Monocarboxylate Transporter Research Articles

Carbonic anhydrase 2 facilitates sorafenib resistance by counteracting MCT4-mediated intracellular pH dysregulation in HCC

Sorafenib, the targeted therapy for hepatocellular carcinoma (HCC), has been utilized in clinics for over a decade. However, its effectiveness is severely hindered by acquired drug resistance, the mechanisms of which remain largely elusive. In this study, we identify that carbonic anhydrase 2 (CA2) is a key regulator of sorafenib resistance. Mechanistically, sorafenib treatment decreases intracellular pH (pHi) by suppressing monocarboxylate transporter 4 (MCT4) expression, while high levels of CA2 counteract MCT4-mediated pHi dysregulation upon sorafenib treatment, maintaining pHi homeostasis to facilitate cell survival and sorafenib resistance. Targeting CA2 re-sensitizes resistant HCC cells to sorafenib both invitro and invivo. Importantly, analysis of clinical samples shows a strong correlation between CA2 expression levels and the therapeutic efficacy of sorafenib in HCC patients. Our findings highlight the significance of CA2 in facilitating sorafenib resistance and propose targeting CA2 as a potential strategy for overcoming sorafenib resistance in HCC patients.

Monocarboxylate Transporter 4 Expression in Thyroid Cancer

Monocarboxylate Transporter 4 Expression in Thyroid Cancer

Post-ischemic inactivation of HIF Prolyl Hydroxylases in endothelium promotes maladaptive kidney repair by inducing glycolysis.

Ischemic acute kidney injury (AKI) is common in hospitalized patients and increases the risk for chronic kidney disease (CKD). Impaired endothelial cell (EC) functions are thought to contribute in AKI to CKD transition, but the underlying mechanisms remain unclear. Here, we identify a critical role for endothelial oxygen sensing prolyl hydroxylase domain (PHD) enzymes 1-3 in regulating post-ischemic kidney repair. In renal endothelium, we observed compartment-specific differences in the expression of the three PHD isoforms in both mice and humans. Post-ischemic concurrent inactivation of endothelial PHD1, PHD2, and PHD3 but not PHD2 alone promoted maladaptive kidney repair characterized by exacerbated tissue injury, fibrosis, and inflammation. Single-cell RNA-seq analysis of the post-ischemic endothelial PHD1, PHD2 and PHD3 deficient (PHDTiEC) kidney revealed an endothelial hypoxia and glycolysis related gene signature, also observed in human kidneys with severe AKI. This metabolic program was coupled to upregulation of the SLC16A3 gene encoding the lactate exporter monocarboxylate transporter 4 (MCT4). Strikingly, treatment with the MCT4 inhibitor syrosingopine restored adaptive kidney repair in PHDTiEC mice. Mechanistically, MCT4 inhibition suppressed pro-inflammatory EC activation reducing monocyte-endothelial cell interaction. Our findings suggest avenues for halting AKI to CKD transition based on selectively targeting the endothelial hypoxia-driven glycolysis/MCT4 axis.

Lactate: a rising star in tumors and inflammation

Lactate has been traditionally regarded as a mere byproduct of glycolysis or metabolic waste. However, an increasing body of literature suggests its critical role in regulating various physiological and pathological processes. Lactate is generally associated with hypoxia, inflammation, viral infections, and tumors. It performs complex physiological roles by activating monocarboxylate transporter (MCT) or the G protein-coupled receptor GPR81 across the cell membrane. Lactate exerts immunosuppressive effects by regulating the functions of various immune cells (such as natural killer cells, T cells, dendritic cells, and monocytes) and its role in macrophage polarization and myeloid-derived suppressor cell (MDSC) differentiation in the tumor microenvironment. Lactic acid has also recently been found to increase the density of CD8+ T cells, thereby enhancing the antitumor immune response. Acute or chronic inflammatory diseases have opposite immune states in the inflammatory disease microenvironment. Factors such as cell types, transcriptional regulators, ionic mediators, and the microenvironment all contribute to the diverse functions lactate exhibits. Herein, we reviewed the pleiotropic effects of lactate on the regulation of various functions of immune cells in the tumor microenvironment and under inflammatory conditions, which may help to provide new insights and potential targets for the diagnosis and treatment of inflammatory diseases and malignancies.

From metabolic byproduct to immune modulator: the role of lactate in tumor immune escape

Lactic acid, a key metabolic byproduct within the tumor microenvironment, has garnered significant attention for its role in immune evasion mechanisms. Tumor cells produce and release large amounts of lactic acid into the tumor microenvironment through aberrant glycolysis via the Warburg effect, leading to a drop in pH. Elevated lactic acid levels profoundly suppress proliferation capacity, cytotoxic functions, and migratory abilities of immune effector cells such as macrophages and natural killer cells at the tumor site. Moreover, lactic acid can modulate the expression of surface molecules on immune cells, interfering with their recognition and attack of tumor cells, and it regulates signaling pathways that promote the expansion and enhanced function of immunosuppressive cells like regulatory T cells, thereby fostering immune tolerance within the tumor microenvironment. Current research is actively exploring strategies targeting lactic acid metabolism to ameliorate tumor immune evasion. Key approaches under investigation include inhibiting the activity of critical enzymes in lactic acid production to reduce its synthesis or blocking lactate transporters to alter intracellular and extracellular lactate distribution. These methods hold promise when combined with existing immunotherapies such as immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies to enhance the immune system’s ability to eliminate tumor cells. This could pave the way for novel combinatorial treatment strategies in clinical cancer therapy, effectively overcoming tumor immune evasion phenomena, and ultimately improving overall treatment efficacy.

In Vitro and In Vivo Antitumor Activities of Isothiourea and Cinnamic Acid Derivative with NOS/MCT Inhibitory Effect.

This work presents the method of synthesis and physicochemical characterization of isothiourea and cinnamic acid original derivative α-cyano-4-hydroxycinnamate 1-cyclohexanoy-l-2-ethylisothiourea (T1114). In studies of the cytotoxic and antitumor activity of T1114, it has been found that the combination in one molecular structure of NOS-inhibitory fragment (1-cyclohexanoyl-2-ethylisothiourea) and a fragment inhibiting monocarboxylate lactate transporters (MCT) (α-cyano-4-hydroxycinnamic acid) does not modify the cytotoxic activity of bifunctional NOS/MCT-inhibitor T1114 in vitro. But in vivo inhibition of NOS and MCT is able to realize effects on the tumor microenvironment and hypoxic tumor cells. Such structural and functional modification has significantly extended the antitumor activity of the new NOS/MCT inhibitor. The bifunctional compound not only realized a more pronounced antitumor effect, but also prevented the development of hypoxic adaptation in solid Ehrlich carcinoma and acquired the ability to overcome the resistance of mouse cervical cancer (RShM-5). Therefore, the combination of NOS-inhibitory, anti-vasculogenic and hypoxia-oriented toxic effects can create new opportunities in antiangiogenic therapy of malignant neoplasms.

Human skeletal muscle possesses an epigenetic memory of high intensity interval training.

Human skeletal muscle displays an epigenetic memory of resistance exercise induced by hypertrophy. It is unknown, however, whether high-intensity interval training (HIIT) also evokes an epigenetic muscle memory. This study employed repeated training intervention interspersed with a detraining period to assess epigenetic memory of HIIT. Twenty healthy subjects (25±5yrs) completed two HIIT interventions (training and retraining) lasting 2 months, separated by 3 months of detraining. Measurements at baseline, after training, detraining and retraining included maximal oxygen consumption (V̇ O2max). Vastus lateralis biopsies were taken for genome-wide DNA methylation and targeted gene expression analyses. V̇ O2max improved during training and retraining (p<0.001) without differences between interventions (p>0.58). Thousands of differentially methylated positions (DMPs) predominantly demonstrated a hypomethylated state after training, retained even after 3-months exercise cessation and into retraining. Five genes; ADAM19, INPP5a, MTHFD1L, CAPN2, SLC16A3 possessed differentially methylated regions (DMRs) with retained hypomethylated memory profiles and increased gene expression. The retained hypomethylation during detraining was associated with an enhancement in expression of the same genes even after 3 months of detraining. SLC16A3, INPP5a, CAPN2 are involved in lactate transport and calcium signaling. Despite similar physiological adaptations between training and retraining, memory profiles were found at epigenetic and gene expression level, characterized by retained hypomethylation and increased gene expression after training into long-term detraining and retraining. These genes were associated with calcium signaling and lactate transport. Whilst significant memory was not observed in physiological parameters, our novel findings indicate that human skeletal muscle possesses an epigenetic memory of HIIT.

Dendrimer/Copper(II) Complex-Mediated siRNA Delivery Disrupts Lactate Metabolism to Reprogram the Local Immune Microenvironment against Tumor Growth and Metastasis.

Solid tumors reprogram metabolic pathways to meet their biosynthesis demands, resulting in elevated levels of metabolites in the tumor microenvironment (TME), including lactate. Excessive accumulation and active transportation of lactate within the TME drives tumor progression, metastasis, and immunosuppression. Interruption of TME lactate metabolism is expected to restore antitumor responses and sensitize tumor immunotherapy. Herein, we developed phenylboronic acid- and pyridine-modified poly(amidoamine) dendrimer/copper(II) (Cu(II)) complexes, namely, D-Cu complexes, to deliver monocarboxylate transporter 4 siRNA (siMCT4) and disrupt the tumor lactate shuttle. The D-Cu complexes are shown to have a Cu(II)-mediated chemodynamic effect and T1-weighted magnetic resonance imaging potential (r1 relaxivity = 1.19 mM-1 s-1), enabling effective siMCT4 delivery to inhibit lactate efflux within cancer cells. In combination with a CD11b immune agonist, the treatment of D-Cu/siMCT4 polyplexes in a mouse breast tumor model alleviates local TME immunosuppression, leading to excellent inhibition of both primary tumor growth and lung metastasis.

Emerging Role of Extracellular pH in Tumor Microenvironment as a Therapeutic Target for Cancer Immunotherapy.

Identifying definitive biomarkers that predict clinical response and resistance to immunotherapy remains a critical challenge. One emerging factor is extracellular acidosis in the tumor microenvironment (TME), which significantly impairs immune cell function and contributes to immunotherapy failure. However, acidic conditions in the TME disrupt the interaction between cancer and immune cells, driving tumor-infiltrating T cells and NK cells into an inactivated, anergic state. Simultaneously, acidosis promotes the recruitment and activation of immunosuppressive cells, such as myeloid-derived suppressor cells and regulatory T cells (Tregs). Notably, tumor acidity enhances exosome release from Tregs, further amplifying immunosuppression. Tumor acidity thus acts as a "protective shield," neutralizing anti-tumor immune responses and transforming immune cells into pro-tumor allies. Therefore, targeting lactate metabolism has emerged as a promising strategy to overcome this barrier, with approaches including buffer agents to neutralize acidic pH and inhibitors to block lactate production or transport, thereby restoring immune cell efficacy in the TME. Recent discoveries have identified genes involved in extracellular pH (pHe) regulation, presenting new therapeutic targets. Moreover, ongoing research aims to elucidate the molecular mechanisms driving extracellular acidification and to develop treatments that modulate pH levels to enhance immunotherapy outcomes. Additionally, future clinical studies are crucial to validate the safety and efficacy of pHe-targeted therapies in cancer patients. Thus, this review explores the regulation of pHe in the TME and its potential role in improving cancer immunotherapy.

TMET-21. METABOLIC PROFILING OF MENINGIOMA REVEALS NOVEL SUBGROUP-SPECIFIC BIOLOGIC INSIGHTS AND OUTCOME DEPENDENCIES

Abstract BACKGROUND Prior studies have elucidated the presence of four consensus molecular groups (MGs) of meningioma, with unique underlying biology and outcomes. The hyperactivation of metabolic pathways may be associated with tumour growth in so-called hypermetabolic (MG3) tumours, and there is a need to better understand the metabolic profiles of these tumours. This study is the first to study the global metabolon of meningioma in the context of modern molecular subgroups. METHODS We performed untargeted metabolic profiling of 53 meningiomas representing each MG and WHO grade. Prognostic biochemicals were identified using Cox regression and further investigated using RNA and protein-based pathway analyses. A larger cohort with available RNA sequencing (n=121) was used to further explore the prognostic influence of relevant pathways, and biochemicals of interest were validated on a subset of these samples (n=35) using targeted high performance liquid chromatography (HPLC). RESULTS Our untargeted approach identified 560 unique biochemicals for downstream analysis. The abundance of N6-trimethyllysine was associated with significantly earlier time to recurrence highly prognostic on our whole cohort (HR [95%CI] = 3.18 [1.45-26.23], p = 0.004) and within hypermetabolic (MG3) tumours (HR [95%CI] = 6.73 [1.72-6.97], p = 0.006); pyruvate was with worse outcomes in proliferative (MG4) tumours specifically (HR [95%CI] = 5.65 [1.073-29.71], p = 0.041). Analysis of implicated gene pathways demonstrated that upregulation of the oxidative phosphorylation pathway portends worse outcomes in the hypermetabolic subgroup but better outcomes in the proliferative subgroup. By contrast, upregulated lactate transporters were associated with worse outcomes in proliferative, but not hypermetabolic, meningiomas. CONCLUSIONS This is the first study to demonstrate a subgroup-specific prognostic role of N6-trimethyllysine and pyruvate in meningioma, offering increasingly granular outcome predictions using a widely accessible technique (HPLC). In addition, we demonstrated key differences in energy utilization between hypermetabolic and proliferative tumours suggesting fundamental differences in preferred energy utilization and reinforcing a need for subgroup-specific therapies.

Disruption of the Physical Interaction Between Carbonic Anhydrase IX and the Monocarboxylate Transporter 4 Impacts Lactate Transport in Breast Cancer Cells.

It has been previously established that breast cancer cells exhibit high expression of the monocarboxylate (lactate) transporters (MCT1 and/or MCT4) and carbonic anhydrase IX (CAIX) and form a functional metabolon for proton-coupled lactate export, thereby stabilizing intracellular pH. CD147 is the MCT accessory protein that facilitates the creation of the MCT/CAIX complex. This study describes how the small molecule Beta-Galactose 2C (BGal2C) blocks the physical and functional interaction between CAIX and either MCT1 or MCT4 in Xenopus oocytes, which reduces the rate of proton and lactate flux with an IC50 of ~90 nM. This value is similar to the Ki for inhibition of CAIX activity. Furthermore, it is shown that BGal2C blocks hypoxia-induced lactate transport in MDA-MB-231 and MCF-7 breast cancer cells, both of which express CAIX. As in oocytes, BGal2C interferes with the physical interaction between CAIX and MCTs in both cell types. Finally, X-ray crystallographic studies highlight unique interactions between BGal2C and a CAIX-mimic that are not observed within the CAII active site and which may underlie the strong specificity of BGal2C for CAIX. These studies demonstrate the utility of a novel sulfonamide in interfering with elevated proton and lactate flux, a hallmark of many solid tumors.

Neurodevelopmental delay as the initial presentation of thyroid hormone resistance syndrome

Thyroid hormone (TH) resistance syndrome is a genetic disorder usually caused by a defect in TH receptors. Moreover, transport and intracellular metabolism alterations have also been described. This case report presents a child with Allan–Herndon–Dudley syndrome characterized by a mutation on the X-linked monocarboxylate transporter 8 gene, a condition that affects the transport of THs across the cell membrane, leading to hypothyroidism in the central nervous system and hyperthyroidism in peripheral tissues, causing severe neurodevelopmental delay manifesting as generalized hypotonia from birth. The utility of monitoring thyroid functions, genetic testing, and triiodothyroacetic acid in the management is highlighted.

Impact of metabolism-related markers on outcomes in ovarian cancer patients: Findings of the MITO16A/MaNGO-OV2 trial.

In ovarian cancer, expression of metabolism-related markers has been investigated in several studies focusing on individual markers; however, a parallel quantitative evaluation of markers mapping to distinct metabolic processes and their prognostic value in large patient cohorts is still lacking. Here, by using immunohistochemistry followed by digital pathology, we investigated the expression of several markers related to glycolysis including monocarboxylate transporter 1 and 4 (MCT1, MCT4), glutamine metabolism (glutaminase, GLS) and hypoxia/acidosis (carbonic anhydrase 9, CA IX) in tissue microarrays of > 300 patients recruited in the MITO16A clinical trial, which involved treatment of ovarian cancer patients with carboplatin/taxol plus bevacizumab. Regarding the prognostic impact of these markers, results indicate that GLS expression correlated with progression-free survival, but this effect disappeared when data were corrected for multiple testing. All other markers showed no correlation with clinical outcome. These results indicate marked heterogeneity of expression of metabolism-associated markers in ovarian cancer; however, there was a lack of association with clinical benefit after chemotherapy/anti-vascular endothelial growth factor treatment. Notwithstanding the lack of prognostic value, knowledge of the pattern of expression of these biomarkers in tumors can be useful for patient stratification purposes when new drugs targeting these metabolic pathways will be tested.

Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism.

CD8+ T cells are critical mediators of antitumor immunity but differentiate into a dysfunctional state, known as T cell exhaustion, after persistent T cell receptor stimulation in the tumor microenvironment (TME). Exhausted T (Tex) cells are characterized by upregulation of coinhibitory molecules and reduced polyfunctionality. T cells in the TME experience an immunosuppressive metabolic environment via reduced levels of nutrients and oxygen and a buildup of lactic acid. Here we show that terminally Tex cells uniquely upregulate Slc16a11, which encodes monocarboxylate transporter 11 (MCT11). Conditional deletion of MCT11 in T cells reduced lactic acid uptake by Tex cells and improved their effector function. Targeting MCT11 with an antibody reduced lactate uptake specifically in Tex cells, which, when used therapeutically in tumor-bearing mice, resulted in reduced tumor growth. These data support a model in which Tex cells upregulate MCT11, rendering them sensitive to lactic acid present at high levels in the TME.

A Metal Coordination Polymer Nanoparticle Synergistically Re-establishes Acidosis and Enhances Chemodynamic Therapy for Glioblastoma

Background: Chemodynamic therapy (CDT) has become increasingly important as a tumor treatment strategy, which relies on intracellular acid and hydrogen peroxide to kill tumor cells by generating hydroxyl radicals (·OH) through Fenton/Fenton-like reactions. However, the weakly alkaline intracellular environment considerably caused by the efflux of lactate and H+ from glioblastoma cells is not conducive to CDT performance. Intracellular acidification induced by inhibiting the transmembrane monocarboxylate transporter 4 (MCT4) can enhance the therapeutic efficacy of CDT. Existing approaches suffer from insufficient MCT4 inhibition, involve complex drug synthesis, and have many unsatisfactory side effects.Methods: In this study, we constructed an anti-tumor nanoparticle formed by self-assembly driven by the coordination interaction of Fe3+ and α-cyano-4-hydroxycinnamate (CHC) to avoid safety issues posed by excessive modification. Fe-CHC nanoparticles were designed to decrease intracellular pH through inhibition of MCT4, which transports lactate/H+ to the extracellular space. The resulting intracellular accumulation of lactate and H+ led to fatal acidosis and promoted ·OH generated by Fenton/Fenton-like reactions with the presence of the Fe3+, thus enhancing CDT-induced tumor cell death.Results:In vitro and in vivo results revealed that Fe-CHC exerted a significant synergistic anti-tumor effect by re-establishing acidosis and enhancing CDT in glioblastoma. Furthermore, the decreased H+ outside the cells caused by the inhibition of lactate/H+ efflux hindered extracellular matrix degradation, thereby inhibiting tumor metastasis.Conclusion: Fe-CHC is an effective anti-cancer agent against glioblastoma. This study provides valuable insights for developing acid-modulating anti-tumor nanoparticles, as well as enriching and optimizing the application of CDT in tumor therapy. Statement of SignificanceOur study pioneers the Fe-CHC nanoparticle, a metal-coordination polymer that targets MCT4 in glioblastoma cells to restore intracellular acidity and synergize with Fe3+ to boost chemodynamic therapy (CDT). Unlike other studies, Fe3+ and CHC work together to maximize the therapeutic potential and safety of Fe-CHC with minimal complexity. This innovative approach not only increased the production of reactive oxygen species within tumor cells, but also hindered tumor metastasis. Our work has important scientific implications for tumor microenvironment regulation and the application of CDT, and will provide a promising pathway for the treatment of aggressive cancers and attract a wide audience through its scientific implications.

In vitro characterization of taurine transport using the human brain microvascular endothelial cell line as a human blood-brain barrier model

Taurine, a sulfur-containing β-amino acid, has various roles in the brain including cellular osmoregulation and neuroprotection. For adequate supply to the brain, taurine has to pass through the blood-brain barrier (BBB); however, the associated mechanism behind crossing the human BBB is not fully understood. Therefore, we characterized taurine transport in vitro using the human brain microvascular endothelial (hCMEC/D3) cell line, a model of human BBB function. [3H]Taurine uptake by hCMEC/D3 cells exhibited time-, as well as extracellular Na+- and Cl−-dependence. The uptake was saturable with a Km of 19 μM and was inhibited by GABA at an IC50 of 328 μM, which were similar to Km values of taurine transporter (TauT)-mediated transport of taurine and GABA, respectively, suggesting that TauT is a major contributor to taurine uptake. For distribution to the brain, taurine must undergo cellular efflux after uptake. Taurine efflux from hCMEC/D3 cells increased for at least 60 min, and monocarboxylate transporter 7 (MCT7)-targeted siRNA significantly reduced MCT7 mRNA levels and [3H]taurine efflux by 93% and 12%, respectively, suggesting that MCT7 partly contributes to taurine efflux from hCMEC/D3 cells. Taken together, these results suggest that TauT and MCT7 function cooperatively in the human BBB.

Reprogramming metabolic microenvironment for nerve regeneration via waterborne polylactic acid-polyurethane copolymer scaffolds

Cell metabolism, as the key driver of inflammation, revascularization and even subsequent tissue regeneration, is controlled by and also conversely influenced by signal transduction. Incorporation of cell metabolism into tissue engineering research holds immense potential for in-situ treatment repair and further understanding of the host-biomaterial cues in body response. In this study, an anti-inflammatory waterborne polyurethane scaffold incorporated with poly-l-lactic acid (PLLA) block was served to repair nerve injuries (LAx-WPU). Lactate was released through the degradation of LAx-WPU scaffolds, and the content increased with the addition of PLLA block over the degradation times. Thenceforth, the production of adenosine triphosphate (ATP) in primary neurons and neuronal axon growth were achieved by taking up lactate through monocarboxylate transporters (MCT2) for energy metabolism under glucose-free environment treated with LAx-WPU degradation solution. After LAx-WPU was implanted to repair brain nerve defects in rats, filamentous neurons elongation, rapid vascularization, and nerve tissue regeneration were realized up to 28 days with the positive expression of microtubule-associated protein (MAP2), β-tubulin (Tuj1), and platelet endothelial cell adhesion molecule (CD31) in the scaffolds. Results highlighted that the LAx-WPU scaffolds up-regulated not only the ATP-ADP-AMP purine metabolism compounds to mainly bridge neuroactive ligand-receptor interaction genes, cAMP pathway genes, and calcium pathway genes for neurocytes but also the ATP-GMP purine metabolism to angiogenesis in Gene Ontology (GO) analysis. Further analysis in reverse showed axonal regeneration is restrained by the inhibition of MCT2, proving LAx-WPU promoted nerve repair depended on lactate for energy. Therefore, LAx-WPU scaffolds construct an expected way to modulate the metabolic microenvironment for inducing nerve regeneration by intrinsic biomaterial metabolism cues without any bioactive factors.

Monocarboxylate transporter dependent mechanism is involved in proliferation, migration, and invasion of human glioblastoma cell lines via activation of PI3K/Akt signaling pathway.

Glioblastoma multiforme is one of the most common primary tumors of the central nervous system, with a very poor prognosis. Cancer cells have been observed to upregulate pH regulators, such as monocarboxylate transporters (MCTs), with an increase in MCT4 expression being observed in several malignancies. MCT4/ recombinant cluster of differentiation 147 (CD147) transporter complex was reported to stimulate vascular endothelial growth factor (VEGF) via the phosphatidylinositol 3 kinase (PI3K) /protein kinase B (Akt) pathway, which has been proven to mediate glioblastoma invasion and migration. The present study aimed to clarify the role of the MCT4/CD147 transporter complex in glioblastoma cell proliferation, migration, and invasion. In this work, lentiviral vectors were used to overexpress MCT4/CD147 and small interfering RNA (siRNA) was used to silence MCT4/CD147 in the human glioma cell lines U87 and U251, respectively. The effects on cell proliferation, migration and invasiveness, as well as the protein expression levels of MCT4 and CD147, extracellular lactate content and Akt activation were assessed by MTT, wound-healing and invasion assays, western blotting and colorimetric method, respectively. The analysis results suggested that cell proliferation, migration, invasion, and Akt activation were decreased by siRNA in all cell lines, but were increased by lentivirus-mediated MCT4 overexpression. These findings suggest that inhibiting the activity and expression of the MCT4/CD147 transporter complex via metabolic-targeting drugs, particularly in cells with a high rate of glycolysis, should be explored as a novel strategy for glioblastoma treatment.

Lactate supplementation after hypoglycemia alleviates cognitive dysfunction induced by recurrent non-severe hypoglycemia in diabetic mice

Recurrent non-severe hypoglycemia (RH) in diabetes is an independent risk factor for cognitive dysfunction. However, the mechanisms and potential therapeutic strategies remain poorly understood. In this study, we aimed to elucidate the mechanisms underlying RH-induced diabetic cognitive impairment. We investigated the effects of RH on lactate metabolism and cognitive function in male C57BL/6 J diabetic mice. After RH, diabetic mice showed decreased brain lactate and adenosine triphosphate levels, decreased expression of lactate transporter proteins MCT1 and MCT4, increased neuroapoptosis, and decreased astrocyte glycolysis in vitro. This was accompanied by increased neuronal mitochondrial reactive oxygen species levels, decreased mitochondrial COX IV activity, impaired mitochondrial morphology and function, impaired synaptic morphology, and decreased expression of synaptic plasticity proteins. Intraperitoneal lactic acid injection improved lactate transport restored neuronal mitochondrial morphology and function, upregulated synaptic plasticity proteins brain-derived neurotrophic factor and early growth response 1, enhanced synaptic ultrastructure, and ultimately improved cognitive dysfunction following RH in diabetic mice. These findings provide insights into the prevention and treatment of cognitive dysfunction in patients with diabetes mellitus caused by RH.

Emodin regulated lactate metabolism by inhibiting MCT1 to delay non-small cell lung cancer progression.

Lung cancer is one of the most common malignant tumors in the world, with high incidence rate and mortality. Monocarboxylate transporter (MCT) 1 has been found to be widely expressed in various tumors and plays a crucial role in regulating energy metabolism. Emodin, as an important traditional Chinese medicine in China, has been reported to inhibit the progression of lung cancer. However, its potential mechanism has not been fully elucidated. The effects of emodin and MCT1 inhibitor AZD3965 on the proliferation, migration, and invasion of lung cancer cells were detected using cell counting kit-8 (CCK-8) assay, wound-healing assay, and transwell small chamber assay. The content of glucose, lactate, and pyruvate in the cell culture medium was detected using a glucose, lactate, and pyruvate detection kit, and also detected protein expression using western blotting. In addition, to investigate the effects of emodin and AZD3965 on lung cancer in vivo, we constructed nude mice subcutaneous transplant tumor model by subcutaneous injection of lung cancer cells. The results showed that emodin and AZD3965 could inhibit the proliferation, migration, and invasion of lung cancer cells. At the same time, they could inhibit the expression of MCT1 in lung cancer cells and promote the release of lactate, but did not affect the content of glucose and pyruvate. In vivo experiments had shown that emodin and AZD3965 could effectively inhibit the growth of lung cancer and inhibit the expression of MCT1. All in all, our data suggested that emodin inhibited the proliferation, migration, and invasion of lung cancer cells, possibly by inhibiting MCT1, providing important theoretical basis for elucidating the mechanism of emodin in treating lung cancer.