Search Results (507)

Mycoplasma bovis is an important pathogen that is associated with respiratory diseases, mastitis, and arthritis in cattle, leading to significant economic losses in the global cattle industry. Most notably in this study, we pioneer the discovery that its secreted effector ENO1 (α-enolase) directly targets host cytoskeletal proteins for metabolic–immune regulation. Using an innovative GST pull-down/mass spectrometry approach, we made the seminal discovery of β-actin (ACTB) as the primary host target of ENO1—the first reported bacterial effector–cytoskeleton interaction mediating metabolic reprogramming. ENO1–ACTB binding depends on a hydrogen bond network involving ACTB’s 117Glu and 372Arg residues. This interaction triggers (1) glycolytic activation via Glut1 upregulation, establishing Warburg effect characteristics (lactic acid accumulation/ATP inhibition), and (2) ROS-mediated activation of dual inflammatory axes (HIF-1α/IL-1β and IL-6/TNF-α). This work establishes three groundbreaking concepts: (1) the first evidence of a pathogen effector hijacking host ACTB for metabolic manipulation, (2) a novel ‘glycolysis–ACTB–ROS-inflammation’ axis, and (3) the first demonstration of bacterial proteins coordinating a Warburg effect with cytokine storms. These findings provide new targets for anti-infection therapies against Mycoplasma bovis. Full article

Background/Objective: The hepatitis B virus (HBV) can cause chronic hepatitis B (CHB), which can rapidly progress into fatal liver cirrhosis (CHB-LC) and hepatocellular carcinoma (CHB-HCC). Methods: In this study, we investigated metabolites associated with distinct clinical stages of HBV infection for the identification of stage-specific serum metabolite biomarkers using ¹H-NMR-based metabolomics. Results: A total of 64 serum metabolites were identified, among which six core discriminatory metabolites, namely isoleucine, tryptophan, histamine (for CHB), and pyruvate, TMAO, lactate (for CHB-HCC), were consistently significant across univariate and multivariate statistical analyses, including ANOVA with FDR, OPLS-DA, and VIP scoring. These metabolites were closely linked to key metabolic pathways, such as propanoate metabolism, pyruvate metabolism, and the Warburg effect. Conclusions: The findings suggest that these six core metabolites serve as potential stage-specific biomarkers for CHB, CHB-LC, and CHB-HCC, respectively, and offer a foundation for the future development of metabolomics-based diagnostic and therapeutic strategies. Full article

Glycolysis and oxidative phosphorylation are the main pathways of cellular energy production. Glucose is metabolized via glycolysis to generate pyruvate, which, under anaerobic conditions, is converted into lactate, while, under aerobic conditions, pyruvate enters mitochondria for oxidative phosphorylation to produce more energy. Accordingly, mitochondrial dysfunction disrupts the energy balance. Lactate, historically perceived as a harmful metabolic byproduct. However, emerging research indicates that lactate has diverse biological functions, encompassing energy regulation, epigenetic remodeling, and signaling activities. Notably, the 2019 study revealed the role of lactate in regulating gene expression through histone and non-histone lactylation, thereby influencing critical biological processes. Metabolic reprogramming is a key adaptive mechanism of cells responding to stresses. The Warburg effect in tumor cells exemplifies this, with glucose preferentially converted to lactate for rapid energy, accompanied by metabolic imbalances, characterized by exacerbated aerobic glycolysis, lactate accumulation, suppressed mitochondrial oxidative phosphorylation, and compromised mitochondrial function, ultimately resulting in a vicious cycle of metabolic dysregulation. As molecular bridges connecting metabolism and epigenetics, lactate and lactylation offer novel therapeutic targets for diseases like cancer and neurodegenerative diseases. This review summarizes the interplay between metabolic reprogramming and mitochondrial dysfunction, while discussing lactate and lactylation’s mechanistic in the pathogenesis of related diseases. Full article

In addition to their well-known role in ATP production, mitochondria are vital to cancer cell metabolism due to their involvement in redox regulation, apoptosis, calcium signaling, and biosynthesis. This review explores how cancer cells drive the extensive reprogramming of mitochondrial structure and function, enabling malignant cells to survive hostile microenvironments, evade therapy, and proliferate rapidly. While glycolysis (the Warburg effect) was once thought to be the dominant force behind cancer metabolism, recent updates underscore the pivotal contribution of mitochondrial oxidative phosphorylation (OXPHOS) to tumor development. Cancer cells often exhibit enhanced mitochondrial ATP production, metabolic flexibility, and the ability to switch between energy sources such as glucose, glutamine, and pyruvate. Equally important are changes in mitochondrial morphology and dynamics. Due to disruptions in fusion and fission processes, regulated by proteins like Drp1 and MFN1/2, cancer cells often display fragmented mitochondria, which are linked to increased motility, metastasis, and tumor progression. Moreover, structural mitochondrial alterations not only contribute to drug resistance but may also serve as biomarkers for therapeutic response. Emerging evidence also points to the influence of oncometabolites and retrograde signaling in reshaping mitochondrial behavior under oncogenic stress. Collectively, these insights position mitochondria as central regulators of cancer biology and attractive targets for therapy. By unraveling the molecular mechanisms underlying mitochondrial reprogramming—from energy production to structural remodeling—researchers can identify new approaches to disrupt cancer metabolism and enhance treatment efficacy. Full article

Instead of being waste product of metabolism, lactate, has become a key metabolic and signaling molecule in both exercise physiology and tumor biology. Carcinogenic cells produce huge amounts of lactate through the Warburg effect, which is a hallmark of aggressive tumors, increasing acidity in the environment that can stimulates angiogenesis, immune evasion, and metastasis. Conversely, while exercise acutely elevates blood lactate concentration but it consider helpful for cancer patients. This paradox raises the following question: is exercise-induced lactate a friend or foe in cancer? This study reviews current evidence on the mechanistic, metabolic, immunological, and clinical impacts of exercise-induced lactate in cancer patients, highlighting the context-dependent effects that render lactate either beneficial or detrimental. Tumor-derived lactate seems to be pro-tumorigenic, driving immune suppression and disease progression, whereas short bursts of lactate from exercise can enhance anti-tumor immunity and metabolic reprogramming under the right conditions. Therefore, lactate’s impact on cancer is “all about the context”. Full article

Lactate dehydrogenase (LDH) catalyzes the reversible interconversion of pyruvate and lactate, coupled with the redox cycling of NADH and NAD⁺. While LDHA has been extensively studied as a therapeutic target, particularly in cancer, due to its role in the Warburg effect, LDHB remains underexplored, despite its involvement in the metabolic reprogramming of specific cancer types, including breast and lung cancers. Most known LDH inhibitors are designed against the LDHA isoform and act competitively at the active site. In contrast, LDHB exhibits distinct kinetic properties, substrate preferences, and structural features, warranting isoform-specific screening strategies. In this study, 115 natural compounds previously reported as LDHA inhibitors were systematically evaluated for LDHB inhibition using an integrated in silico and in vitro approach. Virtual screening identified 16 lead phytochemicals, among which luteolin and quercetin exhibited uncompetitive inhibition of LDHB, as demonstrated by enzyme kinetic assays. These findings were strongly supported by molecular docking analyses, which revealed that both compounds bind at an allosteric site located at the dimer interface, closely resembling the binding mode of the established LDHB uncompetitive inhibitor AXKO-0046. In contrast, comparative docking against LDHA confirmed their active-site binding and competitive inhibition, underscoring their isoform-specific behavior. Our findings highlight the necessity of assay conditions tailored to LDHB’s physiological role and demonstrate the application of a previously validated colorimetric assay for high-throughput screening. This work lays the foundation for the rational design of selective LDHB inhibitors from natural product libraries. Full article

Tumor cells often exhibit mitochondrial dysfunction and a pronounced glycolytic shift (the “Warburg effect”) that alters the tumor microenvironment. These metabolic changes, including mitochondrial DNA mutations and impaired oxidative phosphorylation, confer survival advantages and can reduce sensitivity to chemotherapeutics such as paclitaxel. In hypoxic environments, cancer cells upregulate glycolysis via HIF-1α, consequently lowering the extracellular pH through lactate secretion, which is associated with resistance to paclitaxel. Likewise, cancer-associated fibroblasts and immune cells undergo metabolic reprogramming in the tumor microenvironment. Glycolytic CAFs produce lactate and pyruvate that fuel tumor cells, reinforcing drug resistance, and tumor-driven polarization of macrophages toward an immunosuppressive M2 phenotype further impairs the anti-tumor response. Here, we review recent findings on how these metabolic adaptations attenuate paclitaxel efficacy and discuss strategies to overcome resistance. We highlight 15 key studies that reported cancer types, metabolic alterations, molecular targets, and outcomes related to paclitaxel response. Overall, the data suggest that targeting metabolic vulnerabilities, for example, by inhibiting glycolysis (HK2, PGAM1, and PDK) or modulating mitochondrial function, may restore paclitaxel sensitivity. Understanding metabolic crosstalk in the tumor microenvironment provides a basis for combined therapies that improve outcomes in paclitaxel-resistant cancers. Full article

Eukaryotic cells generate ATP primarily via oxidative and substrate-level phosphorylation. Despite the superior efficiency of oxidative phosphorylation, eukaryotic cells often use both pathways as aerobic glycolysis, even in the presence of oxygen. However, its role in cell survival remains poorly understood. Objectives: In this study, aerobic glycolysis was compared between the Warburg effect in breast cancer cells (MCF7) and the Crabtree effect in a laboratory strain of Saccharomyces cerevisiae (S288C). Methods: The metabolic adaptations of MCF7 and S288C cells were compared following treatment with electron transport chain inhibitors, including FCCP, antimycin A, and oligomycin. Results: MCF7 and S288C cells exhibited strikingly similar metabolic rewiring toward substrate-level phosphorylation upon inhibitor treatment, suggesting that mitochondrial oxidative phosphorylation and cytosolic substrate-level phosphorylation communicate through a common mechanism. Measurement of mitochondrial membrane potential (MMP) and ATP concentrations further indicated that cytosolic ATP was transported into the mitochondria under conditions of reduced electron transport chain activity. This ATP was likely utilized in the reverse mode of H⁺/ATPase to maintain MMP, which contributed to the avoidance of programmed cell death. Conclusions: These results suggest that the ATP supply to mitochondria plays a conserved role in aerobic glycolysis in yeast and mammalian cancer cells. This mechanism likely contributes to cell survival under conditions of fluctuating oxygen availability. Full article

Cancer is hallmarked by uncontrolled cell proliferation and enhanced cell survival, driven by a complex interplay of factors—including genetic and epigenetic changes—that disrupt metabolic and signaling pathways and impair organelle function. While the roles of mitochondria and the endoplasmic reticulum in cancer are widely recognized, emerging research is now drawing attention to the involvement of peroxisomes in tumor biology. Peroxisomes are essential for lipid metabolism, including fatty acid α- and β-oxidation, the synthesis of docosahexaenoic acid, bile acids, and ether lipids, as well as maintaining redox balance. Despite their critical functions, the role of peroxisomes in oncogenesis remains inadequately explored. Prostate cancer (PCa), the second most common cancer in men worldwide, exhibits a unique metabolic profile compared to other solid tumors. In contrast to the glycolysis-driven Warburg effect, primary PCa relies primarily on lipogenesis and oxidative phosphorylation. Peroxisomes are intricately involved in the metabolic adaptations of PCa, influencing both disease progression and therapy resistance. Key alterations in peroxisomal activity in PCa include the increased oxidation of branched-chain fatty acids, upregulation of α-methylacyl coenzyme A racemase (a prominent PCa biomarker), and downregulation of 1-alkyl-glycerone-3-phosphate synthase and catalase. This review critically examines the role of peroxisomes in PCa metabolism, progression, and therapeutic response, exploring their potential as biomarkers and targets for therapy. We also consider their relationship with androgen receptor signaling. A deeper understanding of peroxisome biology in PCa could pave the way for new therapies to improve patient outcomes. Full article

In this contribution, a model order reduction (MOR) strategy for systems characterized by Warburg-type impedance behavior, frequently encountered in electrochemical applications, is addressed. In particular, the interest is focused on the time-domain approach for deriving low-order models of such a system, in contrast to the current approaches based on the frequency domain. By exploiting the peculiar structure of positive real (PR) systems, a characteristic value technique relying on the Riccati Equation Balancing strategy is introduced to approximate such models with reduced complexity. The characteristic values of the system are used to define suitable reduced-order models. A numerical case study is presented to validate the effectiveness of the proposed method. The model is also compared against experimental data from the literature, confirming its capability to capture dominant Warburg behavior. Performance indices are computed to quantitatively assess the approximation accuracy across different model orders. The results are critically compared with those obtained using conventional MOR techniques, allowing a thorough assessment of accuracy, stability, and implementation feasibility. Full article

We have previously shown that in cancer patients, free methylglyoxal (MG), a side-product of glycolysis, is recovered from tumors at significantly higher levels than from their corresponding non-cancerous tissues. We also recently confirmed our initial experimental finding that in these patients, free MG peripheral blood levels correlate positively with tumor growth, making free MG levels a new metabolic biomarker of tumor growth of interest to detect cancer and clinically follow cancer patients with no available biomarkers. Now we measure free MG and lactate produced by different cancer and normal cells cultured at low or high glucose concentration and in normoxic or hypoxic conditions to question whether cancer cells and non-cancer cells in tumors produce and release free MG and lactate. Surprisingly, we found that normal fibroblastic and endothelial cell lines grown in normoxic conditions produce and release high free MG levels, which we confirmed for non-transformed normal fibroblasts, albeit at significantly lower levels. Cancer cells generally significantly increased their free MG production and release when cultured in high glucose concentration, while normal cells generally did not. Furthermore, in normoxic conditions, normal fibroblastic cells, in addition to free MG, may produce and release lactate. From this data, we propose that in malignant tumors, both cancer and fibroblastic stromal cells may contribute to tumor growth and development by producing via glycolysis both free MG and D-lactate, which, in addition to L-lactate, may be part of the core hallmark of cell metabolic reprogramming in cancer. Full article

Tumor cell heterogeneity, e.g., in stroma-rich pancreatic ductal adenocarcinoma (PDAC), includes a differential metabolism of lactate. While being secreted as waste product by most cancer cells characterized by the glycolytic Warburg metabolism, it is utilized by a subset of highly malignant cancer cells running the reverse Warburg metabolism. Key drivers of lactate transport are the carrier proteins SLC16A1 (import/export) and SLC16A3 (export). Expression and function of both carriers are controlled by the chaperone Basigin (BSG), which itself is functionally controlled by the transmembrane protease serine 11B (TMPRSS11B). In this study we explored the impact of TMPRSS11B on the phenotype of PDAC cells under reverse Warburg conditions. Amongst a panel of PDAC cell lines, Panc1 and BxPc3 cells were identified to express TMPRSS11B at a high level, whilst other cell lines such as T3M4 did not. ShRNA-mediated TMPRSS11B knock-down in Panc1 and BxPc3 cells enhanced lactate import through SLC16A1, as shown by GFP/iLACCO1 lactate uptake assay, whereas TMPRSS1B overexpression in T3M4 dampened SLC16A1-driven lactate uptake. Moreover, knock-down and overexpression of TMPRSS11B differentially impacted proliferation and chemoresistance under reverse Warburg conditions in Panc1 or BxPc3 and T3M4 cells, respectively, as well as their stemness properties indicated by altered colony formation rates and expression of the stem cell markers Nanog, Sox2, KLF4 and Oct4. These effects of TMPRSS11B depended on both SLC16A1 and BSG as shown by gene silencing. Immunohistochemical analysis revealed a reciprocal expression of TMPRSS11B and BSG together with SLC16A1 in some areas of tumor tissues from PDAC patients. Those regions exhibiting low or no TMPRSS11B expression but concomitant high expression of SLC16A1 and BSG revealed greater amounts of KLF4. In contrast, other tumor areas exhibiting high expression of TMPRSS11B together with BSG and SLC16A1 were largely negative for KLF4 expression. Thus, the differential expression of TMPRSS11B adds to metabolic heterogeneity in PDAC and its absence supports the reverse Warburg metabolism in PDAC cells by the enhancement of BSG-supported lactate uptake through SLC16A1 and subsequent phenotype alterations towards greater stemness. Full article

Glioblastoma (GBM) is the most common primary brain tumor in adults, with a median survival of 15–18 months. GBM cells, like all tumors, exhibit a metabolic shift known as the Warburg effect, favoring glycolysis even under normoxic conditions. GLUT1 is a primary glucose transporter in GBM cells and has been found to be overexpressed in these cells. The acidic microenvironment created by glycolysis facilitates immune evasion, therapy resistance, and tumor growth. Overexpression of GLUT1 is driven by hypoxia-inducible factor-1α (HIF-1α), c-Myc, and other pathways which have been correlated with tumor aggressiveness as well as poor prognosis Recent studies have highlighted the therapeutic potential of targeting GLUT1 in GBM. Preclinical research shows that GLUT1 inhibitors, such as WZB117 and BAY-876, effectively impair tumor metabolism, reduce cell viability, and improve survival in vitro and in animal models. GLUT1 expression also serves as a prognostic marker, with elevated levels linked to poor outcomes. This review highlights the importance of GLUT1 in GBM biology as a potential therapeutic target and biomarker. Full article

Endometriosis is a chronic gynecological disorder characterized by the presence of endometrial-like tissue outside the uterus, leading to inflammation, pain, and infertility. Emerging evidence indicates that endometriotic lesions exhibit cancer-like properties, including metabolic reprogramming marked by increased glucose uptake, enhanced Warburg’s effect, and altered mitochondrial function. These metabolic adaptations support cell survival under hypoxic conditions and contribute to immune evasion and sustained proliferation. This review summarizes current findings on the molecular mechanisms driving metabolic reprogramming in endometriosis, including the roles of mitochondrial dysfunction, hypoxia-inducible factor (HIF) signaling, the PI3K/AKT/mTOR pathway, inflammatory cytokines, and genetic and epigenetic regulators. In addition, we discuss therapeutic strategies targeting glycolytic pathways using both synthetic inhibitors and natural compounds, which represent promising non-hormonal options. Finally, we highlight the need for further preclinical and clinical studies to validate metabolic interventions and improve outcomes for patients with endometriosis. Full article

Background/Objectives: Oxidative stress, the Warburg effect, and resistance to apoptosis are key hallmarks driving colorectal tumorigenesis. This study aimed to develop novel multi-target compounds capable of modulating these pathways. Methods: A library of 24 newly synthesized compounds—incorporating annulated thiophene, thiazole, quinazolinone, 2-oxoindoline, and 1,2,3-oxadiazole scaffolds, as well as N-(1-(4-hydroxy-3-methoxyphenyl)-3-oxo-3-(2-(phenylcarbamothioyl)hydrazineyl) prop-1-en-2-yl)benzamide—was evaluated for antioxidant activity (DPPH assay), PDK-1 and LDHA inhibition, cytotoxic effects against LoVo and HCT-116 colon carcinoma cells, with parallel assessment of safety profiles on normal HUVECs. The underlying anticancer mechanism of the most active compound was investigated through analysis of cell cycle distribution, apoptosis induction, intracellular reactive oxygen species levels, mitochondrial membrane potential disruption, and expression levels of apoptosis-related genes. Molecular docking assessed binding interactions within LDHA and PDK-1 active sites. The physicochemical, drug-likeness, and ADMET properties of the multi-bioactive candidates were predicted in silico. Results: Among the synthesized compounds, thiophenes 3b and 3d exhibited potent PDK-1/LDHA and DPPH/LDHA inhibitions, along with significant cytotoxic effects on LoVo/HCT-116 cells (IC₅₀ in µM: 190.30/170.21 and 156.60/160.96, respectively), while showing minimal cytotoxicity toward HUVECs. Molecular docking revealed favorable interactions with key amino acid residues within the LDHA and/or PDK-1 active sites. Compound 3d notably induced G2/M (LoVo) and G1 (HCT-116) arrest and promoted apoptosis via enhancing ROS generation, modulating Bax/Bcl-2 expressions, disrupting mitochondrial membrane potential, and ultimately activating caspses-3. In silico predictions indicated their promising drug-likeness and pharmacokinetics, though high lipophilicity, poor solubility (especially for 3b), and potential toxicity risks were identified as limitations. Conclusions: Thiophenes 3b and 3d emerged as promising multi-target candidates; however, structural optimization is warranted to enhance their solubility, bioavailability, and safety to support further development as lead anti-colon cancer agents. Full article