Metabolic dysregulation of tricarboxylic acid cycle and oxidative phosphorylation in glioblastoma.

Glioblastoma multiforme (GBM) exhibits genetic alterations that induce the deregulation of oncogenic pathways, thus promoting metabolic adaptation. The modulation of metabolic enzyme activities is necessary to generate nucleotides, amino acids, and fatty acids, which provide energy and metabolic intermediates essential for fulfilling the biosynthetic needs of glioma cells. Moreover, the TCA cycle produces intermediates that play important roles in the metabolism of glucose, fatty acids, or non-essential amino acids, and act as signaling molecules associated with the activation of oncogenic pathways, transcriptional changes, and epigenetic modifications.

Metabolic Roles of HIF1, c-Myc, and p53 in Glioma Cells.

The metabolic reprogramming that promotes tumorigenesis in glioblastoma is induced by dynamic alterations in the hypoxic tumor microenvironment, as well as in transcriptional and signaling networks, which result in changes in global genetic expression. The signaling pathways PI3K/AKT/mTOR and RAS/RAF/MEK/ERK stimulate cell metabolism, either directly or indirectly, by modulating the transcriptional factors p53, HIF1, and c-Myc. The overexpression of HIF1 and c-Myc, master regulators of cellular metabolism, is a key contributor to the synthesis of bioenergetic molecules that mediate glioma cell transformation, proliferation, survival, migration, and invasion by modifying the transcription levels of key gene groups involved in metabolism.

Role of Glycolytic and Glutamine Metabolism Reprogramming on the Proliferation, Invasion, and Apoptosis Resistance through Modulation of Signaling Pathways in Glioblastoma.

Glioma cells exhibit genetic and metabolic alterations that affect the deregulation of several cellular signal transduction pathways, including those related to glucose metabolism. Moreover, oncogenic signaling pathways induce the expression of metabolic genes, increasing the metabolic enzyme activities and thus the critical biosynthetic pathways to generate nucleotides, amino acids, and fatty acids, which provide energy and metabolic intermediates that are essential to accomplish the biosynthetic needs of glioma cells. In this review, we aim to explore how dysregulated metabolic enzymes and their metabolites from primary metabolism pathways in glioblastoma (GBM) such as glycolysis and glutaminolysis modulate anabolic and catabolic metabolic pathways as well as pro-oncogenic signaling and contribute to the formation, survival, growth, and malignancy of glioma cells.

Transsulfuration pathway: a targeting neuromodulator in Parkinson's disease.

The transsulfuration pathway (TSP) is a metabolic pathway involving sulfur transfer from homocysteine to cysteine. Transsulfuration pathway leads to many sulfur metabolites, principally glutathione, HS, taurine, and cysteine. Key enzymes of the TSP, such as cystathionine β-synthase and cystathionine γ-lyase, are essential regulators at multiple levels in this pathway.

Hypoxia as a Modulator of Inflammation and Immune Response in Cancer.

A clear association between hypoxia and cancer has heretofore been established; however, it has not been completely developed. In this sense, the understanding of the tumoral microenvironment is critical to dissect the complexity of cancer, including the reduction in oxygen distribution inside the tumoral mass, defined as tumoral hypoxia. Moreover, hypoxia not only influences the tumoral cells but also the surrounding cells, including those related to the inflammatory processes.

Crosstalk of the Wnt/β-Catenin Signaling Pathway in the Induction of Apoptosis on Cancer Cells.

The Wnt/β-catenin signaling pathway plays a major role in cell survival and proliferation, as well as in angiogenesis, migration, invasion, metastasis, and stem cell renewal in various cancer types. However, the modulation (either up- or downregulation) of this pathway can inhibit cell proliferation and apoptosis both through β-catenin-dependent and independent mechanisms, and by crosstalk with other signaling pathways in a wide range of malignant tumors. Existing studies have reported conflicting results, indicating that the Wnt signaling can have both oncogenic and tumor-suppressing roles, depending on the cellular context.

Anti-proliferative, pro-apoptotic and anti-invasive effect of the copper coordination compound Cas III-La through the induction of reactive oxygen species and regulation of Wnt/β-catenin pathway in glioma.

Gliomas are the most aggressive neoplasms that affect the central nervous system, being glioblastoma multiforme (GBM) the most malignant. The resistance of GBM to therapies is attributed to its high rate of cell proliferation, angiogenesis, invasion, and resistance to apoptosis; thus, finding alternative therapeutic approaches is vital. In this work, the anti-proliferative, pro-apoptotic, and anti-invasive effect of the copper coordination compound Casiopeina III-La (Cas III-La) on human U373 MG cells was determined and .

Autophagy as a Potential Therapy for Malignant Glioma.

Glioma is the most frequent and aggressive type of brain neoplasm, being anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), its most malignant forms. The survival rate in patients with these neoplasms is 15 months after diagnosis, despite a diversity of treatments, including surgery, radiation, chemotherapy, and immunotherapy. The resistance of GBM to various therapies is due to a highly mutated genome; these genetic changes induce a de-regulation of several signaling pathways and result in higher cell proliferation rates, angiogenesis, invasion, and a marked resistance to apoptosis; this latter trait is a hallmark of highly invasive tumor cells, such as glioma cells.

Role of Epstein-Barr Virus in Glioblastoma.

Gliomas are the most common and most lethal primary malignant adult brain tumors, and glioblastomas are the most frequent. Several risk factors are involved in their pathogenesis; these include environmental factors as well as host factors. The etiology of most gliomas remains unknown.

Autophagic and Apoptotic Pathways as Targets for Chemotherapy in Glioblastoma.

Glioblastoma multiforme is the most malignant and aggressive type of brain tumor, with a mean life expectancy of less than 15 months. This is due in part to the high resistance to apoptosis and moderate resistant to autophagic cell death in glioblastoma cells, and to the poor therapeutic response to conventional therapies. Autophagic cell death represents an alternative mechanism to overcome the resistance of glioblastoma to pro-apoptosis-related therapies.

Increase Signaling of Wnt/β-Catenin Pathway and Presence of Apoptosis in Cerebellum of Kindled Rats.

Background: Epilepsy is one of the most common neurological disorders in humans, and the role of the cerebellum in its physiopathology remains the subject of study. The Purkinje cells (PC), whose axons target the dentate and interpositus nuclei, form the main cerebellar output to forebrain structures involved in epilepsy. Cerebellar atrophy related to loss of PC has been reported in chronic epilepsy although its mechanism remains unclear.

In vitro evaluation of apoptotic effect of bis(acetylacetonato-k O,O')(1,10-phenanthroline-k N,N')Zn(II) complex.

Phenanthroline derivatives have been reported as potential bioactive compounds because of their ability to interact with DNA. To evaluate the antiproliferative effect of bis(acetylacetonate-k O,O)(1,10-phenanthroline-k N,N)Zn(II) or Zn(acac) (phen) complex, the compound was obtained in a simple manner and further characterized to determine crystal structure, thermal behavior, morphology, and spectroscopic properties. The structure of the complex was confirmed by X-ray single structure as well as by 1H and 13C nuclear magnetic resonance (NMR) in dmso-d6 (dimethyl sulfoxide) solution and in the solid state by 13C CP/MAS.

Decreased Expression of Sox-1 in Cerebellum of Rat with Generalized Seizures Induced by Kindling Model.

The single feature of all malformations in cortical development is the clinical association with epilepsy. It has been proven that Sox-1 expression is essential during neurodevelopment and it is reported that Sox-1 knockout mice present spontaneous generalized seizures. Particularly in cerebellum, Sox-1 plays a key role in the Bergmann´s glia (BG) function, which allows the correct function of the Purkinje cells (PC).

Anti-apoptotic, anti-oxidant, and anti-inflammatory effects of thalidomide on cerebral ischemia/reperfusion injury in rats.

Thalidomide has shown protective effects in different models of ischemia/reperfusion damage. To elucidate the mechanisms of such protection, this study assessed the effects of thalidomide on the oxidative stress and inflammatory response induced by ischemia/reperfusion episodes in rats. Rats underwent middle cerebral artery occlusion (MCAO) for 2hours.

Neuroprotective effect of thalidomide on MPTP-induced toxicity.

Thalidomide is a sedative with unique pharmacological properties; studies on epilepsy and brain ischemia have shown intense neuroprotective effects. We analyzed the effect of thalidomide treatment on the neurotoxicity caused by the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahidropyridine (MPTP) in mice. Thalidomide was administered at two times; before and after the exposure to MPTP.

Antioxidant properties of xanthones from Calophyllum brasiliense: prevention of oxidative damage induced by FeSO₄.

Background: Reactive oxygen species (ROS) are important mediators in a number of degenerative diseases. Oxidative stress refers to the imbalance between the production of ROS and the ability to scavenge these species through endogenous antioxidant systems. Since antioxidants can inhibit oxidative processes, it becomes relevant to describe natural compounds with antioxidant properties which may be designed as therapies to decrease oxidative damage and stimulate endogenous cytoprotective systems.

Antiapoptotic Effects of EGb 761.

Ginkgo biloba extracts have long been used in Chinese traditional medicine for hundreds of years. The most significant extract obtained from Ginkgo biloba leaves has been EGb 761, a widely used phytopharmaceutical product in Europe. EGb 761 is a well-defined mixture of active compounds, which contains two main active substances: flavonoid glycosides (24-26%) and terpene lactones (6-8%).

Multiple molecular and cellular mechanisms of action of lycopene in cancer inhibition.

Epidemiological studies suggest that including fruits, vegetables, and whole grains in regular dietary intake might prevent and reverse cellular carcinogenesis, reducing the incidence of primary tumours. Bioactive components present in food can simultaneously modulate more than one carcinogenic process, including cancer metabolism, hormonal balance, transcriptional activity, cell-cycle control, apoptosis, inflammation, angiogenesis and metastasis. Some studies have shown an inverse correlation between a diet rich in fruits, vegetables, and carotenoids and a low incidence of different types of cancer.

Copper compound induces autophagy and apoptosis of glioma cells by reactive oxygen species and JNK activation.

Background: Glioblastoma multiforme (GBM) is the most aggressive of the primary brain tumors, with a grim prognosis despite intensive treatment. In the past decades, progress in research has not significantly increased overall survival rate.

Methods: The in vitro antineoplastic effect and mechanism of action of Casiopeina III-ia (Cas III-ia), a copper compound, on rat malignant glioma C6 cells was investigated.

Co-carcinogenic effect of cyclohexanol on the development of preneoplastic lesions in a rat hepatocarcinogenesis model.

Cyclohexanol is a basic industrial chemical widely used because of its versatility as an industrial solvent. No studies have been conducted to evaluate the carcinogenic/co-carcinogenic hazards associated with cyclohexanol exposure. In male Fisher 344 rats liver preneoplastic lesions were induced by N-nitrosodiethylamine (150 mg/Kg) i.

Casiopeina III-ia induces apoptosis in HCT-15 cells in vitro through caspase-dependent mechanisms and has antitumor effect in vivo.

The aim of this study was to evaluate the in vitro and in vivo effects of the new chemotherapy agent Casiopeina III-ia [(4,4'-dimethyl-2,2'-bipiridine)(acetylacetonate) Copper (II) nitrate] on HCT-15 (p53-/-) colon cellular line. In vitro, the drug reduced the viability and induced necrosis and apoptosis in a dose dependent manner, without affecting cell cycle phases. Apoptosis was related to Bax increasing levels, suggesting a caspase-dependent mechanism of death, as verified by nucleosomal fragmentation of DNA.

S-adenosyl-methionine decreases ethanol-induced apoptosis in primary hepatocyte cultures by a c-Jun N-terminal kinase activity-independent mechanism.

Aim: To determine the role of c-Jun N-terminal kinase (JNK) activity in ethanol-induced apoptosis and the modulation of this signaling cascade by S-Adenosyl-methionine (AdoMet).

Methods: Primary hepatocyte cultures were pretreated with 100 micromol/L SP600125, a selective JNK inhibitor, 1 mL/L DMSO or 4 mmol/L AdoMet and then exposed to 100 mmo/L ethanol. Hepatocyte apoptosis was determined by the TUNEL and DNA ladder assays.

Cas IIgly induces apoptosis in glioma C6 cells in vitro and in vivo through caspase-dependent and caspase-independent mechanisms.

In this work, we investigated the effects of Casiopeina II-gly (Cas IIgly)--a new copper compound exhibiting antineoplastic activity--on glioma C6 cells under both in vitro and in vivo conditions, as an approach to identify potential therapeutic agents against malignant glioma. The exposure of C6 cells to Cas IIgly significantly inhibited cell proliferation, increased reactive oxygen species (ROS) formation, and induced apoptosis in a dose-dependent manner. In cultured C6 cells, Cas IIgly caused mitochondrio-nuclear translocation of apoptosis induction factor (AIF) and endonuclease G at all concentrations tested; in contrast, fragmentation of nucleosomal DNA, cytochrome c release, and caspase-3 activation were observed at high concentrations.

Inhibitory effect of vitamin e administration on the progression of liver regeneration induced by partial hepatectomy in rats.

We have proposed that controlled peroxidative modifications of membranes could be playing a role in the early steps of liver regeneration. Hence, lipid peroxidation (LP) was modified in vivo by treatment with vitamin E in rats subjected to partial hepatectomy (PH), and its influence on liver regeneration was evaluated. Our results, using several methods to monitor LP, indicate that vitamin E administration promoted a decreased LP rate in liver subcellular membranes.