Showing papers on "Pyruvate dehydrogenase kinase published in 2023"
TL;DR: In this paper , a brief review on the emerging role of pyruvate metabolism in MQC and MAM function, and how dysfunction in these processes leads to metabolic and inflammatory diseases.
Abstract: Pyruvate metabolism, a key pathway in glycolysis and oxidative phosphorylation, is crucial for energy homeostasis and mitochondrial quality control (MQC), including fusion/fission dynamics and mitophagy. Alterations in pyruvate flux and MQC are associated with reactive oxygen species accumulation and Ca2+ flux into the mitochondria, which can induce mitochondrial ultrastructural changes, mitochondrial dysfunction and metabolic dysregulation. Perturbations in MQC are emerging as a central mechanism for the pathogenesis of various metabolic diseases, such as neurodegenerative diseases, diabetes and insulin resistance-related diseases. Mitochondrial Ca2+ regulates the pyruvate dehydrogenase complex (PDC), which is central to pyruvate metabolism, by promoting its dephosphorylation. Increase of pyruvate dehydrogenase kinase (PDK) is associated with perturbation of mitochondria-associated membranes (MAMs) function and Ca2+ flux. Pyruvate metabolism also plays an important role in immune cell activation and function, dysregulation of which also leads to insulin resistance and inflammatory disease. Pyruvate metabolism affects macrophage polarization, mitochondrial dynamics and MAM formation, which are critical in determining macrophage function and immune response. MAMs and MQCs have also been intensively studied in macrophage and T cell immunity. Metabolic reprogramming connected with pyruvate metabolism, mitochondrial dynamics and MAM formation are important to macrophages polarization (M1/M2) and function. T cell differentiation is also directly linked to pyruvate metabolism, with inhibition of pyruvate oxidation by PDKs promoting proinflammatory T cell polarization. This article provides a brief review on the emerging role of pyruvate metabolism in MQC and MAM function, and how dysfunction in these processes leads to metabolic and inflammatory diseases.
1 citations
TL;DR: In this paper , the authors discuss recent findings on pyruvate kinase activators as new therapeutic option in hereditary red cell disorders such as thalassemic syndromes or sickle cell disease (SCD).
Abstract: In red cells, pyruvate kinase is a key enzyme in the final step of glycolytic degradative process, which generates a constant energy supply via ATP production. This commentary discusses recent findings on pyruvate kinase activators as new therapeutic option in hereditary red cell disorders such as thalassemic syndromes or sickle cell disease (SCD).Mitapivat and etavopivat are two oral pyruvate kinase activators. Studies in a mouse model for β thalassemia have shown beneficial effects of mitapivat on both red cell survival and ineffective erythropoiesis, with an amelioration of iron homeostasis. This was confirmed in a proof-of-concept study in patients with nontransfusion-dependent thalassemias. Both mitapivat and etavopivat have been evaluated in mouse models for SCD, showing an increased 2-3DPG/ATP ratio and a reduction in haemolysis as well as in sickling. These data were confirmed in proof-of-concept clinical studies with both molecules carried in patients with SCD.Preclinical and clinical evidence indicate that pyruvate kinase activators represent new therapeutic option in hemoglobinopathies or SCD. Other red cell disorders such as hereditary spherocytosis or hereditary anaemias characterized by defective erythropoiesis might represent additional areas to investigate the therapeutic impact of pyruvate kinase activators.
1 citations
TL;DR: In this article , the effects of pyruvic acid derivatives on 6-hydroxydopamine-induced SH-SY5Y cell apoptosis were investigated, and it was shown that pyruvate increased protein levels of cleaved caspase-3, phosphorylated endoplasmic reticulum kinase (pERK), and extracellular signal-regulated kinase.
Abstract: Parkinson disease is a chronic progressive neurodegenerative disorder with a prevalence that increases with age. The glycolytic end-product pyruvate, has antioxidant and neuroprotective feature. Here, we investigated the effects of ethyl pyruvate (EP), a pyruvic acid derivative, on 6-hydroxydopamine-induced SH-SY5Y cell apoptosis. Ethyl pyruvate decreased protein levels of cleaved caspase-3, phosphorylated endoplasmic reticulum kinase (pERK), and extracellular signal-regulated kinase (ERK), suggesting that EP reduces apoptosis via the ERK signaling pathway. Ethyl pyruvate also decreased oxygen species (ROS) and neuromelanin contents, suggesting that it suppresses ROS-mediated neuromelanin synthesis. Furthermore, increased protein levels of Beclin-1 and LC-II, and LC-II:LC-I ratios indicated that EP upregulates autophagy.
1 citations
TL;DR: In this paper , a combined deletion of pyruvate dehydrogenase kinase (PDK) 2 and 4 inhibits platelet function and arterial thrombosis.
1 citations
TL;DR: In this paper , mild hypoxia treatment following global ischemic injury paradoxically improved recovery of myocardial mitochondrial respiration and metabolism and was associated with improved physiological recovery and survival.
Abstract: Introduction: Mitochondrial injury occurs following cellular ischemia in the setting of myocardial infarction, stroke, and cardiac arrest (CA). Effective strategies for reducing injury are limited. Hypoxia has shown benefit in reversing mitochondrial mediated neurodegenerative disease but is little studied in the setting of post-ischemic injury and is regarded as potentially harmful. In this study, we investigated the effects of mild hypoxia on global post-ischemic injury following CA. We hypothesized that brief mild hypoxia following CA would improve mitochondrial function resulting in improved cellular metabolism and physiological recovery. Methods and Results: Anesthetized C57BL6 mice underwent brief asystolic CA (12 min) followed bycardiopulmonary resuscitation(CPR). One hour following successful CPR, mice were randomized to receive a brief episode (6 hours) of normoxia (21% O2) or hypoxia (10% O2) in an environmental chamber. Post intervention, the mice were returned to room air (21% O2). Mild hypoxia improved cardiac mitochondrial complex 1 respiration in the heart by 28% and ATP-related oxygen consumption by 49% (n=3, P<0.05 vs normoxia, respectively) compared to normoxia treated mice. Hypoxia was further associated with improved glucose oxidation in heart as evidenced by decreases in pyruvate dehydrogenase kinase 4 (PDK4) gene and protein expression (n=4, P<0.05 vs normoxia, respectively) as well as decreases in pyruvate dehydrogenase phosphorylation (n=4, P<0.05, respectively) in heart. Hypoxia decreased lactate dehydrogenase (LDH) expression and lactate concentration in heart compared to normoxia treated controls (n=4, P<0.05 vs normoxia, respectively). ROS production in heart by 20% (n=6, P<0.05) was also decreased by mild hypoxia when compared to normoxia post CA. These changes were associated with improved recovery of myocardial function, neurological recovery, and 10-day survival following CA (n=13, P<0.05 vs normoxia, respectively). Conclusion: Brief mild hypoxia treatment following global ischemic injury paradoxically improved recovery of myocardial mitochondrial respiration and metabolism and was associated with improved physiological recovery and survival. Post-ischemia hypoxia is a potential therapeutic strategy for mitochondrial ischemic injury and requires further study. No financial disclosures. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
TL;DR: In tumor cells, 3-oxoacid-CoAtransferase (SCOT) and ACAT1 (ACAT1) are a major source of mitochondrial CoA as discussed by the authors .
Abstract: In tumor cells, ketolysis “via” succinyl-CoA: 3-oxoacid-CoAtransferase (SCOT) and acetyl-CoA acetyltransferase 1 (ACAT1) is a major source of mitochondrial acetyl-CoA. Active ACAT1 tetramers stabilize by tyrosine phosphorylation, which facilitates the SCOT reaction and ketolysis. Tyrosine phosphorylation of pyruvate kinase PK M2 has the opposite effect, stabilizing inactive dimers, while pyruvate dehydrogenase (PDH), which is already inhibited by phosphorylation, is acetylated by ACAT1 and is doubly locked. This closes the glycolytic supply of acetyl-CoA. In addition, since tumor cells must synthesize fatty acids to create new membranes, they automatically turn off the degradation of fatty acids into acetyl-CoA (“via” the malonyl-CoA brake for the fatty acid carnityl transporter). Thus, inhibiting SCOT the specific ketolytic enzyme and ACAT1 should hold back tumor progression. However, tumor cells are still able to take up external acetate and convert it into acetyl-CoA in their cytosol “via” an acetyl-CoA synthetase, which feeds the lipogenic pathway; additionally, inhibiting this enzyme would make it difficult for tumor cells to form new lipid membrane and survive.
TL;DR: In this paper , the authors show that the intracellular replication of Mycobacteroides massiliense in macrophages depends on host pyruvate dehydrogenase kinase (PDK) activity.
TL;DR: In this article , pyruvate dehydrogenase was proved to be a key regulator of the metabolic switch in postmenopausal osteoporosis and the efficacy of Icariin.
03 Apr 2023
TL;DR: Relative expression of HIF-1a and PPAR is discussed in this paper , where the relation expression of PPAR and HIF1a is discussed as well. But
Abstract: <p>Relative expression of HIF-1a and PPARa</p>
03 Apr 2023
TL;DR: In this article , a combination of dichloroacetate and radiotherapy was shown to improve the survival of glioblastoma-bearing mice with a single tumor cell type.
Abstract: <div>Abstract<p>Because radiotherapy significantly increases median survival in patients with glioblastoma, the modulation of radiation resistance is of significant interest. High glycolytic states of tumor cells are known to correlate strongly with radioresistance; thus, the concept of metabolic targeting needs to be investigated in combination with radiotherapy. Metabolically, the elevated glycolysis in glioblastoma cells was observed postradiotherapy together with upregulated hypoxia-inducible factor (HIF)-1α and its target pyruvate dehydrogenase kinase 1 (PDK1). Dichloroacetate, a PDK inhibitor currently being used to treat lactic acidosis, can modify tumor metabolism by activating mitochondrial activity to force glycolytic tumor cells into oxidative phosphorylation. Dichloroacetate alone demonstrated modest antitumor effects in both <i>in vitro</i> and <i>in vivo</i> models of glioblastoma and has the ability to reverse the radiotherapy-induced glycolytic shift when given in combination. <i>In vitro</i>, an enhanced inhibition of clonogenicity of a panel of glioblastoma cells was observed when dichloroacetate was combined with radiotherapy. Further mechanistic investigation revealed that dichloroacetate sensitized glioblastoma cells to radiotherapy by inducing the cell-cycle arrest at the G<sub>2</sub>–M phase, reducing mitochondrial reserve capacity, and increasing the oxidative stress as well as DNA damage in glioblastoma cells together with radiotherapy. <i>In vivo</i>, the combinatorial treatment of dichloroacetate and radiotherapy improved the survival of orthotopic glioblastoma-bearing mice. In conclusion, this study provides the proof of concept that dichloroacetate can effectively sensitize glioblastoma cells to radiotherapy by modulating the metabolic state of tumor cells. These findings warrant further evaluation of the combination of dichloroacetate and radiotherapy in clinical trials. <i>Mol Cancer Ther; 14(8); 1794–804. ©2015 AACR</i>.</p></div>
TL;DR: This article showed that expression of PDH inhibitory enzyme, pyruvate dehydrogenase kinase 4 (PDK4), is significantly upregulated in human senescent stromal cells.
Abstract: Abstract Cellular senescence is a permanent state of cell cycle arrest and occurs in proliferating cells subjected to various stresses. Although senescent cells remain metabolically active, little is known about their metabolic landscape and in vivo pathophysiological implications. Here we show that expression of the pyruvate dehydrogenase (PDH) inhibitory enzyme, pyruvate dehydrogenase kinase 4 (PDK4), is significantly upregulated in human senescent stromal cells. Preferentially expressed upon genotoxicity-induced senescence, PDK4 is negatively correlated with posttreatment survival of cancer patients. Upon cellular senescence, PDK4 shifts glucose metabolic flux from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, causing enhanced lactate production and forming an acidic microenvironment. However, distinct from the cancer cell-featured ‘Warburg effect’, senescent cells maintain an intensive use of pyruvate through the tricarboxylic acid cycle (TCA), displaying increased respiration and redox activity, indicative of a special form of metabolic reprogramming. Conditioned media from PDK4+ stromal cells change global expression and promote malignancy of recipient cancer cells in vitro and accelerate tumor progression in vivo. Nevertheless, specific targeting PDK4 curtails the adverse effects of senescent cells in cell-based assays, while promoting tumor regression and extending posttreatment survival in preclinical trials. Of note, increased levels of lactate in circulating blood after chemotherapy predicts lower survival in cancer clinics. PDK4 upregulation and ensuing lactate production are thus among key features of senescence, in addition to the established cell-autonomous and non-cell-autonomous hallmarks of senescent cells, providing a novel therapeutic target for future clinical oncology. Together, our study substantiates the hypercatabolic capacity of senescent cells, and reveals a metabolic link between senescence-associated acidic microenvironment and age-related pathologies, including but not limited to cancer. Citation Format: Xuefeng Dou, Judith Campisi, Yu Sun. Senescent cells develop PDK4-dependent hypercatabolism and form an acidic microenvironment to drive cancer resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB274.
TL;DR: This article showed that pyruvate dehydrogenase (PDH) is an essential metabolic switch and a bottleneck for the glycolytic production of acetyl-CoA, and showed that PDP1 is sensitive to reactive oxygen species-mediated inactivation, leading to the downregulation of H3 pan acetylation and NANOG levels.
Abstract: Precise control of pluripotency is a requirement for the safe and effective use of hPSCs in research and therapies. Here we report that pyruvate dehydrogenase upregulates histone H3 pan acetylation and levels of pluripotency marker NANOG in 5% O2. Pyruvate dehydrogenase (PDH) is an essential metabolic switch and a bottleneck for the glycolytic production of acetyl-CoA. Silencing of gene expression showed that PDH is regulated by the activity of its phosphatase PDP1. We show that PDP1 is sensitive to reactive oxygen species-mediated inactivation, leading to the downregulation of H3 pan acetylation and NANOG levels. Furthermore, we show that FGF2, a cytokine commonly used to maintain pluripotency activates pyruvate dehydrogenase through MEK1/2-ERK1/2 signaling pathway-mediated downregulation of ROS in 5% O2, thus promoting histone acetylation. Our results show the importance of pyruvate dehydrogenase in regulating energy metabolism and its connection to pluripotency. Furthermore, our data highlight the role of reactive oxygen species and redox homeostasis in pluripotency maintenance and differentiation. Highlights - PDP1-induced activation of PDH leads to increased histone H3 pan acetylation and NANOG levels in hPSCs - Reactive oxygen species (ROS) inactivate PDP1 and decrease histone H3 pan acetylation and NANOG levels in hPSCs - MEK1/2-ERK1/2 signaling-mediated downregulation of ROS in 5% O2 activates PDH in hPSCs Graphical abstract
TL;DR: In this article , the role of pyruvate dehydrogenase kinase 4 (PDK4) in the development of bladder cancer was investigated in a validated mouse model of BCa.
Abstract: Simple Summary Pyruvate dehydrogenase kinase 4 (PDK4) is a protein that serves as a switch for how the body regulates metabolism. Prior research indicates that blocking the effect of PDK4 with some drugs slows the growth of bladder cancer cells. These experiments relied on cancer cell lines and not tumors grown in mouse models of cancer, which are more closely related to human disease. In a validated mouse model of bladder cancer, mice that did not express PDK4 were found to have larger tumors than mice expressing PDK4 at later points of tumor progression. As tumors became larger, there was a loss of expression of PDK4 in mice that normally expressed it. Human samples with bladder cancer had lower expression of PDK4 than those without bladder cancer. These data indicate that PDK4 may be an unexpected tumor suppressor in bladder cancer. Abstract Pyruvate dehydrogenase kinase 4 (PDK4) is a mitochondrial isozyme in the PDK family (PDK1-4) partially responsible for phosphorylation of pyruvate dehydrogenase (PDH). Phosphorylation of PDH is thought to result in a pro-proliferative shift in metabolism that sustains growth of cancer cells. Previous data from our lab indicate the pan-PDK inhibitor dichloroacetate (DCA) or acute genetic knockdown of PDK4 blocks proliferation of bladder cancer (BCa) cells. The goal of this study was to determine the role of PDK4 in an in vivo BCa model, with the hypothesis that genetic depletion of PDK4 would impair formation of BCa. PDK4−/− or WT animals were exposed to N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN) for 16 weeks, and tumors were allowed to develop for up to 7 additional weeks. PDK4−/− mice had significantly larger tumors at later time points. When animals were treated with cisplatin, PDK4−/− animals still had larger tumors than WT mice. PDK4 expression was assessed in human tissue and in mice. WT mice lost expression of PDK4 as tumors became muscle-invasive. Similar results were observed in human samples, wherein tumors had less expression of PDK4 than benign tissue. In summary, PDK4 has a complex, multifunctional role in BCa and may represent an underrecognized tumor suppressor.
TL;DR: In this article, a bioluminescent resonance transfer (BRET) was used to detect conformational changes caused by pyruvate/inhibitor binding the MPC and lysine mutant MPC2 constructs were generated by site-directed mutagenesis.
Abstract: Background/Objective: The normal heart can acutely switch fuel sources based on delivery. While this is beneficial in physiological scenarios, this flexibility is often lost in cardiac pathologies. During fasting, blood glucose levels drop and increased free fatty acid delivery causes the heart to shut off glucose/pyruvate oxidation and increase fat oxidation. This balance, known as the Randle cycle, has mainly been attributed to regulation of pyruvate dehydrogenase (PDH) activity via PDH phosphorylation. Hypothesis: Decreased pyruvate transport into the mitochondria via posttranslational modifications of the mitochondrial pyruvate carrier (MPC) plays a role in regulating cardiac pyruvate oxidation. Methods: Wildtype mice were allowed to consume normal chow ad libitum or were fasted for 24 hours. After euthanasia, plasma and hearts were collected and left-ventricular muscle fibers were saponin permeabilized and mitochondrial respiration measured in an Oroboros Oxygraph O2k. Cardiac protein lysates were immunoprecipitated with anti-acetyl-lysine beads, and western blotted using standard procedures. A bioluminescent resonance transfer (BRET) assay to detect conformational changes caused by pyruvate/inhibitor binding the MPC was used, and lysine mutant MPC2 constructs were generated by site-directed mutagenesis. Lastly, MPC2-/- H9C2 cardiomyocytes were generated by CRISPR, and respiration measured by Seahorse bioanalyzer in these cells after transfection with WT or lysine mutant MPC2 constructs. Results: 24h fasting reduced blood glucose and insulin concentrations, and increased circulating free fatty acids. Cardiac mitochondrial oxidation of pyruvate/malate was decreased, while oxidation of fatty acids (palmitoyl-CoA+carnitine) was increased in fasted hearts. Western blotting of cardiac lysates showed the expected increase in phosphorylation of PDH-E1α in fasted hearts, known to decrease PDH activity. Immunoprecipitating cardiac lysates with anti-acetyl-lysine beads and blotting for MPC2 suggested increased acetylation of MPC2 in fasted hearts. Using a model structure of the MPC, we have recently proposed and validated lysine 49 (K49) of MPC2 as a critical pyruvate binding site within the MPC. To assess the possible importance of K49 acetylation we mutated K49 to glutamine to mimic acetylation and observed that this K49Q-MPC2 mutant was no longer able to bind pyruvate or competitive inhibitors in a MPC BRET assay. We next created MPC2 knockout H9C2 cardiomyocytes by CRISPR-Cas9 and observed complete loss of MPC2 and MPC1 expression in these cells which decreased pyruvate respiration compared to wildtype H9C2s. Overexpression of wildtype MPC1 and MPC2 constructs increased pyruvate respiration in these MPC-/- cells, while overexpression of the MPC2-K49Q mutant was unable to improve pyruvate respiration. Conclusion: Fasting results in decreased cardiac oxidation of pyruvate in part by acetylation of the MPC and decreased mitochondrial pyruvate transport. National Institutes of Health and SLU institutional funding. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
31 Mar 2023
TL;DR: In this article , a mechanistic explanation for why glycolysis is aberrantly activated in normoxic cancer cells, offering insights into this long-standing hallmark of cancer termed the Warburg effect.
Abstract: <div>Abstract<p>Downregulation of pyruvate dehydrogenase (PDH) is critical for the aberrant preferential activation of glycolysis in cancer cells under normoxic conditions. Phosphorylation-dependent inhibition of PDH is a relevant event in this process, but it is not durable as it relies on PDH kinases that are activated ordinarily under hypoxic conditions. Thus, it remains unclear how PDH is durably downregulated in cancer cells that are not hypoxic. Building on evidence that PDH activity depends on the stability of a multi-protein PDH complex, we found that the PDH-E1β subunit of the PDH complex is downregulated to inhibit PDH activity under conditions of prolonged hypoxia. After restoration of normoxic conditions, reduced expression of PDH-E1β was sustained such that glycolysis remained highly activated. Notably, PDH-E1β silencing in cancer cells produced a metabolic state strongly resembling the Warburg effect, but inhibited tumor growth. Conversely, enforced exogenous expression of PDH-E1β durably increased PDH activity and promoted the malignant growth of breast cancer cells <i>in vivo</i>. Taken together, our results establish the specific mechanism through which PDH acts as an oncogenic factor by tuning glycolytic metabolism in cancer cells.</p><p><b>Significance:</b> This seminal study offers a mechanistic explanation for why glycolysis is aberrantly activated in normoxic cancer cells, offering insights into this long-standing hallmark of cancer termed the Warburg effect. <i>Cancer Res; 78(7); 1592–603. ©2018 AACR</i>.</p></div>
TL;DR: In this paper , a small-molecule PDK inhibitor dichloroacetate (DCA) was used to restore arterial PDH activity and showed that the PDK/PDH axis is a major immunometabolic pathway, regulating immune cell polarization, plaque development and fibrous cap formation in Apoe−/− mice.
Abstract: Abstract Aims Recent studies have revealed a close connection between cellular metabolism and the chronic inflammatory process of atherosclerosis. While the link between systemic metabolism and atherosclerosis is well established, the implications of altered metabolism in the artery wall are less understood. Pyruvate dehydrogenase kinase (PDK)-dependent inhibition of pyruvate dehydrogenase (PDH) has been identified as a major metabolic step regulating inflammation. Whether the PDK/PDH axis plays a role in vascular inflammation and atherosclerotic cardiovascular disease remains unclear. Methods and results Gene profiling of human atherosclerotic plaques revealed a strong correlation between PDK1 and PDK4 transcript levels and the expression of pro-inflammatory and destabilizing genes. Remarkably, the PDK1 and PDK4 expression correlated with a more vulnerable plaque phenotype, and PDK1 expression was found to predict future major adverse cardiovascular events. Using the small-molecule PDK inhibitor dichloroacetate (DCA) that restores arterial PDH activity, we demonstrated that the PDK/PDH axis is a major immunometabolic pathway, regulating immune cell polarization, plaque development, and fibrous cap formation in Apoe−/− mice. Surprisingly, we discovered that DCA regulates succinate release and mitigates its GPR91-dependent signals promoting NLRP3 inflammasome activation and IL-1β secretion by macrophages in the plaque. Conclusions We have demonstrated for the first time that the PDK/PDH axis is associated with vascular inflammation in humans and particularly that the PDK1 isozyme is associated with more severe disease and could predict secondary cardiovascular events. Moreover, we demonstrate that targeting the PDK/PDH axis with DCA skews the immune system, inhibits vascular inflammation and atherogenesis, and promotes plaque stability features in Apoe−/− mice. These results point toward a promising treatment to combat atherosclerosis.
TL;DR: Dichloroacetate (DCA) is a naturally occurring xenobiotic that has been used as an investigational drug for over 50 years as mentioned in this paper , originally found to lower blood glucose levels and alter fat metabolism in diabetic rats, this small molecule was found to serve primarily as a pyruvate dehydrogenase kinase inhibitor.
Abstract: Dichloroacetate (DCA) is a naturally occurring xenobiotic that has been used as an investigational drug for over 50 years. Originally found to lower blood glucose levels and alter fat metabolism in diabetic rats, this small molecule was found to serve primarily as a pyruvate dehydrogenase kinase inhibitor. Pyruvate dehydrogenase kinase inhibits pyruvate dehydrogenase complex, the catalyst for oxidative decarboxylation of pyruvate to produce acetyl coenzyme A. Several congenital and acquired disease states share a similar pathobiology with respect to glucose homeostasis under distress that leads to a preferential shift from the more efficient oxidative phosphorylation to glycolysis. By reversing this process, DCA can increase available energy and reduce lactic acidosis. The purpose of this review is to examine the literature surrounding this metabolic messenger as it presents exciting opportunities for future investigation and clinical application in therapy including cancer, metabolic disorders, cerebral ischemia, trauma, and sepsis.
03 Apr 2023
TL;DR: Relative expression of HIF-1a and PPAR is discussed in this paper , where the relation expression of PPAR and HIF1a is discussed as well. But
Abstract: <p>Relative expression of HIF-1a and PPARa</p>
03 Apr 2023
TL;DR: Combination Index (CINI) as mentioned in this paper is a combination index that combines the combination index of the two measures of the CINI and the CILG, respectively.
Abstract: <p>Combination Index</p>
03 Apr 2023
TL;DR: Proliferation HTB-5 and HHTB-9 with cisplatin, DCA, or both as mentioned in this paper , and HTHB-10 with DCA or both.
Abstract: <p>Proliferation HTB-5 and HTB-9 with cisplatin, DCA or both</p>
03 Apr 2023
TL;DR: Xenograft tumor volume as mentioned in this paper was the largest tumor volume in the last decade in the United States, and was found to be cancer-specific only, i.e.,
Abstract: <p>Xenograft tumor volume</p>
31 Mar 2023
TL;DR: In this article , the authors investigated whether cancer cell metabolism defines its susceptibility to OV and if OV-induced metabolic perturbations can be therapeutically targeted, using mass spectrometry-based metabolomics and extracellular flux analysis on a panel of cancer cell lines.
Abstract: <div>Abstract<p>Oncolytic viruses (OV) such as reovirus preferentially infect and kill cancer cells. Thus, the mechanisms that dictate the susceptibility of cancer cells to OV-induced cytotoxicity hold the key to their success in clinics. Here, we investigated whether cancer cell metabolism defines its susceptibility to OV and if OV-induced metabolic perturbations can be therapeutically targeted. Using mass spectrometry–based metabolomics and extracellular flux analysis on a panel of cancer cell lines with varying degrees of susceptibility to reovirus, we found that OV-induced changes in central energy metabolism, pyruvate metabolism, and oxidative stress correlate with their susceptibility to reovirus. In particular, reovirus infection accentuated Warburg-like metabolic perturbations in cell lines relatively resistant to oncolysis. These metabolic changes were facilitated by oxidative stress–induced inhibitory phosphorylation of pyruvate dehydrogenase (PDH) that impaired the routing of pyruvate into the tricarboxylic acid cycle and established a metabolic state unsupportive of OV replication. From the therapeutic perspective, reactivation of PDH in cancer cells that were weakly sensitive for reovirus, either through PDH kinase (PDK) inhibitors dichloroacetate and AZD7545 or short hairpin RNA–specific depletion of PDK1, enhanced the efficacy of reovirus-induced oncolysis <i>in vitro</i> and <i>in vivo</i>. These findings identify targeted metabolic reprogramming as a possible combination strategy to enhance the antitumor effects of OV in clinics.</p>Significance:<p>This study proposes targeted metabolic reprogramming as a valid combinatorial strategy to enhance the translational efficacy of oncolytic virus–based cancer therapies.</p></div>
31 Mar 2023
TL;DR: In this article , a mechanistic explanation for why glycolysis is aberrantly activated in normoxic cancer cells, offering insights into this long-standing hallmark of cancer termed the Warburg effect.
Abstract: <div>Abstract<p>Downregulation of pyruvate dehydrogenase (PDH) is critical for the aberrant preferential activation of glycolysis in cancer cells under normoxic conditions. Phosphorylation-dependent inhibition of PDH is a relevant event in this process, but it is not durable as it relies on PDH kinases that are activated ordinarily under hypoxic conditions. Thus, it remains unclear how PDH is durably downregulated in cancer cells that are not hypoxic. Building on evidence that PDH activity depends on the stability of a multi-protein PDH complex, we found that the PDH-E1β subunit of the PDH complex is downregulated to inhibit PDH activity under conditions of prolonged hypoxia. After restoration of normoxic conditions, reduced expression of PDH-E1β was sustained such that glycolysis remained highly activated. Notably, PDH-E1β silencing in cancer cells produced a metabolic state strongly resembling the Warburg effect, but inhibited tumor growth. Conversely, enforced exogenous expression of PDH-E1β durably increased PDH activity and promoted the malignant growth of breast cancer cells <i>in vivo</i>. Taken together, our results establish the specific mechanism through which PDH acts as an oncogenic factor by tuning glycolytic metabolism in cancer cells.</p><p><b>Significance:</b> This seminal study offers a mechanistic explanation for why glycolysis is aberrantly activated in normoxic cancer cells, offering insights into this long-standing hallmark of cancer termed the Warburg effect. <i>Cancer Res; 78(7); 1592–603. ©2018 AACR</i>.</p></div>
03 Apr 2023
TL;DR: In this article , upregulation of the pyruvate dehydrogenase kinase (PDK1-PDK4) is associated with aerobic glycolysis and chemoresistance through inhibition of PDH, and inhibition of the PDK4 with dichloroacetate (DCA) resulted in increased PDH activity, reduced cell growth, and phase arrest.
Abstract: <div>Abstract<p>Advanced bladder cancer remains a major source of mortality, with poor treatment options. Cisplatin-based chemotherapy is the standard treatment, however many patients are or become resistant. One potential cause of chemoresistance is the Warburg effect, a metabolic switch to aerobic glycolysis that occurs in many cancers. Upregulation of the pyruvate dehydrogenase kinase family (PDK1–PDK4) is associated with aerobic glycolysis and chemoresistance through inhibition of the pyruvate dehydrogenase complex (PDH). We have previously observed upregulation of PDK4 in high-grade compared with low-grade bladder cancers. We initiated this study to determine if inhibition of PDK4 could reduce tumor growth rates or sensitize bladder cancer cells to cisplatin. Upregulation of PDK4 in malignant bladder cancer cell lines as compared with benign transformed urothelial cells was confirmed using qPCR. Inhibition of PDK4 with dichloroacetate (DCA) resulted in increased PDH activity, reduced cell growth, and G<sub>0</sub>–G<sub>1</sub> phase arrest in bladder cancer cells. Similarly, siRNA knockdown of PDK4 inhibited bladder cancer cell proliferation. Cotreatment of bladder cancer cells with cisplatin and DCA did not increase caspase-3 activity but did enhance overall cell death <i>in vitro</i>. Although daily treatment with 200 mg/kg DCA alone did not reduce tumor volumes in a xenograft model, combination treatment with cisplatin resulted in dramatically reduced tumor volumes as compared with either DCA or cisplatin alone. This was attributed to substantial intratumoral necrosis. These findings indicate inhibition of PDK4 may potentiate cisplatin-induced cell death and warrant further studies investigating the mechanism through which this occurs. <i>Mol Cancer Ther; 17(9); 2004–12. ©2018 AACR</i>.</p></div>
TL;DR: In this article , the role of pyruvate dehydrogenase kinases (PDKs) in sarcopenia was discussed and shown to be associated with perturbation of mitochondria-associated membranes and mitochondrial quality control.
Abstract: Sarcopenia, defined as a progressive loss of muscle mass and function, is typified by mitochondrial dysfunction and loss of mitochondrial resilience. Sarcopenia is associated not only with aging, but also with various metabolic diseases characterized by mitochondrial dyshomeostasis. Pyruvate dehydrogenase kinases (PDKs) are mitochondrial enzymes that inhibit the pyruvate dehydrogenase complex, which controls pyruvate entry into the tricarboxylic acid cycle and the subsequent adenosine triphosphate production required for normal cellular activities. PDK4 is upregulated in mitochondrial dysfunction-related metabolic diseases, especially pathologic muscle conditions associated with enhanced muscle proteolysis and aberrant myogenesis. Increases in PDK4 are associated with perturbation of mitochondria-associated membranes and mitochondrial quality control, which are emerging as a central mechanism in the pathogenesis of metabolic disease-associated muscle atrophy. Here, we review how mitochondrial dysfunction affects sarcopenia, focusing on the role of PDK4 in mitochondrial homeostasis. We discuss the molecular mechanisms underlying the effects of PDK4 on mitochondrial dysfunction in sarcopenia and show that targeting mitochondria could be a therapeutic target for treating sarcopenia.
03 Apr 2023
TL;DR: Proliferation HTB-5 and HHTB-9 with cisplatin, DCA, or both as mentioned in this paper , and HTHB-10 with DCA or both.
Abstract: <p>Proliferation HTB-5 and HTB-9 with cisplatin, DCA or both</p>
TL;DR: The mitochondrial pyruvate carrier (MPC) as discussed by the authors is composed of SLC54 family members, which form functional hetero-dimers, and is expressed in the inner mitochondrial membrane.
Abstract: Pyruvate is oxidized to acetyl‐CoA by pyruvate dehydrogenase which is localized in the mitochondrial matrix. The mitochondrial pyruvate carrier (MPC) is composed of SLC54 family members (MPC1 and MPC2) [1, 5], which form functional hetero-dimers [9, 8]. The MPC is expressed in the inner mitochondrial membrane and involved in the import of pyruvate into mitochondria [1, 5]. Ubiquitous disruption of either MPC1 or MPC2 expression results in embryonic lethality [11, 12]. Clinically relevant concentrations of the insulin sensitizers, thiazolidinediones, inhibit the MPC [3]. Other clinically relevant inhibitors of the MPC complex are lonidamine [7, 8], quinolone antibacterials [6], entacapone and nitrofurantoin [8].