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Metabolic reprogramming, a newly recognized trait of tumor biology, is an intensively studied prospect for oncology medicines. For numerous tumors and cancer cell subpopulations, oxidative phosphorylation (OXPHOS) is essential for their biosynthetic and bioenergetic functions. Cancer cells with mutations in isocitrate dehydrogenase 1 (IDH1) exhibit differentiation arrest, epigenetic and transcriptional reprogramming, and sensitivity to mitochondrial OXPHOS inhibitors. In this study, we report that berberine, which is widely used in China to treat intestinal infections, acted solely at the mitochondrial electron transport chain (ETC) complex I, and that its association with IDH1 mutant inhibitor (IDH1mi) AG-120 decreased mitochondrial activity and enhanced antileukemic effect in vitro andin vivo. Our study gives a scientific rationale for the therapy of IDH1 mutant acute myeloid leukemia (AML) patients using combinatory mitochondrial targeted medicines, particularly those who are resistant to or relapsing from IDH1mi.
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Berberina , Leucemia Mieloide Aguda , Humanos , Fosforilación Oxidativa , Transporte de Electrón , Mitocondrias , Isocitrato DeshidrogenasaRESUMEN
PURPOSE: The understanding of cognitive symptoms in patients with IDH-Mutant gliomas (IDH-Mut) is rapidly developing. In this article, we summarize the neuroscientific knowledge base regarding the influence of IDH-Mut tumors and their treatment on cognition and provide guidance regarding the management of these symptoms in patients. METHODS: We performed a review of peer reviewed publications relevant to IDH-Mut glioma and cognitive outcomes and provide an overview of the literature as well as a case example to clarify management strategies. RESULTS: At the time of presentation, patients with IDH-Mut gliomas have a favorable cognitive profile as compared with those with IDH-wild type (WT) tumors. The relatively low cognitive burden may reflect the slower growth rate of IDH-Mut tumors, which is less disruptive to both local and widespread neural networks. Human connectomic research using a variety of modalities has demonstrated relatively preserved network efficiency in patients with IDH-Mut gliomas as compared with IDH-WT tumors. Risk of cognitive decline from surgery can potentially be mitigated by careful integration of intra-operative mapping. Longer term cognitive risks of tumor treatment, including chemotherapy and radiation, are best managed by instituting neuropsychological assessment as part of the long-term care of patients with IDH-Mutant glioma. A specific timeline for such integrative care is provided. CONCLUSIONS: Given the relative recency of the IDH-mutation based classification of gliomas, as well as the long time course of this disease, a thoughtful and comprehensive strategy to studying patient outcomes and devising methods of cognitive risk reduction is required.
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Neoplasias Encefálicas , Glioma , Humanos , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neuropsicología , Glioma/complicaciones , Glioma/genética , Glioma/terapia , Isocitrato Deshidrogenasa/genética , MutaciónRESUMEN
BACKGROUND: Altered microRNA profiles have been observed not only in tumour tissues but also in biofluids, where they circulate in a stable form thus representing interesting biomarker candidates. This study aimed to identify a microRNA signature as a non-invasive biomarker and to investigate its impact on glioma biology. METHODS: MicroRNAs were selected using a global expression profile in preoperative serum samples from 37 glioma patients. Comparison between serum samples from age and gender-matched controls was performed by using the droplet digital PCR. The ROC curve and Kaplan-Meier survival analyses were used to evaluate the diagnostic/prognostic values. The functional role of the identified signature was assessed by gain/loss of function strategies in glioma cells. RESULTS: A three-microRNA signature (miR-1-3p/-26a-1-3p/-487b-3p) was differentially expressed in the serum of patients according to the isocitrate dehydrogenase (IDH) genes mutation status and correlated with both patient Overall and Progression Free Survival. The identified signature was also downregulated in the serum of patients compared to controls. Consistent with these results, the signature expression and release in the conditioned medium of glioma cells was lower in IDH-wild type cells compared to the mutated counterpart. Furthermore, in silico analysis of glioma datasets showed a consistent deregulation of the signature according to the IDH mutation status in glioma tumour tissues. Ectopic expression of the signature negatively affects several glioma functions. Notably, it impacts the glioma invasive phenotype by directly targeting the invadopodia-related proteins TKS4, TKS5 and EFHD2. CONCLUSIONS: We identified a three microRNA signature as a promising complementary or even an independent non-invasive diagnostic/prognostic biomarker. The signature displays oncosuppressive functions in glioma cells and impacts on proteins crucial for migration and invasion, providing potential targets for therapeutic intervention.
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Neoplasias Encefálicas , MicroARN Circulante , Glioma , MicroARNs , Humanos , Neoplasias Encefálicas/patología , Biomarcadores de Tumor/genética , Glioma/patología , MicroARNs/genética , Pronóstico , Isocitrato Deshidrogenasa/genética , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Proteínas de Unión al CalcioRESUMEN
Mutations in the Krebs cycle enzyme IDH1 (isocitrate dehydrogenase (NADP(+)) 1) are associated with better prognosis in gliomas. Though IDH1 mutant (IDH1R132H) tumors are characterized by their antiproliferative signatures maintained through hypermethylation of DNA and chromatin, mechanisms affecting cell death pathways in these tumors are not well elucidated. On investigating the crosstalk between the IDH1 mutant epigenome, ferritinophagy and inflammation, diminished expression of PRMT1 (protein arginine methyltransferase 1) and its associated asymmetric dimethyl epigenetic mark H4R3me2a was observed in IDH1R132H gliomas. Reduced expression of PRMT1 was concurrent with diminished levels of PTX3, a key secretory factor involved in cancer-related inflammation. Lack of PRMT1 H4R3me2a in IDH1 mutant glioma failed to epigenetically activate the expression of PTX3 with a reduction in YY1 (YY1 transcription factor) binding on its promoter. Transcriptional activation and subsequent secretion of PTX3 from cells was required for maintaining macroautophagic/autophagic balance as pharmacological or genetic ablation of PTX3 secretion in wild-type IDH1 significantly increased autophagic flux. Additionally, PTX3-deficient IDH1 mutant gliomas exhibited heightened autophagic signatures. Furthermore, we demonstrate that the PRMT1-PTX3 axis is important in regulating the levels of ferritin genes/iron storage and inhibition of this axis triggered ferritinophagic flux. This study highlights the conserved role of IDH1 mutants in augmenting ferritinophagic flux in gliomas irrespective of genetic landscape through inhibition of the PRMT1-PTX3 axis. This is the first study describing ferritinophagy in IDH1 mutant gliomas with mechanistic details. Of clinical importance, our study suggests that the PRMT1-PTX3 ferritinophagy regulatory circuit could be exploited for therapeutic gains.Abbreviations: 2-HG: D-2-hydroxyglutarate; BafA1: bafilomycin A1; ChIP: chromatin immunoprecipitation; FTH1: ferritin heavy chain 1; FTL: ferritin light chain; GBM: glioblastoma; HMOX1/HO-1: heme oxygenase 1; IHC: immunohistochemistry; IDH1: isocitrate dehydrogenase(NADP(+))1; MDC: monodansylcadaverine; NCOA4: nuclear receptor coactivator 4; NFE2L2/Nrf2: NFE2 like bZIP transcription factor 2; PTX3/TSG-14: pentraxin 3; PRMT: protein arginine methyltransferase; SLC40A1: solute carrier family 40 member 1; Tan IIA: tanshinone IIA; TCA: trichloroacetic acid; TEM: transmission electron microscopy; TNF: tumor necrosis factor.
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Neoplasias Encefálicas , Glioma , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Isocitrato Deshidrogenasa/uso terapéutico , Proteína-Arginina N-Metiltransferasas/genética , NADP , Autofagia/genética , Glioma/patología , Mutación/genética , Factor de Transcripción YY1 , Neoplasias Encefálicas/patología , Proteínas Represoras/genéticaRESUMEN
Microplastics (MPs) can adsorb persistent organic pollutants such as oil hydrocarbons and may facilitate their transfer to organisms (Trojan horse effect). The aim of this study was to examine the effects of a 21 day dietary exposure to polystyrene MPs of 4.5 µm at 1000 particles/mL, alone and with sorbed oil compounds from the water accommodated fraction (WAF) of a naphthenic North Sea crude oil at two dilutions (25 % and 100 %), on marine mussels. An additional group of mussels was exposed to 25 % WAF for comparison. PAHs were accumulated in mussels exposed to WAF but not in those exposed to MPs with sorbed oil compounds from WAF (MPs-WAF), partly due to the low concentration of PAHs in the studied crude oil. Exposure to MPs or to WAF alone altered the activity of enzymes involved in aerobic (isocitrate dehydrogenase) and biotransformation metabolism (glutathione S-transferase). Prevalence of oocyte atresia and volume density of basophilic cells were higher and absorption efficiency lower in mussels exposed to MPs and to WAF than in controls. After 21 days MPs caused DNA damage (Comet assay) in mussel hemocytes. In conclusion, a Trojan horse effect was not observed but both MPs and oil WAF caused an array of deleterious effects on marine mussels at different levels of biological organization.
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Mytilus , Petróleo , Contaminantes Químicos del Agua , Animales , Microplásticos , Petróleo/toxicidad , Petróleo/metabolismo , Plásticos/toxicidad , Plásticos/metabolismo , Poliestirenos/metabolismo , Agua/metabolismo , Contaminantes Orgánicos Persistentes , Mar del Norte , Isocitrato Deshidrogenasa/metabolismo , Isocitrato Deshidrogenasa/farmacología , Contaminantes Químicos del Agua/análisis , Glutatión Transferasa/metabolismoRESUMEN
Understanding how carcinogenesis can expose cancers to synthetically lethal vulnerabilities has been an essential underpinning of development of modern anticancer therapeutics. Isocitrate dehydrogenase wild-type (IDHWT) glioblastoma multiforme (GBM), which is known to have upregulated branched-chain amino acid transaminase 1 (BCAT1) expression, has not had treatments developed to the same extent as the IDH mutant counterpart, despite making up the majority of cases. In this issue, Zhang and colleagues utilize a metabolic screen to identify α-ketoglutarate (AKG) as a synthetically lethal treatment in conjunction with BCAT1 inhibition in IDHWT GBM. These treatments synergize in a multipronged approach that limits substrate catabolism and disrupts mitochondrial homeostasis through perturbing the balance of NAD+/NADH, leading to mTORC1 inhibition and a reduction of nucleotide biosynthesis. Based on these results, the authors propose combination treatment targeting branched chain amino acid catabolism as a potential option for patients with IDHWT GBM. See related article by Zhang et al., p. 2388.
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Glioblastoma , Glioblastoma/genética , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Ácidos Cetoglutáricos/farmacología , Mutaciones Letales Sintéticas/efectos de los fármacos , Transaminasas/genética , Transaminasas/metabolismoRESUMEN
Enchondromas and chondrosarcomas are common cartilage neoplasms that are either benign or malignant, respectively. The majority of these tumors harbor mutations in either IDH1 or IDH2. Glutamine metabolism has been implicated as a critical regulator of tumors with IDH mutations. Using genetic and pharmacological approaches, we demonstrated that glutaminase-mediated glutamine metabolism played distinct roles in enchondromas and chondrosarcomas with IDH1 or IDH2 mutations. Glutamine affected cell differentiation and viability in these tumors differently through different downstream metabolites. During murine enchondroma-like lesion development, glutamine-derived α-ketoglutarate promoted hypertrophic chondrocyte differentiation and regulated chondrocyte proliferation. Deletion of glutaminase in chondrocytes with Idh1 mutation increased the number and size of enchondroma-like lesions. In contrast, pharmacological inhibition of glutaminase in chondrosarcoma xenografts reduced overall tumor burden partially because glutamine-derived non-essential amino acids played an important role in preventing cell apoptosis. This study demonstrates that glutamine metabolism plays different roles in tumor initiation and cancer maintenance. Supplementation of α-ketoglutarate and inhibiting GLS may provide a therapeutic approach to suppress enchondroma and chondrosarcoma tumor growth, respectively. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Neoplasias Óseas , Condroma , Condrosarcoma , Glutamina , Isocitrato Deshidrogenasa , Mutación , Animales , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Cartílago/metabolismo , Condroma/genética , Condroma/metabolismo , Condroma/patología , Condrosarcoma/genética , Condrosarcoma/metabolismo , Condrosarcoma/patología , Glutaminasa/genética , Glutaminasa/metabolismo , Glutamina/genética , Glutamina/metabolismo , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Ácidos Cetoglutáricos , RatonesRESUMEN
With improved outcome following aggressive treatment in patients with grade 2 and 3 IDH-mutant (IDHmt), 1p/19q codeleted oligodendroglioma and IDHmt, non-codeleted astrocytoma, prolonged surveillance is desirable for early detection of tumor growth and malignant transformation. Current National Comprehensive Cancer Network (NCCN) guidelines provide imaging follow-up recommendations based on molecular classification of lower-grade gliomas, although individualized imaging guidelines based on treatments received and after tumor recurrence are not clearly specified. Other available guidelines have yet to incorporate the molecular biomarkers that inform the WHO classification of gliomas, and in some cases do not adequately consider current knowledge on IDHmt glioma growth rate and recurrence patterns. Moreover, these guidelines also do not provide specific recommendations for concerning clinical symptoms or radiographic findings warranting imaging studies out of prespecified intervals. Focusing on molecularly defined grade 2 and 3 IDHmt astrocytomas and oligodendrogliomas, we review current knowledge of tumor growth rates and time to tumor progression for each tumor type and propose a range of recommended MRI surveillance intervals for both the newly diagnosed and recurrent tumor setting. Additionally, we summarize situations in which imaging is advisable outside of these intervals.
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Astrocitoma , Neoplasias Encefálicas , Glioma , Oligodendroglioma , Adulto , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Glioma/diagnóstico por imagen , Glioma/genética , Glioma/patología , Humanos , Isocitrato Deshidrogenasa/genética , Mutación , Oligodendroglioma/diagnóstico por imagen , Oligodendroglioma/genética , Estudios Retrospectivos , Organización Mundial de la SaludRESUMEN
Isocitrate dehydrogenase 1 (IDH1) has been investigated as a promising therapeutic target in select cancers with a mutated version of the enzyme (mtIDH1). With only one phase III trial published to date and two indications approved for routine clinical use by the FDA, we reviewed the entire clinical trial portfolio to broadly understand mtIDH1 inhibitor activity in patients. We queried PubMed.gov and ClinicalTrials.gov to identify published and ongoing clinical trials related to IDH1 and cancer. Progression-free survival (PFS), overall survival (OS), 2-hydroxyglutarate levels, and adverse events were summarized. To date, ten clinical trials investigating mtIDH1 inhibitors among patients with diverse malignancies (cholangiocarcinoma, acute myeloid leukemia, chondrosarcoma, glioma) have been published. Almost every trial (80%) has investigated ivosidenib. In multiple phase I trials, ivosidenib treatment resulted in promising radiographic and biochemical responses with improved survival outcomes (relative to historic data) among patients with both solid and hematologic mtIDH1 malignancies. Among patients enrolled in a phase III trial with advanced cholangiocarcinoma, ivosidenib resulted in a PFS rate of 32% at 6 months, as compared to 0% with placebo. There was a 5.2 month increase in OS with ivosidenib relative to placebo, after considering crossover. The treatment-specific grade ≥3 adverse event rate of ivosidenib was 2%-26% among all patients, and was just 3.6% among 284 patients who had a solid tumor across four trials. Although <1% of malignancies harbor IDH1 mutations, small molecule mtIDH1 inhibitors, namely ivosidenib, appear to be biologically active and well tolerated in patients with solid and hematologic mtIDH1 malignancies.
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Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Glicina/análogos & derivados , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Piridinas/uso terapéutico , Compuestos de Anilina/efectos adversos , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Bencimidazoles/efectos adversos , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Ensayos Clínicos como Asunto , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacología , Glicina/efectos adversos , Glicina/farmacología , Glicina/uso terapéutico , Humanos , Isocitrato Deshidrogenasa/genética , Mutación , Neoplasias/mortalidad , Piridinas/efectos adversos , Piridinas/farmacologíaRESUMEN
The new subtypes of diffuse gliomas are recognized by the World Health Organization (WHO) on the basis of genotypes, e.g., isocitrate dehydrogenase and chromosome arms 1p/19q, in addition to the histologic phenotype. Glioma subtype identification can provide valid guidances for both risk-benefit assessment and clinical decision. The feature representations of gliomas in magnetic resonance imaging (MRI) have been prevalent for revealing underlying subtype status. However, since gliomas are highly heterogeneous tumors with quite variable imaging phenotypes, learning discriminative feature representations in MRI for gliomas remains challenging. In this paper, we propose a deep cross-view co-regularized representation learning framework for glioma subtype identification, in which view representation learning and multiple constraints are integrated into a unified paradigm. Specifically, we first learn latent view-specific representations based on cross-view images generated from MRI via a bi-directional mapping connecting original imaging space and latent space, and view-correlated regularizer and output-consistent regularizer in the latent space are employed to explore view correlation and derive view consistency, respectively. We further learn view-sharable representations which can explore complementary information of multiple views by projecting the view-specific representations into a holistically shared space and enhancing via adversary learning strategy. Finally, the view-specific and view-sharable representations are incorporated for identifying glioma subtype. Experimental results on multi-site datasets demonstrate the proposed method outperforms several state-of-the-art methods in detection of glioma subtype status.
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Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/diagnóstico por imagen , Glioma/diagnóstico por imagen , Humanos , Isocitrato Deshidrogenasa , Imagen por Resonancia MagnéticaRESUMEN
Organic acids are key components that determine the taste and flavor of fruits and play a vital role in maintaining fruit quality and nutritive value. In this study, the fruits of two cultivars of passion fruit Yellow (Passiflora edulis f. flavicarpa) and purple (Passiflora edulis f. edulis) were harvested at five different developmental stages (i.e., fruitlet, green, veraison, near-mature and mature stage) from an orchard located in subtropical region of Fujian Province, China. The contents of six organic acids were quantified using ultra-performance liquid chromatography (UPLC), activities of citric acid related enzymes were determined, and expression levels of genes involved in citric acid metabolism were measured by quantitative real-time PCR (qRT-PCR). The results revealed that citric acid was the predominant organic acid in both cultivars during fruit development. The highest citric acid contents were observed in both cultivars at green stage, which were reduced with fruit maturity. Correlation analysis showed that citrate synthase (CS), cytosolic aconitase (Cyt-ACO) and cytosolic isocitrate dehydrogenase (Cyt-IDH) may be involved in regulating citric acid biosynthesis. Meanwhile, the PeCS2, PeACO4, PeACO5 and PeIDH1 genes may play an important role in regulating the accumulation of citric acid. This study provides new insights for future elucidation of key mechanisms regulating organic acid biosynthesis in passion fruit.
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Ácido Cítrico/análisis , Frutas/química , Frutas/genética , Compuestos Orgánicos/análisis , Passiflora/química , Passiflora/genética , China , Frutas/crecimiento & desarrollo , Regulación de la Expresión Génica de las Plantas , Genes de Plantas/genética , Isocitrato Deshidrogenasa , Valor Nutritivo , Passiflora/crecimiento & desarrollo , Extractos VegetalesRESUMEN
Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2H-1λ2-quinoline-2,5(6H)-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (+)-119 (NCATS-SM5637, NSC 791985). In an engineered mIDH1-U87-xenograft mouse model, after a single oral dose of 30 mg/kg, 16 h post dose, between 16 and 48 h, (+)-119 showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).
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Inhibidores Enzimáticos/química , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Piridonas/química , Animales , Encéfalo/metabolismo , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Femenino , Glicina/análogos & derivados , Glicina/uso terapéutico , Semivida , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Ratones , Ratones Desnudos , Microsomas Hepáticos/metabolismo , Mutagénesis Sitio-Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Piridinas/uso terapéutico , Piridonas/metabolismo , Piridonas/uso terapéutico , Ratas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVES: Stroke is one of the leading causes of disability and death worldwide, and ischaemic stroke is the most common subtype. Moreover, we found that L-borneol has an obvious therapeutic effect on cerebral ischaemia. This study aimed to investigate the potential mechanism of L-borneol in permanent middle cerebral artery occlusion (pMCAO) rats via the mitochondrial calcium uniporter (MCU)-related apoptosis cascade. METHODS: A pMCAO model was used to simulate cerebral ischaemia, and neurological function was evaluated. Cerebral infarction was observed by TTC staining. HE staining was also used to reflect the pathophysiological changes in the rat hippocampus and cortex. Furthermore, MCU-related signals and apoptosis signalling pathways were detected at both the gene and protein levels. RESULTS: The neurological function scores of the high-dose L-borneol (H-B) group, medium-dose L-borneol (M-B) group and low-dose L-borneol (L-B) group were significantly lower than that of the model group at 24 h (P < 0.05, P < 0.01). High and medium doses of L-borneol could reverse the cerebral infarction area, similar to Nimotop. After HE staining, the cells in the H-B group and M-B group were neatly and densely arranged, with largely normal morphological structures. High-dose L-borneol could significantly reduce the gene and protein levels of Apaf-1, Bad and Caspase-3 and increase the expression of Bcl-2 (P < 0.05, P < 0.01). In addition, the MCU expression of the H-B group was significantly decreased compared with that of the model group at both the gene and protein levels (P < 0.05, P < 0.01). The expression of IDH2 was similar to that of MCU but not MEP (P < 0.05, P < 0.01). CONCLUSION: L-borneol can achieve brain protection by downregulating the excessive expression of MCU-related signalling pathway and further inhibiting the apoptosis of neurons during pMCAO.
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Apoptosis/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Canfanos/farmacología , Fármacos Neuroprotectores/farmacología , Animales , Isquemia Encefálica/patología , Canales de Calcio/metabolismo , Canfanos/administración & dosificación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Infarto de la Arteria Cerebral Media , Isocitrato Deshidrogenasa/genética , Masculino , Fármacos Neuroprotectores/administración & dosificación , Nimodipina/farmacología , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
Photobiomodulation with 808 nm laser light electively stimulates Complexes III and IV of the mitochondrial respiratory chain, while Complexes I and II are not affected. At the wavelength of 1064 nm, Complexes I, III, and IV are excited, while Complex II and some mitochondrial matrix enzymes seem to be not receptive to photons at that wavelength. Complex IV was also activated by 633 nm. The mechanism of action of wavelengths in the range 900-1000 nm on mitochondria is less understood or not described. Oxidative stress from reactive oxygen species (ROS) generated by mitochondrial activity is an inescapable consequence of aerobic metabolism. The antioxidant enzyme system for ROS scavenging can keep them under control. However, alterations in mitochondrial activity can cause an increment of ROS production. ROS and ATP can play a role in cell death, cell proliferation, and cell cycle arrest. In our work, bovine liver isolated mitochondria were irradiated for 60 sec, in continuous wave mode with 980 nm and powers from 0.1 to 1.4 W (0.1 W increment at every step) to generate energies from 6 to 84 J, fluences from 7.7 to 107.7 J/cm2, power densities from 0.13 to 1.79 W/cm2, and spot size 0.78 cm2. The control was equal to 0 W. The activity of the mitochondria's complexes, Krebs cycle enzymes, ATP production, oxygen consumption, generation of ROS, and oxidative stress were detected. Lower powers (0.1-0.2 W) showed an inhibitory effect; those that were intermediate (0.3-0.7 W) did not display an effect, and the higher powers (0.8-1.1 W) induced an increment of ATP synthesis. Increasing the power (1.2-1.4 W) recovered the ATP production to the control level. The interaction occurred on Complexes III and IV, as well as ATP production and oxygen consumption. Results showed that 0.1 W uncoupled the respiratory chain and induced higher oxidative stress and drastic inhibition of ATP production. Conversely, 0.8 W kept mitochondria coupled and induced an increase of ATP production by increments of Complex III and IV activities. An augmentation of oxidative stress was also observed, probably as a consequence of the increased oxygen consumption and mitochondrial isolation experimental conditions. No effect was observed using 0.5 W, and no effect was observed on the enzymes of the Krebs cycle.
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Láseres de Semiconductores , Terapia por Luz de Baja Intensidad , Mitocondrias/metabolismo , Mitocondrias/efectos de la radiación , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Animales , Bovinos , Respiración de la Célula/efectos de la radiación , Complejo III de Transporte de Electrones/metabolismo , Complejo IV de Transporte de Electrones/metabolismo , Femenino , Isocitrato Deshidrogenasa/metabolismo , Peroxidación de Lípido/efectos de la radiación , Malato Deshidrogenasa/metabolismo , Masculino , Fosforilación Oxidativa/efectos de la radiación , Estrés Oxidativo/efectos de la radiación , ATPasas de Translocación de Protón/metabolismo , Superóxidos/metabolismo , TemperaturaRESUMEN
PURPOSE: To investigate the value of the iodine concentration (IC) measured by dual-layer detector spectral CT (DLDSCT) in evaluating the factors related to the treatment scheme and survival prognosis of patients with glioma. METHODS: From 2018 to 2019, we prospectively collected the data of 99 patients with glioma. The degree of CT enhancement and the IC of low grade gliomas (LGGs, II), high grade gliomas (HGGs, III and IV), grade II and III gliomas, were compared. The predictive performance of the degree of CT enhancement and IC was examined via receiver operating characteristic (ROC) analysis. The correlations between IC and Ki-67 labeling index, isocitrate dehydrogenase (IDH) mutation, chromosome 1p/19q deletion status of the tumor were examined. RESULTS: Both IC and the degree of CT enhancement of patients with HGG were significantly higher than those of patients with LGG (p < 0.001; χ2 =41.707, pâ¯<⯠0.001); IC had large area under the ROC curve for diagnostic HGG (0.931; 95 % CI: 0.882-0.979; pâ¯<⯠0.001). The IC in the grade III gliomas was significantly higher than that in grade II gliomas (p < 0.001); IC had a large area under the ROC curve for diagnostic grade III gliomas (0.865; 95 % CI: 0.779-0.952; pâ¯<⯠0.001). There was a significant positive correlation between IC and Ki-67 LI (râ¯=â¯0.679; p < 0.001). CONCLUSIONS: The DLDSCT technology can be used as a supplementary method to provide more information for preoperative grading of the gliomas and the prognosis assessment of the patients.
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Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/diagnóstico por imagen , Glioma/diagnóstico por imagen , Glioma/cirugía , Humanos , Isocitrato Deshidrogenasa/genética , Mutación , Clasificación del Tumor , Tomografía Computarizada por Rayos XRESUMEN
Isocitrate dehydrogenase (IDH) is one key rate-limiting enzyme in the tricarboxylic acid cycle, which is related to various cancers. Tomatillo (Physalis ixocarpa), a special tomato, is widely consumed as nutritious vegetable in Mexico, USA, etc. As a rich source for withanolides, the fruits of P. ixocarpa were investigated, leading to the isolation of 11 type-A withanolides including 4 new ones (1 is an artificial withanolide). All these withanolides were evaluated for their inhibition on mutant IDH1 enzyme activity. Among them, physalin F (11) exhibited potent enzyme inhibitory activity and binding affinity with mutant IDH1. It inhibits the proliferation of HT1080 cells by selectively inhibiting the activity of mutant IDH1. Since Ixocarpalactone A, another major type-B withanolide in this plant, could act on another energy metabolism target PHGDH, the presence of different types of withanolides in tomatillo and their synergistic effect could make it a potential antitumor functional food or drug.
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Antineoplásicos Fitogénicos/farmacología , Inhibidores Enzimáticos/farmacología , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Physalis/química , Extractos Vegetales/farmacología , Witanólidos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Humanos , Isocitrato Deshidrogenasa/genética , Estructura Molecular , Mutación , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Relación Estructura-Actividad , Células Tumorales Cultivadas , Witanólidos/química , Witanólidos/aislamiento & purificaciónRESUMEN
BACKGROUND: Glioblastoma multiforme (GBM) is the most frequent, lethal and aggressive tumour of the central nervous system in adults. The discovery of novel anti-GBM agents based on the isocitrate dehydrogenase (IDH) mutant phenotypes and classifications have attracted comprehensive attention. PURPOSE: Diterpenoids are a class of naturally occurring 20-carbon isoprenoid compounds, and have previously been shown to possess high cytotoxicity for a variety of human tumours in many scientific reports. In the present study, 31 cassane diterpenoids of four types, namely, butanolide lactone cassane diterpenoids (I) (1-10), tricyclic cassane diterpenoids (II) (11-15), polyoxybutanolide lactone cassane diterpenoids (III) (16-23), and fused furan ring cassane diterpenoids (IV) (24-31), were tested for their anti-glioblastoma activity and mechanism underlying based on IDH1 mutant phenotypes of primary GBM cell cultures and human oligodendroglioma (HOG) cell lines. RESULTS: We confirmed that tricyclic-type (II) and compound 13 (Caesalpin A, CSA) showed the best anti-neoplastic potencies in IDH1 mutant glioma cells compared with the other types and compounds. Furthermore, the structure-relationship analysis indicated that the carbonyl group at C-12 and an α, ß-unsaturated ketone unit fundamentally contributed to enhancing the anti-glioma activity. Studies investigating the mechanism demonstrated that CSA induced oxidative stress via causing glutathione reduction and NOS activation by negatively regulating glutaminase (GLS), which proved to be highly dependent on IDH mutant type glioblastoma. Finally, GLS overexpression reversed the CSA-induced anti-glioma effects in vitro and in vivo, which indicated that the reduction of GLS contributed to the CSA-induced proliferation inhibition and apoptosis in HOG-IDH1-mu cells. CONCLUSION: Therefore, the present results demonstrated that compared with other diterpenoids, tricyclic-type diterpenoids could be a targeted drug candidate for the treatment of secondary IDH1 mutant type glioblastoma through negatively regulating GLS.
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Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/patología , Diterpenos/farmacología , Glioblastoma/patología , Glutaminasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/genética , Mutación , Línea Celular Tumoral , Humanos , Estrés OxidativoRESUMEN
The 2016 World Health Organization classification of central nervous system tumor firstly introduces molecular diagnosis to glioma, while the molecular features of adult thalamic gliomas (ATGs) in a relatively large sample have not been reported. We aimed at exploring molecular characteristics in ATGs. The data of 97 and 575 newly diagnosed ATGs and superficial gliomas (SGs) patients were collected, and we performed a comparative analysis of molecular characteristics between them. We analyzed expressions of molecules as follow: H3 K27M, isocitrate dehydrogenase1 (IDH1), Ki-67, O6-Methylguanine-DNA methyltransferase (MGMT) promoter, EGFR, p53, ATRX, GFAP, Oligo2, PTEN, MGMT, and MMP9 by immunohistochemistry. Direct gene sequencing was performed to test the H3 K27M, IDH1, and TERT promoter mutation. The median age at diagnosis of ATGs was 36.0 years, and majority of them were high-grade glioma. We found a significant difference in H3 K27M mutation (P = 0.003), IDH1 mutation (P < 0.001), MGMT promoter methylation (P = 0.005), and Ki67 > 0.1 (P < 0.001) between ATGs and SGs. The statuses of IDH1 (P < 0.001), MGMT promoter (P < 0.001), and Ki67 (P < 0.001) were significantly different between these two groups in lower-grade gliomas. And statuses of IDH1 (P < 0.001), Ki67 (P < 0.001), and EGFR (P = 0.032) were different between these two groups in high-grade gliomas. Only Ki67 > 0.1 was differentially expressed between lower- and high-grade gliomas in ATGs (P = 0.014). The high occurrence of H3 K27M mutation and Ki67 > 0.1, rare occurrence of IDH1 mutation, and MGMT promoter methylation in ATGs suggested that ATGs may be a distinct type of glioma entity.
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Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Tálamo/metabolismo , Adulto , Anciano , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Metilación de ADN , Metilasas de Modificación del ADN/genética , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Glioma/genética , Glioma/patología , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Persona de Mediana Edad , Mutación , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Proteína Nuclear Ligada al Cromosoma X/genética , Proteína Nuclear Ligada al Cromosoma X/metabolismoRESUMEN
PURPOSE: BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects. PATIENTS AND METHODS: The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with mIDH1 solid tumors. RESULTS: In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150-1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG (n = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG. CONCLUSIONS: BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.