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1.
Sci Rep ; 14(1): 13852, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38879681

RESUMO

Neurological and cardiac injuries are significant contributors to morbidity and mortality following pediatric in-hospital cardiac arrest (IHCA). Preservation of mitochondrial function may be critical for reducing these injuries. Dimethyl fumarate (DMF) has shown potential to enhance mitochondrial content and reduce oxidative damage. To investigate the efficacy of DMF in mitigating mitochondrial injury in a pediatric porcine model of IHCA, toddler-aged piglets were subjected to asphyxia-induced CA, followed by ventricular fibrillation, high-quality cardiopulmonary resuscitation, and random assignment to receive either DMF (30 mg/kg) or placebo for four days. Sham animals underwent similar anesthesia protocols without CA. After four days, tissues were analyzed for mitochondrial markers. In the brain, untreated CA animals exhibited a reduced expression of proteins of the oxidative phosphorylation system (CI, CIV, CV) and decreased mitochondrial respiration (p < 0.001). Despite alterations in mitochondrial content and morphology in the myocardium, as assessed per transmission electron microscopy, mitochondrial function was unchanged. DMF treatment counteracted 25% of the proteomic changes induced by CA in the brain, and preserved mitochondrial structure in the myocardium. DMF demonstrates a potential therapeutic benefit in preserving mitochondrial integrity following asphyxia-induced IHCA. Further investigation is warranted to fully elucidate DMF's protective mechanisms and optimize its therapeutic application in post-arrest care.


Assuntos
Asfixia , Fumarato de Dimetilo , Modelos Animais de Doenças , Parada Cardíaca , Mitocôndrias , Animais , Parada Cardíaca/metabolismo , Parada Cardíaca/tratamento farmacológico , Asfixia/metabolismo , Asfixia/tratamento farmacológico , Asfixia/complicações , Suínos , Fumarato de Dimetilo/farmacologia , Fumarato de Dimetilo/uso terapêutico , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Humanos , Miocárdio/metabolismo , Miocárdio/patologia , Fosforilação Oxidativa/efeitos dos fármacos
2.
Sci Transl Med ; 16(751): eadi5336, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38865484

RESUMO

In chronic myeloid leukemia (CML), the persistence of leukemic stem cells (LSCs) after treatment with tyrosine kinase inhibitors (TKIs), such as imatinib, can lead to disease relapse. It is known that therapy-resistant LSCs rely on oxidative phosphorylation (OXPHOS) for their survival and that targeting mitochondrial respiration sensitizes CML LSCs to imatinib treatment. However, current OXPHOS inhibitors have demonstrated limited efficacy or have shown adverse effects in clinical trials, highlighting that identification of clinically safe oxidative pathway inhibitors is warranted. We performed a high-throughput drug repurposing screen designed to identify mitochondrial metabolism inhibitors in myeloid leukemia cells. This identified lomerizine, a US Food and Drug Administration (FDA)-approved voltage-gated Ca2+ channel blocker now used for the treatment of migraines, as one of the top hits. Transcriptome analysis revealed increased expression of voltage-gated CACNA1D and receptor-activated TRPC6 Ca2+ channels in CML LSCs (CD34+CD38-) compared with normal counterparts. This correlated with increased endoplasmic reticulum (ER) mass and increased ER and mitochondrial Ca2+ content in CML stem/progenitor cells. We demonstrate that lomerizine-mediated inhibition of Ca2+ uptake leads to ER and mitochondrial Ca2+ depletion, with similar effects seen after CACNA1D and TRPC6 knockdown. Through stable isotope-assisted metabolomics and functional assays, we observe that lomerizine treatment inhibits mitochondrial isocitrate dehydrogenase activity and mitochondrial oxidative metabolism and selectively sensitizes CML LSCs to imatinib treatment. In addition, combination treatment with imatinib and lomerizine reduced CML tumor burden, targeted CML LSCs, and extended survival in xenotransplantation model of human CML, suggesting this as a potential therapeutic strategy to prevent disease relapse in patients.


Assuntos
Reposicionamento de Medicamentos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Mitocôndrias , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Animais , Linhagem Celular Tumoral , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Cálcio/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico
3.
J Transl Med ; 22(1): 535, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38840216

RESUMO

BACKGROUND: Inflammation and endothelial barrier dysfunction are the major pathophysiological changes in acute respiratory distress syndrome (ARDS). Sphingosine-1-phosphate receptor 3 (S1PR3), a G protein-coupled receptor, has been found to mediate inflammation and endothelial cell (EC) integrity. However, the function of S1PR3 in ARDS has not been fully elucidated. METHODS: We used a murine lipopolysaccharide (LPS)-induced ARDS model and an LPS- stimulated ECs model to investigate the role of S1PR3 in anti-inflammatory effects and endothelial barrier protection during ARDS. RESULTS: We found that S1PR3 expression was increased in the lung tissues of mice with LPS-induced ARDS. TY-52156, a selective S1PR3 inhibitor, effectively attenuated LPS-induced inflammation by suppressing the expression of proinflammatory cytokines and restored the endothelial barrier by repairing adherens junctions and reducing vascular leakage. S1PR3 inhibition was achieved by an adeno-associated virus in vivo and a small interfering RNA in vitro. Both the in vivo and in vitro studies demonstrated that pharmacological or genetic inhibition of S1PR3 protected against ARDS by inhibiting the NF-κB pathway and improving mitochondrial oxidative phosphorylation. CONCLUSIONS: S1PR3 inhibition protects against LPS-induced ARDS via suppression of pulmonary inflammation and promotion of the endothelial barrier by inhibiting NF-κB and improving mitochondrial oxidative phosphorylation, indicating that S1PR3 is a potential therapeutic target for ARDS.


Assuntos
Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Mitocôndrias , NF-kappa B , Fosforilação Oxidativa , Síndrome do Desconforto Respiratório , Receptores de Esfingosina-1-Fosfato , Animais , Humanos , Masculino , Camundongos , Citocinas/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Inflamação/patologia , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , NF-kappa B/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Receptores de Lisoesfingolipídeo/metabolismo , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/patologia , Receptores de Esfingosina-1-Fosfato/metabolismo , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores
4.
Cell Physiol Biochem ; 58(3): 226-249, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38857359

RESUMO

BACKGROUND/AIMS: Important benefits of intermittent hypoxic training (IHT) have emerged as an effective tool for enhancing adaptive potential in different pathological states, among which acute hypoxia dominates. Therefore, the aim of our study was to evaluate the mechanisms related to the effects of the nitric oxide system (nitrites, nitrates, carbamide, and total polyamine content) on ADP-stimulated oxygen consumption and oxidative phosphorylation in heart and liver mitochondria and biomarkers of oxidative stress in the blood, heart, and liver of rats exposed to the IHT method and acute hypoxia and treated with the amino acid L-arginine (600 mg/kg, 30 min) or the NO synthase inhibitor L-NNA (35 mg/kg, 30 min) prior to each IHT session. METHODS: We analysed the modulation of the system of oxygen-dependent processes (mitochondrial respiration with the oxygraphic method, microsomal oxidation, and lipoperoxidation processes using biochemical methods) in tissues during IHT in the formation of short-term and long-term effects (30, 60, and 180 days after the last IHT session) with simultaneous administration of L-arginine. In particular, we investigated how mitochondrial functions are modulated during intermittent hypoxia with the use of oxidation substrates (succinate or α-ketoglutarate) in bioenergetic mechanisms of cellular stability and adaptation. RESULTS: The IHT method is associated with a significant increase in the production of endogenous nitric oxide measured by the levels of its stable metabolite, nitrite anion, in both plasma (almost 7-fold) and erythrocytes (more than 7-fold) of rats. The intensification of nitric oxide-dependent pathways of metabolic transformations in the energy supply processes in the heart and liver, accompanied by oscillatory mechanisms of adaptation in the interval mode, causes a probable decrease in the production of urea and polyamines in plasma and liver, but not in erythrocytes. The administration of L-arginine prior to the IHT sessions increased the level of the nitrite-reducing component of the nitric oxide cycle, which persisted for up to 180 days of the experiment. CONCLUSION: Thus, the efficacy of IHT and its nitrite-dependent component shown in this study is associated with the formation of long-term adaptive responses by preventing the intensification of lipoperoxidation processes in tissues due to pronounced changes in the main enzymes of antioxidant defence and stabilisation of erythrocyte membranes, which has a pronounced protective effect on the system of regulation of oxygen-dependent processes as a whole.


Assuntos
Arginina , Hipóxia , Consumo de Oxigênio , Ratos Wistar , Animais , Masculino , Hipóxia/metabolismo , Ratos , Arginina/farmacologia , Arginina/análogos & derivados , Arginina/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Óxido Nítrico/metabolismo , Oxigênio/metabolismo , Adaptação Fisiológica , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Nitritos/metabolismo
5.
Free Radic Biol Med ; 220: 312-323, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38740101

RESUMO

Podocytes are crucial for regulating glomerular permeability. They have foot processes that are integral to the renal filtration barrier. Understanding their energy metabolism could shed light on the pathogenesis of filtration barrier injury. Lactate has been increasingly recognized as more than a waste product and has emerged as a significant metabolic fuel and reserve. The recent identification of lactate transporters in podocytes, the expression of which is modulated by glucose levels and lactate, highlights lactate's relevance. The present study investigated the impact of lactate on podocyte respiratory efficiency and mitochondrial dynamics. We confirmed lactate oxidation in podocytes, suggesting its role in cellular energy production. Under conditions of glucose deprivation or lactate supplementation, a significant shift was seen toward oxidative phosphorylation, reflected by an increase in the oxygen consumption rate/extracellular acidification rate ratio. Notably, lactate dehydrogenase A (LDHA) and lactate dehydrogenase B (LDHB) isoforms, which are involved in lactate conversion to pyruvate, were detected in podocytes for the first time. The presence of lactate led to higher intracellular pyruvate levels, greater LDH activity, and higher LDHB expression. Furthermore, lactate exposure increased mitochondrial DNA-to-nuclear DNA ratios and resulted in upregulation of the mitochondrial biogenesis markers peroxisome proliferator-activated receptor coactivator-1α and transcription factor A mitochondrial, regardless of glucose availability. Changes in mitochondrial size and shape were observed in lactate-exposed podocytes. These findings suggest that lactate is a pivotal energy source for podocytes, especially during energy fluctuations. Understanding lactate's role in podocyte metabolism could offer insights into renal function and pathologies that involve podocyte injury.


Assuntos
L-Lactato Desidrogenase , Ácido Láctico , Dinâmica Mitocondrial , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Podócitos , Podócitos/metabolismo , Podócitos/patologia , Animais , Ratos , Ácido Láctico/metabolismo , L-Lactato Desidrogenase/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Glucose/metabolismo , Metabolismo Energético , Lactato Desidrogenase 5/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , DNA Mitocondrial/metabolismo , DNA Mitocondrial/genética , Consumo de Oxigênio , Células Cultivadas , Ácido Pirúvico/metabolismo , Isoenzimas
6.
J Ethnopharmacol ; 331: 118344, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-38754641

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Dermatophytes are notorious pathogens capable of infecting various mammals skin, posing serious threats to human health and overall life quality worldwide. Artemisia argyi has been recorded and applied for over a thousand years to treat skin itching. Although it has the potential to be developed as a plant-based antifungal agent, it's antifungal activity and action mechanism of active ingredients are still unclear. AIM OF THE STUDY: The aim of this study was to investigate the chemical composition, antifungal activity against skin fungi, and potential mechanisms of Artemisia argyi essential oil (AEO). MATERIALS AND METHODS: The chemical composition of AEO was analyzed by gas chromatography-mass spectrometry (GC-MS) firstly. Flat growth restraint and double half dilution tests was performed to evaluate AEO antifungal activity against Microsporum gypseum, Trichophyton mentagrophytes, and Trichophyton rubrum. And then, the physiological mechanism of AEO inhibiting dermatophytes was systematically explored through scanning electron microscopy, relative conductivity, membrane leakage, ROS content, and antioxidant enzyme activity. Finally, the main pathways were screened through transcriptome sequencing, while the related genes expression levels and enzyme activity were validated. RESULTS: Monoterpenes and sesquiterpenoids were the most highly representative class of AEO. AEO had powerful antifungal activity against M. gypseum, T. mentagrophytes, and T. rubrum, with minimum inhibitory concentration (MIC) values of 0.6, 1.2, and 1.2 µL/mL, respectively. Moreover, AEO can also damage the cell membrane integrity of T. mentagrophytes, resulting in cellular extravasation of intracellular substances. Transcriptome analysis revealed that the main target of AEO is to inhibit electron transfer and oxidative phosphorylation during respiration, ultimately leading to obstruction of normal ATP synthesis and energy metabolism in mitochondria. And a large amount of ROS will generate due to the incompletely catalysis of oxygen under mitochondrial complexes. Coupled with the decrease of antioxidant enzyme (SOD, POD) activity, excessive accumulation of ROS will cause serious oxidative damage to cells and eventually exhibiting antifungal activity against dermatophytes. CONCLUSIONS: The present study demonstrated that Artemisia argyi was a valuable source of active compounds with antifungal activity. These findings support AEO as a potential agent to inhibit dermatophytes and prevent related dermatophytoses.


Assuntos
Antifúngicos , Artemisia , Arthrodermataceae , Óleos Voláteis , Fosforilação Oxidativa , Estresse Oxidativo , Artemisia/química , Antifúngicos/farmacologia , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Arthrodermataceae/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Cromatografia Gasosa-Espectrometria de Massas
7.
Cell Rep Med ; 5(5): 101519, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38692271

RESUMO

Osteosarcoma (OS) is the most common malignant bone tumor with a poor prognosis. Here, we show that the nuclear receptor RORγ may serve as a potential therapeutic target in OS. OS exhibits a hyperactivated oxidative phosphorylation (OXPHOS) program, which fuels the carbon source to promote tumor progression. We found that RORγ is overexpressed in OS tumors and is linked to hyperactivated OXPHOS. RORγ induces the expression of PGC-1ß and physically interacts with it to activate the OXPHOS program by upregulating the expression of respiratory chain component genes. Inhibition of RORγ strongly inhibits OXPHOS activation, downregulates mitochondrial functions, and increases ROS production, which results in OS cell apoptosis and ferroptosis. RORγ inverse agonists strongly suppressed OS tumor growth and progression and sensitized OS tumors to chemotherapy. Taken together, our results indicate that RORγ is a critical regulator of the OXPHOS program in OS and provides an effective therapeutic strategy for this deadly disease.


Assuntos
Neoplasias Ósseas , Mitocôndrias , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Osteossarcoma , Fosforilação Oxidativa , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Osteossarcoma/genética , Humanos , Fosforilação Oxidativa/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Linhagem Celular Tumoral , Animais , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/tratamento farmacológico , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Ferroptose/genética , Ferroptose/efeitos dos fármacos , Camundongos Nus , Masculino , Proliferação de Células , Proteínas de Ligação a RNA
8.
Chem Biol Interact ; 396: 111042, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38735455

RESUMO

Ionic liquids (ILs) are a class of low melting point salts with physicochemical properties suitable for a range of industrial applications such as chemical processing and battery design. Major challenges to the wide-scale adoption of ILs in industry include their eco- and cytotoxic effects, however, this opens up the possibility of the use of ILs use as novel anticancer agents. Understanding the structural features that promote IL cytotoxicity is therefore important. Key structural features that can impact IL cytotoxicity include size and lipophilicity of the cationic head group. In this study, the cytotoxic effects of acridinium-based ILs containing relatively large tri- and tetracyclic cations were evaluated. It was found that 9-phenylacridinium-based ILs are potent cytotoxic agents that reduce the viability of human MDA-MB-231 breast cancer cells with IC50 concentrations in the nanomolar range. In mechanistic studies, it was found that unlike the pyridinium-based analogue, [C16Py][I], acridinium-based ILs did not inhibit oxidative phosphorylation or induce reactive oxygen species formation, and may instead target other mitochondrial processes or components such as mitochondrial DNA.


Assuntos
Acridinas , Líquidos Iônicos , Espécies Reativas de Oxigênio , Humanos , Líquidos Iônicos/química , Líquidos Iônicos/farmacologia , Acridinas/química , Acridinas/farmacologia , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Fosforilação Oxidativa/efeitos dos fármacos
9.
Redox Biol ; 73: 103191, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38762951

RESUMO

Activation of inflammation is tightly associated with metabolic reprogramming in macrophages. The iron-containing tetrapyrrole heme can induce pro-oxidant and pro-inflammatory effects in murine macrophages, but has been associated with polarization towards an anti-inflammatory phenotype in human macrophages. In the current study, we compared the regulatory responses to heme and the prototypical Toll-like receptor (TLR)4 ligand lipopolysaccharide (LPS) in human and mouse macrophages with a particular focus on alterations of cellular bioenergetics. In human macrophages, bulk RNA-sequencing analysis indicated that heme led to an anti-inflammatory transcriptional profile, whereas LPS induced a classical pro-inflammatory gene response. Co-stimulation of heme with LPS caused opposing regulatory patterns of inflammatory activation and cellular bioenergetics in human and mouse macrophages. Specifically, in LPS-stimulated murine, but not human macrophages, heme led to a marked suppression of oxidative phosphorylation and an up-regulation of glycolysis. The species-specific alterations in cellular bioenergetics and inflammatory responses to heme were critically dependent on the availability of nitric oxide (NO) that is generated in inflammatory mouse, but not human macrophages. Accordingly, studies with an inducible nitric oxide synthase (iNOS) inhibitor in mouse, and a pharmacological NO donor in human macrophages, reveal that NO is responsible for the opposing effects of heme in these cells. Taken together, the current findings indicate that NO is critical for the immunomodulatory role of heme in macrophages.


Assuntos
Heme , Inflamação , Lipopolissacarídeos , Macrófagos , Óxido Nítrico , Humanos , Heme/metabolismo , Animais , Óxido Nítrico/metabolismo , Camundongos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Inflamação/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Fosforilação Oxidativa/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Glicólise/efeitos dos fármacos
10.
Cell Death Dis ; 15(5): 311, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38697987

RESUMO

Cancer cells are highly dependent on bioenergetic processes to support their growth and survival. Disruption of metabolic pathways, particularly by targeting the mitochondrial electron transport chain complexes (ETC-I to V) has become an attractive therapeutic strategy. As a result, the search for clinically effective new respiratory chain inhibitors with minimized adverse effects is a major goal. Here, we characterize a new OXPHOS inhibitor compound called MS-L6, which behaves as an inhibitor of ETC-I, combining inhibition of NADH oxidation and uncoupling effect. MS-L6 is effective on both intact and sub-mitochondrial particles, indicating that its efficacy does not depend on its accumulation within the mitochondria. MS-L6 reduces ATP synthesis and induces a metabolic shift with increased glucose consumption and lactate production in cancer cell lines. MS-L6 either dose-dependently inhibits cell proliferation or induces cell death in a variety of cancer cell lines, including B-cell and T-cell lymphomas as well as pediatric sarcoma. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI-1) partially restores the viability of B-lymphoma cells treated with MS-L6, demonstrating that the inhibition of NADH oxidation is functionally linked to its cytotoxic effect. Furthermore, MS-L6 administration induces robust inhibition of lymphoma tumor growth in two murine xenograft models without toxicity. Thus, our data present MS-L6 as an inhibitor of OXPHOS, with a dual mechanism of action on the respiratory chain and with potent antitumor properties in preclinical models, positioning it as the pioneering member of a promising drug class to be evaluated for cancer therapy. MS-L6 exerts dual mitochondrial effects: ETC-I inhibition and uncoupling of OXPHOS. In cancer cells, MS-L6 inhibited ETC-I at least 5 times more than in isolated rat hepatocytes. These mitochondrial effects lead to energy collapse in cancer cells, resulting in proliferation arrest and cell death. In contrast, hepatocytes which completely and rapidly inactivated this molecule, restored their energy status and survived exposure to MS-L6 without apparent toxicity.


Assuntos
Antineoplásicos , Proliferação de Células , Complexo I de Transporte de Elétrons , Mitocôndrias , Proteínas de Saccharomyces cerevisiae , Animais , Humanos , Complexo I de Transporte de Elétrons/metabolismo , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Antineoplásicos/farmacologia , Camundongos , Linhagem Celular Tumoral , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desacopladores/farmacologia , Fosforilação Oxidativa/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Ratos , NADH Desidrogenase/metabolismo , NADH Desidrogenase/antagonistas & inibidores
11.
Signal Transduct Target Ther ; 9(1): 125, 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38734691

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a 'highly transmissible respiratory pathogen, leading to severe multi-organ damage. However, knowledge regarding SARS-CoV-2-induced cellular alterations is limited. In this study, we report that SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics and activates the EGFR-mediated cell survival signal cascade during the early stage of viral infection. SARS-CoV-2 causes an increase in mitochondrial transmembrane potential via the SARS-CoV-2 RNA-nucleocapsid cluster, thereby abnormally promoting mitochondrial elongation and the OXPHOS process, followed by enhancing ATP production. Furthermore, SARS-CoV-2 activates the EGFR signal cascade and subsequently induces mitochondrial EGFR trafficking, contributing to abnormal OXPHOS process and viral propagation. Approved EGFR inhibitors remarkably reduce SARS-CoV-2 propagation, among which vandetanib exhibits the highest antiviral efficacy. Treatment of SARS-CoV-2-infected cells with vandetanib decreases SARS-CoV-2-induced EGFR trafficking to the mitochondria and restores SARS-CoV-2-induced aberrant elevation in OXPHOS process and ATP generation, thereby resulting in the reduction of SARS-CoV-2 propagation. Furthermore, oral administration of vandetanib to SARS-CoV-2-infected hACE2 transgenic mice reduces SARS-CoV-2 propagation in lung tissue and mitigates SARS-CoV-2-induced lung inflammation. Vandetanib also exhibits potent antiviral activity against various SARS-CoV-2 variants of concern, including alpha, beta, delta and omicron, in in vitro cell culture experiments. Taken together, our findings provide novel insight into SARS-CoV-2-induced alterations in mitochondrial dynamics and EGFR trafficking during the early stage of viral infection and their roles in robust SARS-CoV-2 propagation, suggesting that EGFR is an attractive host target for combating COVID-19.


Assuntos
COVID-19 , Receptores ErbB , Mitocôndrias , SARS-CoV-2 , Replicação Viral , SARS-CoV-2/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/genética , Mitocôndrias/efeitos dos fármacos , Humanos , Animais , Camundongos , COVID-19/virologia , COVID-19/metabolismo , COVID-19/genética , Receptores ErbB/metabolismo , Receptores ErbB/genética , Replicação Viral/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Células Vero , Chlorocebus aethiops , Antivirais/farmacologia , Tratamento Farmacológico da COVID-19 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
12.
J Transl Med ; 22(1): 437, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38720345

RESUMO

BACKGROUND: Biological-derived hydroxyapatite is widely used as a bone substitute for addressing bone defects, but its limited osteoconductive properties necessitate further improvement. The osteo-immunomodulatory properties hold crucial promise in maintaining bone homeostasis, and precise modulation of macrophage polarization is essential in this process. Metabolism serves as a guiding force for immunity, and fluoride modification represents a promising strategy for modulating the osteoimmunological environment by regulating immunometabolism. In this context, we synthesized fluorinated porcine hydroxyapatite (FPHA), and has demonstrated its enhanced biological properties and osteogenic capacity. However, it remains unknown whether and how FPHA affects the immune microenvironment of the bone defects. METHODS: FPHA was synthesized and its composition and structural properties were confirmed. Macrophages were cultured with FPHA extract to investigate the effects of FPHA on their polarization and the related osteo-immune microenvironment. Furthermore, total RNA of these macrophages was extracted, and RNA-seq analysis was performed to explore the underlying mechanisms associated with the observed changes in macrophages. The metabolic states were evaluated with a Seahorse analyzer. Additionally, immunohistochemical staining was performed to evaluate the macrophages response after implantation of the novel bone substitutes in critical size calvarial defects in SD rats. RESULTS: The incorporation of fluoride ions in FPHA was validated. FPHA promoted macrophage proliferation and enhanced the expression of M2 markers while suppressing the expression of M1 markers. Additionally, FPHA inhibited the expression of inflammatory factors and upregulated the expression of osteogenic factors, thereby enhancing the osteogenic differentiation capacity of the rBMSCs. RNA-seq analysis suggested that the polarization-regulating function of FPHA may be related to changes in cellular metabolism. Further experiments confirmed that FPHA enhanced mitochondrial function and promoted the metabolic shift of macrophages from glycolysis to oxidative phosphorylation. Moreover, in vivo experiments validated the above results in the calvarial defect model in SD rats. CONCLUSION: In summary, our study reveals that FPHA induces a metabolic shift in macrophages from glycolysis to oxidative phosphorylation. This shift leads to an increased tendency toward M2 polarization in macrophages, consequently creating a favorable osteo-immune microenvironment. These findings provide valuable insights into the impact of incorporating an appropriate concentration of fluoride on immunometabolism and macrophage mitochondrial function, which have important implications for the development of fluoride-modified immunometabolism-based bone regenerative biomaterials and the clinical application of FPHA or other fluoride-containing materials.


Assuntos
Durapatita , Glicólise , Macrófagos , Fosforilação Oxidativa , Ratos Sprague-Dawley , Animais , Durapatita/química , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Ratos , Suínos , Proliferação de Células/efeitos dos fármacos , Masculino , Osteogênese/efeitos dos fármacos , Crânio/patologia , Crânio/efeitos dos fármacos , Camundongos , Microambiente Celular/efeitos dos fármacos , Células RAW 264.7 , Osso e Ossos/metabolismo , Osso e Ossos/efeitos dos fármacos
13.
J Transl Med ; 22(1): 431, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38715059

RESUMO

BACKGROUND: In humans, two ubiquitously expressed N-myristoyltransferases, NMT1 and NMT2, catalyze myristate transfer to proteins to facilitate membrane targeting and signaling. We investigated the expression of NMTs in numerous cancers and found that NMT2 levels are dysregulated by epigenetic suppression, particularly so in hematologic malignancies. This suggests that pharmacological inhibition of the remaining NMT1 could allow for the selective killing of these cells, sparing normal cells with both NMTs. METHODS AND RESULTS: Transcriptomic analysis of 1200 NMT inhibitor (NMTI)-treated cancer cell lines revealed that NMTI sensitivity relates not only to NMT2 loss or NMT1 dependency, but also correlates with a myristoylation inhibition sensitivity signature comprising 54 genes (MISS-54) enriched in hematologic cancers as well as testis, brain, lung, ovary, and colon cancers. Because non-myristoylated proteins are degraded by a glycine-specific N-degron, differential proteomics revealed the major impact of abrogating NMT1 genetically using CRISPR/Cas9 in cancer cells was surprisingly to reduce mitochondrial respiratory complex I proteins rather than cell signaling proteins, some of which were also reduced, albeit to a lesser extent. Cancer cell treatments with the first-in-class NMTI PCLX-001 (zelenirstat), which is undergoing human phase 1/2a trials in advanced lymphoma and solid tumors, recapitulated these effects. The most downregulated myristoylated mitochondrial protein was NDUFAF4, a complex I assembly factor. Knockout of NDUFAF4 or in vitro cell treatment with zelenirstat resulted in loss of complex I, oxidative phosphorylation and respiration, which impacted metabolomes. CONCLUSIONS: Targeting of both, oxidative phosphorylation and cell signaling partly explains the lethal effects of zelenirstat in select cancer types. While the prognostic value of the sensitivity score MISS-54 remains to be validated in patients, our findings continue to warrant the clinical development of zelenirstat as cancer treatment.


Assuntos
Aciltransferases , Neoplasias , Fosforilação Oxidativa , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/genética , Linhagem Celular Tumoral , Fosforilação Oxidativa/efeitos dos fármacos , Aciltransferases/metabolismo , Ácido Mirístico/metabolismo , Proteômica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Multiômica
14.
Nat Commun ; 15(1): 4195, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38760351

RESUMO

Osimertinib (Osi) is a widely used epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). However, the emergence of resistance is inevitable, partly due to the gradual evolution of adaptive resistant cells during initial treatment. Here, we find that Osi treatment rapidly triggers adaptive resistance in tumor cells. Metabolomics analysis reveals a significant enhancement of oxidative phosphorylation (OXPHOS) in Osi adaptive-resistant cells. Mechanically, Osi treatment induces an elevation of NCOA4, a key protein of ferritinophagy, which maintains the synthesis of iron-sulfur cluster (ISC) proteins of electron transport chain and OXPHOS. Additionally, active ISC protein synthesis in adaptive-resistant cells significantly increases the sensitivity to copper ions. Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA4-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy.


Assuntos
Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB , Ferritinas , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Ferritinas/metabolismo , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Coativadores de Receptor Nuclear/metabolismo , Coativadores de Receptor Nuclear/genética , Fosforilação Oxidativa/efeitos dos fármacos , Animais , Camundongos , Cobre/metabolismo , Autofagia/efeitos dos fármacos , Camundongos Nus , Indóis , Pirimidinas
15.
Proc Natl Acad Sci U S A ; 121(20): e2318119121, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38709930

RESUMO

Brain metastasis of advanced breast cancer often results in deleterious consequences. Metastases to the brain lead to significant challenges in treatment options, as the blood-brain barrier (BBB) prevents conventional therapy. Thus, we hypothesized that creation of a nanoparticle (NP) that distributes to both primary tumor site and across the BBB for secondary brain tumor can be extremely beneficial. Here, we report a simple targeting strategy to attack both the primary breast and secondary brain tumors utilizing a single NP platform. The nature of these mitochondrion-targeted, BBB-penetrating NPs allow for simultaneous targeting and drug delivery to the hyperpolarized mitochondrial membrane of the extracranial primary tumor site in addition to tumors at the brain. By utilizing a combination of such dual anatomical distributing NPs loaded with therapeutics, we demonstrate a proof-of-concept idea to combat the increased metabolic plasticity of brain metastases by lowering two major energy sources, oxidative phosphorylation (OXPHOS) and glycolysis. By utilizing complementary studies and genomic analyses, we demonstrate the utility of a chemotherapeutic prodrug to decrease OXPHOS and glycolysis by pairing with a NP loaded with pyruvate dehydrogenase kinase 1 inhibitor. Decreasing glycolysis aims to combat the metabolic flexibility of both primary and secondary tumors for therapeutic outcome. We also address the in vivo safety parameters by addressing peripheral neuropathy and neurobehavior outcomes. Our results also demonstrate that this combination therapeutic approach utilizes mitochondrial genome targeting strategy to overcome DNA repair-based chemoresistance mechanisms.


Assuntos
Barreira Hematoencefálica , Neoplasias Encefálicas , Neoplasias da Mama , Nanopartículas , Fosforilação Oxidativa , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/patologia , Animais , Humanos , Feminino , Nanopartículas/química , Camundongos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Fosforilação Oxidativa/efeitos dos fármacos , Linhagem Celular Tumoral , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Glicólise/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico
16.
Cell Rep ; 43(4): 114067, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38583150

RESUMO

Mitochondrial dysfunction critically contributes to many major human diseases. The impact of specific gut microbial metabolites on mitochondrial functions of animals and the underlying mechanisms remain to be uncovered. Here, we report a profound role of bacterial peptidoglycan muropeptides in promoting mitochondrial functions in multiple mammalian models. Muropeptide addition to human intestinal epithelial cells (IECs) leads to increased oxidative respiration and ATP production and decreased oxidative stress. Strikingly, muropeptide treatment recovers mitochondrial structure and functions and inhibits several pathological phenotypes of fibroblast cells derived from patients with mitochondrial disease. In mice, muropeptides accumulate in mitochondria of IECs and promote small intestinal homeostasis and nutrient absorption by modulating energy metabolism. Muropeptides directly bind to ATP synthase, stabilize the complex, and promote its enzymatic activity in vitro, supporting the hypothesis that muropeptides promote mitochondria homeostasis at least in part by acting as ATP synthase agonists. This study reveals a potential treatment for human mitochondrial diseases.


Assuntos
Mitocôndrias , Fosforilação Oxidativa , Animais , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Peptidoglicano/metabolismo , Camundongos Endogâmicos C57BL , Trifosfato de Adenosina/metabolismo
17.
Redox Biol ; 72: 103142, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38581860

RESUMO

Platelets are the critical target for preventing and treating pathological thrombus formation. However, despite current antiplatelet therapy, cardiovascular mortality remains high, and cardiovascular events continue in prescribed patients. In this study, first results were obtained with ortho-carbonyl hydroquinones as antiplatelet agents; we found that linking triphenylphosphonium cation to a bicyclic ortho-carbonyl hydroquinone moiety by a short alkyl chain significantly improved their antiplatelet effect by affecting the mitochondrial functioning. The mechanism of action involves uncoupling OXPHOS, which leads to an increase in mitochondrial ROS production and a decrease in the mitochondrial membrane potential and OCR. This alteration disrupts the energy production by mitochondrial function necessary for the platelet activation process. These effects are responsive to the complete structure of the compounds and not to isolated parts of the compounds tested. The results obtained in this research can be used as the basis for developing new antiplatelet agents that target mitochondria.


Assuntos
Plaquetas , Hidroquinonas , Potencial da Membrana Mitocondrial , Mitocôndrias , Compostos Organofosforados , Inibidores da Agregação Plaquetária , Espécies Reativas de Oxigênio , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Humanos , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/química , Hidroquinonas/farmacologia , Hidroquinonas/química , Plaquetas/metabolismo , Plaquetas/efeitos dos fármacos , Compostos Organofosforados/farmacologia , Compostos Organofosforados/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Ativação Plaquetária/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos
18.
Environ Int ; 186: 108643, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38615544

RESUMO

Exposure to bisphenol S (BPS) is known to adversely affect neuronal development. As pivotal components of neuronal polarization, axons and dendrites are indispensable structures within neurons, crucial for the maintenance of nervous system function. Here, we investigated the impact of BPS exposure on axonal and dendritic development both in vivo and in vitro. Our results revealed that exposure to BPS during pregnancy and lactation led to a reduction in the complexity, density, and length of axons and dendrites in the prefrontal cortex (PFC) of offspring. Employing RNA sequencing technology to elucidate the underlying mechanisms of axonal and dendritic damage induced by BPS, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis highlighted a significant alteration in the oxidative phosphorylation (OXPHOS) pathway, essential for mitochondrial function. Subsequent experiments demonstrate BPS-induced impairment in mitochondrial function, including damaged morphology, decreased adenosine triphosphate (ATP) and superoxide dismutase (SOD) levels, and increased reactive oxygen species and malondialdehyde (MDA). These alterations coincided with the downregulated expression of OXPHOS pathway-related genes (ATP6V1B1, ATP5K, NDUFC1, NDUFC2, NDUFA3, COX6B1) and Myosin 19 (Myo19). Notably, Myo19 overexpression restored the BPS-induced mitochondrial dysfunction by alleviating the inhibition of OXPHOS pathway. Consequently, this amelioration was associated with a reduction in BPS-induced axonal and dendritic injury observed in cultured neurons of the PFC.


Assuntos
Axônios , Dendritos , Mitocôndrias , Fosforilação Oxidativa , Fenóis , Sulfonas , Animais , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fenóis/toxicidade , Dendritos/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Feminino , Sulfonas/toxicidade , Axônios/efeitos dos fármacos , Gravidez , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Camundongos
19.
Bioorg Chem ; 147: 107325, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38583247

RESUMO

Dual suppression of oxidative phosphorylation (OXPHOS) and glycolysis can disrupt metabolic adaption of cancer cells, inhibiting energy supply and leading to successful cancer therapy. Herein, we have developed an α-tocopheryl succinate (α-TOS)-functionalized iridium(III) complex Ir2, a highly lipophilic mitochondria targeting anticancer molecule, could inhibit both oxidative phosphorylation (OXPHOS) and glycolysis, resulting in the energy blockage and cancer growth suppression. Mechanistic studies reveal that complex Ir2 induces reactive oxygen species (ROS) elevation and mitochondrial depolarization, and triggers DNA oxidative damage. These damages could evoke the cancer cell death with the mitochondrial-relevant apoptosis and autophagy. 3D tumor spheroids experiment demonstrates that Ir2 owned superior antiproliferation performance, as the potent anticancer agent in vivo. This study not only provided a new path for dual inhibition of both mitochondrial OXPHOS and glycolytic metabolisms with a novel α-TOS-functionalized metallodrug, but also further demonstrated that the mitochondrial-relevant therapy could be effective in enhancing the anticancer performance.


Assuntos
Antineoplásicos , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Glicólise , Fosforilação Oxidativa , Humanos , Fosforilação Oxidativa/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Animais , Irídio/química , Irídio/farmacologia , Relação Estrutura-Atividade , Espécies Reativas de Oxigênio/metabolismo , Relação Dose-Resposta a Droga , Apoptose/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Camundongos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Camundongos Endogâmicos BALB C , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia
20.
Mol Med ; 30(1): 56, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38671369

RESUMO

BACKGROUND: Ginsenoside Rh2 (G-Rh2), a steroidal compound extracted from roots of ginseng, has been extensively studied in tumor therapy. However, its specific regulatory mechanism in non-small cell lung cancer (NSCLC) is not well understood. Pyruvate dehydrogenase kinase 4 (PDK4), a central regulator of cellular energy metabolism, is highly expressed in various malignant tumors. We investigated the impact of G-Rh2 on the malignant progression of NSCLC and how it regulated PDK4 to influence tumor aerobic glycolysis and mitochondrial function. METHOD: We examined the inhibitory effect of G-Rh2 on NSCLC through I proliferation assay, migration assay and flow cytometry in vitro. Subsequently, we verified the ability of G-Rh2 to inhibit tumor growth and metastasis by constructing subcutaneous tumor and metastasis models in nude mice. Proteomics analysis was conducted to analyze the action pathways of G-Rh2. Additionally, we assessed glycolysis and mitochondrial function using seahorse, PET-CT, Western blot, and RT-qPCR. RESULT: Treatment with G-Rh2 significantly inhibited tumor proliferation and migration ability both in vitro and in vivo. Furthermore, G-Rh2 inhibited the tumor's aerobic glycolytic capacity, including glucose uptake and lactate production, through the HIF1-α/PDK4 pathway. Overexpression of PDK4 demonstrated that G-Rh2 targeted the inhibition of PDK4 expression, thereby restoring mitochondrial function, promoting reactive oxygen species (ROS) accumulation, and inducing apoptosis. When combined with sodium dichloroacetate, a PDK inhibitor, it complemented the inhibitory capacity of PDKs, acting synergistically as a detoxifier. CONCLUSION: G-Rh2 could target and down-regulate the expression of HIF-1α, resulting in decreased expression of glycolytic enzymes and inhibition of aerobic glycolysis in tumors. Additionally, by directly targeting mitochondrial PDK, it elevated mitochondrial oxidative phosphorylation and enhanced ROS accumulation, thereby promoting tumor cells to undergo normal apoptotic processes.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Ginsenosídeos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Neoplasias Pulmonares , Fosforilação Oxidativa , Piruvato Desidrogenase Quinase de Transferência de Acetil , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Humanos , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Camundongos , Linhagem Celular Tumoral , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Camundongos Nus , Movimento Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
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