods: Patient-derived organoids (PDOs) were established from tumor biopsies collected from patients with metastatic PDAC, including three PDOs from basal-like and five PDOs from classical tumors. Metabolic analyses included assessment of differences in metabolic activity using Seahorse Glycolysis and Mito Stress tests and 13C-glucose metabolites tracing analysis. In order to investigate the influence of mitochondrial pyruvate transport on metabolic differences, PDOs were treated with the mitochondrial pyruvate carrier 1 (MPC1) inhibitor UK-5099. Prognostic relevance of MPC1 was determined using a tumor tissue microarray (TMA) in resectable, and proteomics profiling in metastatic PDAC datasets. Whole genome and transcriptome sequencing, differential gene expression and gene set enrichment analyses were performed in PDOs. Results: Metastatic PDAC PDOs showed subtype-specific differences in glycolysis and oxidative phosphorylation (OXPHOS). Basal-like tumor-derived PDOs had a lower baseline extracellular acidification rate, but higher glycolytic reserves and oxygen consumption rate (OCR) than classical tumor-derived PDOs. OCR difference was eliminated following treatment with UK-5099. In the 13C-glucose metabolites tracing experiment, a basal-like tumor PDO showed lower fractions of some M + 2 metabolites but higher sensitivity to UK-5099 mediated reduction in M + 2 metabolites than a classical tumor PDO. Protein level analyses revealed lower MPC1 protein levels in basal-like PDAC cases and association of low MPC1 levels with clinicopathologic parameters of tumor aggressiveness in PDAC. PDO differential gene expression analyses identified additional subtype-specific cellular pathways and potential disease outcome biomarkers. Conclusions: Our findings point to distinct metabolic profiles in PDAC subtypes with basal-like tumor PDOs showing higher OXPHOS and sensitivity to MPC1 inhibition. Subtypes-specific metabolic vulnerabilities may be exploited for selective therapeutic targeting. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma tumors exhibit resistance to chemotherapy, targeted therapies, and even immunotherapy. Dendritic cells use glucose to support their effector functions and play a key role in anti-tumor immunity by promoting cytotoxic CD8+ T cell activity. However, the effects of glucose and lactate levels on dendritic cells in pancreatic ductal adenocarcinoma are unclear. In this study, we aimed to clarify how glucose and lactate can impact the dendritic cell antigen-presenting function and elucidate the relevant mechanisms. Methods: Glycolytic activity and immune cell infiltration in pancreatic ductal adenocarcinoma were evaluated using patient-derived organoids and resected specimens. Cell lines with increased or decreased glycolysis were established from KPC mice. Flow cytometry and single-cell RNA sequencing were used to evaluate the impacts on the tumor microenvironment. The effects of glucose and lactate on the bone marrow-derived dendritic cell antigen-presenting function were detected by flow cytometry. Results: The pancreatic ductal adenocarcinoma tumor microenvironment exhibited low glucose and high lactate concentrations from varying levels of glycolytic activity in cancer cells. In mouse transplantation models, tumors with increased glycolysis showed enhanced myeloid-derived suppressor cell infiltration and reduced dendritic cell and CD8+ T cell infiltration, whereas tumors with decreased glycolysis displayed the opposite trends. In three-dimensional co-culture, increased glycolysis in cancer cells suppressed the antigen-presenting function of bone marrow-derived dendritic cells. In addition, low-glucose and high-lactate media inhibited the antigen-presenting and mitochondrial functions of bone marrow-derived dendritic cells. Conclusions: Our study demonstrates the impact of dynamic glycolytic reprogramming on the composition of immune cells in the tumor microenvironment of pancreatic ductal adenocarcinoma, especially on the antigen-presenting function of dendritic cells. [ABSTRACT FROM AUTHOR]

Background: C-X-C receptor 4(CXCR4) is widely considered to be a highly conserved G protein-coupled receptor, widely involved in the pathophysiological processes in the human body, including fibrosis. However, its role in regulating macrophage-related inflammation in the fibrotic process of prostatitis has not been confirmed. Here, we aim to describe the role of CXCR4 in modulating macrophage M1 polarization through glycolysis in the development of prostatitis fibrosis. Methods: Use inducible experimental chronic prostatitis as a model of prostatic fibrosis. Reduce CXCR4 expression in immortalized bone marrow-derived macrophages using lentivirus. In the fibrotic mouse model, use adenovirus carrying CXCR4 agonists to detect the silencing of CXCR4 and assess the in vivo effects. Results: In this study, we demonstrated that reducing CXCR4 expression during LPS treatment of macrophages can alleviate M1 polarization. Silencing CXCR4 can inhibit glycolytic metabolism, enhance mitochondrial function, and promote macrophage transition from M1 to M2. Additionally, in vivo functional experiments using AAV carrying CXCR4 showed that blocking CXCR4 in experimental autoimmune prostatitis (EAP) can alleviate inflammation and experimental prostate fibrosis development. Mechanistically, CXCR4, a chemokine receptor, when silenced, weakens the PI3K/AKT/mTOR pathway as its downstream signal, reducing c-MYC expression. PFKFB3, a key enzyme involved in glucose metabolism, is a target gene of c-MYC, thus impacting macrophage polarization and glycolytic metabolism processes. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) is a great clinical challenge because of its aggressiveness and poor prognosis. Zinc Finger Protein 64 (ZFP64), as a transcriptional factor, is responsible for the development and progression of cancers. This study aims to investigate whether ZFP64 regulates stem cell-like properties and tumorigenesis in BC by the glycolytic pathway. Results: It was demonstrated that ZFP64 was overexpressed in BC specimens compared to adjacent normal tissues, and patients with high ZFP64 expression had shorter overall survival and disease-free survival. The analysis of the association of ZFP64 expression with clinicopathological characteristics showed that high ZFP64 expression is closely associated with N stage, TNM stage, and progesterone receptor status. Knockdown of ZFP64 suppressed the viability and colony formation capacity of BC cells by CCK8 and colony formation assays. The subcutaneous xenograft models revealed that ZFP64 knockdown reduced the volume of formatted tumors, and decreased Ki67 expression in tumors. The opposite effects on cell proliferation and tumorigenesis were demonstrated by ZFP64 overexpression. Furthermore, we suggested that the stem cell-like properties of BC cells were inhibited by ZFP64 depletion, as evidenced by the decreased size and number of formatted mammospheres, the downregulated expressions of OCT4, Nanog, and SOX2 proteins, as well as the reduced proportion of CD44+/CD24− subpopulations. Mechanistically, glycolysis was revealed to mediate the effect of ZFP64 using mRNA-seq analysis. Results showed that ZFP64 knockdown blocked the glycolytic process, as indicated by decreasing glycolytic metabolites, inhibiting glucose consumption, and reducing lactate and ATP production. As a transcription factor, we identified that ZFP64 was directly bound to the promoters of glycolysis-related genes (ALDOC, ENO2, HK2, and SPAG4), and induced the transcription of these genes by ChIP and dual-luciferase reporter assays. Blocking the glycolytic pathway by the inhibition of glycolytic enzymes ENO2/HK2 suppressed the high proliferation and stem cell-like properties of BC cells induced by ZFP64 overexpression. Conclusions: These data support that ZFP64 promotes stem cell-like properties and tumorigenesis of BC by activating glycolysis in a transcriptional mechanism. [ABSTRACT FROM AUTHOR]

Cancer cells undergo significant metabolic reprogramming to support their rapid growth and survival. This study examines important metabolic pathways like glycolysis, oxidative phosphorylation, glutaminolysis, and lipid metabolism, focusing on how they are regulated and their contributions to the development of tumors. The interplay between oncogenes, tumor suppressors, epigenetic modifications, and the tumor microenvironment in modulating these pathways is examined. Furthermore, we discuss the therapeutic potential of targeting cancer metabolism, presenting inhibitors of glycolysis, glutaminolysis, the TCA cycle, fatty acid oxidation, LDH, and glucose transport, alongside emerging strategies targeting oxidative phosphorylation and lipid synthesis. Despite the promise, challenges such as metabolic plasticity and the need for combination therapies and robust biomarkers persist, underscoring the necessity for continued research in this dynamic field. [ABSTRACT FROM AUTHOR]

Background: In-depth understanding of dynamic expression profiles of human granulosa cells (GCs) during follicular development will contribute to the diagnostic and targeted interventions for female infertility. However, genome-scale analysis of long non-coding ribonucleic acid (lncRNA) in GCs across diverse developmental stages is challenging. Meanwhile, further research is needed to determine how aberrant lncRNA expression participates in ovarian diseases. Methods: Granulosa cell-related lncRNAs data spanning five follicular development stages were retrieved and filtered from the NCBI dataset (GSE107746). Stage-specific lncRNA expression patterns and mRNA-lncRNA co-expression networks were identified with bioinformatic approaches. Subsequently, the expression pattern of SNHG18 was detected in GCs during ovarian aging. And SNHG18 siRNA or overexpression plasmids were transfected to SVOG cells in examining the regulatory roles of SNHG18 in GC proliferation and apoptosis. Moreover, whether PKCɛ/SNHG18 signaling take part in GC glycolysis via ENO1 were verified in SVOG cells. Results: We demonstrated that GC-related lncRNAs were specifically expressed across different developmental stages, and coordinated crucial biological functions like mitotic cell cycle and metabolic processes in the folliculogenesis. Thereafter, we noticed a strong correlation of PRKCE and SNHG18 expression in our analysis. With downregulated SNHG18 of GCs identified in the context of ovarian aging, SNHG18 knockdown could further induce cell apoptosis, retard cell proliferation and exacerbate DNA damage in SVOG cell. Moreover, downregulated PKCɛ/SNHG18 pathway interrupted the SVOG cell glycolysis by lowering the ENO1 expression. Conclusions: Altogether, our results revealed that folliculogenesis-related lncRNA SNHG18 participated in the pathogenesis of ovarian aging, which may provide novel biomarkers for ovarian function and new insights for the infertility treatment. [ABSTRACT FROM AUTHOR]

Glioma is a primary brain tumor that grows quickly, has an unfavorable prognosis, and can spread intracerebrally. Glioma cells rely on glucose as the major energy source, and glycolysis plays a critical role in tumorigenesis and progression. Substrate utilization shifts throughout glioma progression to facilitate energy generation and biomass accumulation. This metabolic reprogramming promotes glioma cell proliferation and metastasis and ultimately decreases the efficacy of conventional treatments. Non-coding RNAs (ncRNAs) are involved in several glucose metabolism pathways during tumor initiation and progression. These RNAs influence cell viability and glucose metabolism by modulating the expression of key genes of the glycolytic pathway. They can directly or indirectly affect glycolysis in glioma cells by influencing the transcription and post-transcriptional regulation of oncogenes and suppressor genes. In this review, we discussed the role of ncRNAs in the metabolic reprogramming of glioma cells and tumor microenvironments and their abnormal expression in the glucometabolic pathway in glioma. In addition, we consolidated the existing theoretical knowledge to facilitate the use of this emerging class of biomarkers as biological indicators and potential therapeutic targets for glioma. [ABSTRACT FROM AUTHOR]

Ovarian cancer is an extremely malignant gynaecological tumour with a poor patient prognosis and is often associated with chemoresistance. Thus, exploring new therapeutic approaches to improving tumour chemosensitivity is important. The expression of transcription elongation factor B polypeptide 2 (TCEB2) gene is reportedly upregulated in ovarian cancer tumour tissues with acquired resistance, but the specific mechanism involved in tumour resistance remains unclear. In this study, we found that TCEB2 was abnormally highly expressed in cisplatin-resistant tumour tissues and cells. TCEB2 silencing also inhibited the growth and glycolysis of SKOV-3/cisplatin (DDP) and A2780/DDP cells. We further incubated human umbilical vein endothelial cells (HUVECs) with culture supernatants from cisplatin-resistant cells having TCEB2 knockdown. Results revealed that the migration, invasion, and angiogenesis of HUVECs were significantly inhibited. Online bioinformatics analysis revealed that the hypoxia-inducible factor-1A (HIF-1A) protein may bind to TCEB2, and TCEB2 silencing inhibited SKOV-3/DDP cell growth and glycolysis by downregulating HIF1A expression. Similarly, TCEB2 promoted HUVEC migration, invasion, and angiogenesis by upregulating HIF1A expression. In vivo experiments showed that TCEB2 silencing enhanced the sensitivity of ovarian cancer nude mice to cisplatin and that TCEB2 knockdown inhibited the glycolysis and angiogenesis of tumour cells. Our findings can serve as a reference for treating chemoresistant ovarian cancer. [ABSTRACT FROM AUTHOR]

Introduction: Triple-negative breast cancer (TNBC) represents a significant global health crisis due to its resistance to conventional therapies and lack of specific molecular targets. This study explored the potential of Eriocephalus racemosus (E. racemosus) as an alternative treatment for TNBC. The cytotoxic properties and high-resolution respirometry mitochondrial activities of E. racemosus against the MDA-MB 231 TNBC cell line were evaluated. Methods: Hexane solvent and bioactive fraction extractions of E. racemosus were performed, while mass spectrometry-based metabolite profiling was used to identify the phytochemical constituents of the extracts. The extracts were further tested against MDA-MB 231 TNBC cells to determine their cytotoxicity. The mode of cell death was determined using flow cytometry. The activities of caspases 3, 8, and 9 were assessed using a multiplex activity assay kit. Glycolytic activity and High-resolution respirometry measurements of mitochondrial function in the MDA-MB 231 cell line were conducted using the Seahorse XFp and Oroboros O2K. Results: Metabolite profiling of E. racemosus plant crude extracts identified the presence of coumarins, flavonoids, sesquiterpenoids, triterpenoids, and unknown compounds. The extracts demonstrated promising cytotoxic activities, with a half maximal inhibitory concentration (IC50) of 12.84 µg/mL for the crude hexane extract and 15.49 µg/mL for the bioactive fraction. Further, the crude hexane and bioactive fraction extracts induced apoptosis in the MDA-MB-231 TNBC cells, like the reference drug cisplatin (17.44%, 17.26% and 20.25%, respectively) compared to untreated cells. Caspase 3 activities confirmed the induction of apoptosis in both cisplatin and the plant crude extracts, while caspase 8 and 9 activities confirmed the activation of both the intrinsic and extrinsic apoptosis pathways. Increased levels of glycolytic activity were observed in the hexane crude extract. High-resolution respiratory measurements showed elevated mitochondrial activities in all mitochondrial states except for complex-IV activity. Conclusion: These findings support further exploration of E. racemosus as a potential therapeutic agent for TNBC, offering a promising avenue for the development of targeted treatments with minimal adverse effects. [ABSTRACT FROM AUTHOR]

Objective: Renal ischemia/reperfusion injury (IRI) is a major cause of acute kidney injury (AKI), which is associated with high incidence and mortality. AST-120 is an oral carbonaceous adsorbent that can alleviate kidney damage. This study aimed to explore the effects of AST-120 on renal IRI and the molecular mechanism. Methods: A renal IRI mouse model was established and administrated AST-120, and differentially expressed genes were screened using RNA sequencing. Renal function and pathology were analyzed in mice. Hypoxia/reoxygenation (H/R) cell model was generated, and glycolysis was evaluated by detecting lactate levels and Seahorse analysis. Histone lactylation was analyzed by western blotting, and its relationship with hexokinase 2 (HK2) was assessed using chromatin immunoprecipitation. Results: The results showed that HK2 expression was increased after IRI, and AST-120 decreased HK2 expression. Knockout of HK2 attenuated renal IRI and inhibits glycolysis. AST-120 inhibited renal IRI in the presence of HK2 rather than HK2 absence. In proximal tubular cells, knockdown of HK2 suppressed glycolysis and H3K18 lactylation caused by H/R. H3K18 lactylation was enriched in HK2 promoter and upregulated HK2 levels. Rescue experiments revealed that lactate reversed IRI that suppressed by HK2 knockdown. Conclusions: In conclusion, AST-120 alleviates renal IRI via suppressing HK2-mediated glycolysis, which suppresses H3K18 lactylation and further reduces HK2 levels. This study proposes a novel mechanism by which AST-120 alleviates IRI. [ABSTRACT FROM AUTHOR]

Background: In prior research employing iTRAQ (Isobaric Tags for Relative and Absolute Quantitation) technology, we identified a range of proteins in breast cancer tissues exhibiting high levels of acetylation. Despite this advancement, the specific functions and implications of these acetylated proteins in the context of cancer biology have yet to be elucidated. This study aims to systematically investigate the functional roles of these acetylated proteins with the objective of identifying potential therapeutic targets within breast cancer pathophysiology. Methods: Acetylated targets were identified through bioinformatics, with their expression and acetylation subsequently confirmed. Proteomic analysis and validation studies identified potential acetyltransferases and deacetylases. We evaluated metabolic functions via assays for catalytic activity, glucose consumption, ATP levels, and lactate production. Cell proliferation and metastasis were assessed through viability, cycle analysis, clonogenic assays, PCNA uptake, wound healing, Transwell assays, and MMP/EMT marker detection. Results: Acetylated proteins in breast cancer were primarily involved in metabolism, significantly impacting glycolysis and the tricarboxylic acid cycle. Notably, PGK1 showed the highest acetylation at lysine 323 and exhibited increased expression and acetylation across breast cancer tissues, particularly in T47D and MCF-7 cells. Notably, 18 varieties acetyltransferases or deacetylases were identified in T47D cells, among which p300 and Sirtuin3 were validated for their interaction with PGK1. Acetylation at 323 K enhanced PGK1's metabolic role by boosting its activity, glucose uptake, ATP production, and lactate output. This modification also promoted cell proliferation, as evidenced by increased viability, S phase ratio, clonality, and PCNA levels. Furthermore, PGK1-323 K acetylation facilitated metastasis, improving wound healing, cell invasion, and upregulating MMP2, MMP9, N-cadherin, and Vimentin while downregulating E-cadherin. Conclusion: PGK1-323 K acetylation was significantly elevated in T47D and MCF-7 luminal A breast cancer cells and this acetylation could be regulated by p300 and Sirtuin3. PGK1-323 K acetylation promoted cell glycolysis, proliferation, and metastasis, highlighting novel epigenetic targets for breast cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Excavation of key molecules can help identify therapeutic targets and improve the prognosis of pancreatic cancer. This study evaluated the roles of SUMO3 in cell viability, glycolysis, gemcitabine (GEM) sensitivity, and the antitumor activity of butyric acid (BA) in pancreatic cancer. Methods: The mRNA and protein levels of SUMO3 were detected by qRT-PCR, Western blot, and immunohistochemical assay. SUMO3 was silenced or overexpressed in pancreatic cancer cells with or without Wnt/β-catenin pathway inhibitor, glycolysis inhibitor, GEM, or BA treatment. Cell viability was measured using the Cell Counting Kit-8 assay. Glycolysis was measured by determining the extracellular acidification rate, ATP level, and lactate content. Apoptosis was measured by flow cytometry, and TUNEL staining was used to examine in vitro and in vivo sensitivity to GEM chemotherapy. Luciferase reporter and chromatin immunoprecipitation assays were conducted to detect the binding of the SUMO3 promoter and NF-κB p65. Results: SUMO3 was increased and associated with poor survival in pancreatic cancer. SUMO3 knockdown decreased cell viability and glycolysis in vitro and inhibited tumor growth in vivo. SUMO3 overexpression increased cell viability and glycolysis in vitro through the β-catenin pathway. SUMO3 knockdown increased GEM sensitivity, whereas SUMO3 overexpression decreased GEM sensitivity and inhibited the antitumor activity of BA. BA promoted histone acetylation and p-IκBα expression to inhibit NF-κB p65-mediated SUMO3 transcription. Conclusion: SUMO3 acted as an active molecule in cell survival and growth by enhancing glycolysis in response to either GEM or BA. The mechanism was related to the constitutive IκBα/NF-κB/SUMO3/β-catenin signaling pathway. [ABSTRACT FROM AUTHOR]