450 research outputs found
Potential applications of NRF2 inhibitors in cancer therapy
No full textThe NRF2/KEAP1 pathway represents one of the most important cell defense mechanisms against exogenous or endogenous stressors. Indeed, by increasing the expression of several cytoprotective genes, the transcription factor NRF2 can shelter cells and tissues from multiple sources of damage including xenobiotic, electrophilic, metabolic, and oxidative stress. Importantly, the aberrant activation or accumulation of NRF2, a common event in many tumors, confers a selective advantage to cancer cells and is associated to malignant progression, therapy resistance, and poor prognosis. Hence, in the last years, NRF2 has emerged as a promising target in cancer treatment and many efforts have been made to identify therapeutic strategies aimed at disrupting its prooncogenic role. By summarizing the results from past and recent studies, in this review, we provide an overview concerning the NRF2/KEAP1 pathway, its biological impact in solid and hematologic malignancies, and the molecular mechanisms causing NRF2 hyperactivation in cancer cells. Finally, we also describe some of the most promising therapeutic approaches that have been successfully employed to counteract NRF2 activity in tumors, with a particular emphasis on the development of natural compounds and the adoption of drug repurposing strategies
Controversy about pharmacological modulation of Nrf2 for cancer therapy
No full textConventional anticancer therapies such as radiotherapy and chemotherapies are associated with oxidative stress generating reactive oxygen species (ROS) and reactive aldehydes like 4-hydroxynonenal in cancer cells that govern them to die. The main mechanism activated due to exposure of the cell to these reactive species is the Nrf2-Keap1 pathway. Although Nrf2 was firstly perceived as a tumor suppressor that inhibits tumor initiation and cancer metastasis, more recent data reveal its role also as a pro-oncogenic factor. Discovery of the upregulation of Nrf2 in different types of cancer supports such undesirable pathophysiological roles of Nrf2. The upregulation of Nrf2 leads to activation of cytoprotective genes thus helping malignant cells to withstand high levels of ROS and to avoid apoptosis, eventually becoming resistant to conventional anticancer therapy. Therefore, new treatment strategies are needed for eradication of cancer and in this review, we will explore two opposing approaches for modulation of Nrf2 in cancer treatments. Keywords: Cancer, Nrf2, Oxidative stress, Cancer therapy, Growth regulation, 4-hydroxynonena
In vitro interaction of 5‐aminoorotic acid and its gallium(III) complex with superoxide radical, generated by two model systems
No full textIncreased levels of the superoxide radical are associated with oxidative damage to healthy tissues and with elimination of malignant cells in a living body. It is desirable that a chemotherapeutic combines pro‐oxidant behavior around and inside tumors with antioxidant action near healthy cells. A complex consisting of a pro‐oxidant cation and antioxidant ligands could be a potential anticancer agent. Ga(III) salts are known anticancer substances, and 5‐aminoorotic acid (HAOA) is a ligand with antioxidant properties. The in vitro effects of HAOA and its complex with Ga(III) (gallium(III) 5‐aminoorotate (GaAOA)) on the in vitro accumulation of superoxide and other free radicals were estimated. Model systems such as potassium superoxide (KO2), xanthine/xanthine oxidase (X/XO), and rat blood serum were utilized. Data suggested better antioxidant effect of GaAOA compared to HAOA. Evidently, all three ligands of GaAOA participated in the scavenging of superoxide. The effects in rat blood serum were more nuanced, considering the chemical and biochemical complexity of this model system. It was observed that the free‐radical‐scavenging action of both compounds investigated may be manifested via both hydrogen donation and electron transfer pathways. It was proposed that the radical‐scavenging activities (RSAs) of HAOA and its complex with Ga(III) may be due to a complex process, depending on the concentration, and on the environment, nature, and size of the free radical. The electron transfer pathway was considered as more probable in comparison to hydrogen donation in the scavenging of superoxide by 5‐aminoorotic acid and its gallium(III) complex
Pharmacological applications of Nrf2 inhibitors as potential antineoplastic drugs
No full textOxidative stress (OS) is associated with many diseases ranging from cancer to neurodegenerative disorders. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is one of the most effective cytoprotective controller against OS. Modulation of Nrf2 pathway constitutes a remarkable strategy in the antineoplastic treatments. A big number of Nrf2-antioxidant response element activators have been screened for use as chemo-preventive drugs in OS associated diseases like cancer even though activation of Nrf2 happens in a variety of cancers. Research proved that hyperactivation of the Nrf2 pathway produces a situation that helps the survival of normal as well as malignant cells, protecting them against OS, anticancer drugs, and radiotherapy. In this review, the modulation of the Nrf2 pathway, anticancer activity and challenges associated with the development of an Nrf2-based anti-cancer treatment approaches are discussed. © 2019 by the authors. Licensee MDPI, Basel, Switzerland
Effect of selected substances on heat-induced aggregation of albumin, IgG and lysozyme
No full textCompounds capable of inhibiting protein aggregation may find pharmacological applications in the treatment of a number of diseases called protein condensation diseases [Benedek (1997)], which include cataract, biliary and urinary lithiasis and certain rheumatic diseases. We examined the effect of selected compounds on heat-induced aggregation human serum albumin (HSA), IgG and lysozyme. HSA (0.2% w/v in 0.066 M sodium phosphate pH 5.3 at 22 degrees C), IgG (0.5% w/v in 0.066 M Tris pH 8.0 at 22 degrees C), and L (0.2 % w/v in 0.066 M CAPS pH 11.0 at 22 degrees C) were heated for 30 min at 70 degrees C in the presence or absence of different concentrations of the substance under examination and heat-induced aggregation of 100 microl aliquots was evaluated by measuring the absorbance at 595 nm using an automatic microplate reader. In these conditions, inhibition of aggregation could be due to an anti-denaturant effect or to interferences with the aggregation of denatured molecules, as previously described [Saso, Casini et al. (1998)]. However, this distinction may not be pharmacologically relevant when the target of the therapy is the prevention of abnormal phenomena of protein aggregation. Inorganic salts like NaCl and CaCl2 were active on the three proteins (IgG > HSA > L) but many ligands of HSA such as tryptophan, N-acetyl-tryptophan, caprylic acid, capric acid, cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid and bendazac were active on their carrier but not on IgG and L, indicating that the latter proteins are more difficult to protect and that specific anti-denaturant and/or anti-aggregant compounds should be developed
Antidenaturant drugs for cataract and other condensation diseases
No full text'Condensation diseases' are heterogeneous pathological conditions in which the primary pathogenetic step is the loss of solubility of specific substances, resulting in the formation of a condensed phase. Typical examples are cataract, nephrolithiasis, gallstone disease and certain rheumatic conditions in which protein denaturation, aggregation and precipitation may occur. Since the condensing molecules are often proteins, antidenaturant agents should be considered rational drugs for the treatment of these diseases. Surprisingly, however, only a few molecules with these properties are currently available for therapeutic use, including bendazac for cataract
Student activism: a comparative analysis between the Student Nonviolent Coordinating Committee (SNCC) and the Student South African Student Organization ( SASO) 1960-1977, 2000
No full textThe main aim of this study is to make comprehensible the actual interactions or connections between the Student Nonviolent Coordinating Committee (SNCC) and the South African Student Organization (SASO) in their black freedom struggle between 1960-1977.The primary focus is on how broadly similar conceptualizations of black liberation by black students were modified or reinterpreted to suit local circumstances, and what occurred when similar ideologies were acted upon under conditions that were in some ways very different. There were cross-cultural links and mutual awareness between the freedom struggle of students in the United States and South Africa. For instance, in their condemnation of apartheid policy in South Africa during 1962, SNCC activists were confronting white power on behalf of black South Africans. In the same vein, SASO activists were inspired by the history of SNCC freedom struggle in the United States. They even employed SNCC and its Black Power language in their formulation of policies and ideology. This ideological congruence between SNCC and SASO manifested itself in a number of instances. First, students in both organizations confronted comparable questions on the methods to be used in their freedom struggle. The alternative in both cases was nonviolent resistance to challenge the status quo, and a revolutionary violence to overthrow the system. Although this similarity, per se, does not tell the whole story, evidence by SASO activists conclusively proves that SASO's moral idealism was largely influenced by SNCC. This is not, however, to suggest that SASO was a carbon copy of SNCC; yet the profound effect of SNCC and its Black Power variant on SASOs particular language and slant must be recognized and acknowledged if the developments of the 1970s are to be understood in the total context of the black south African intellectual struggle. Another issue that arose in the context of students' discussions was the role of whites in the black struggle. In South Africa, this took place under the rubric of Black Consciousness; in the United States it was espoused under the slogan of Black power. How all these common ideological and tactical issues were debated and finally resolved, and how the theoretical and practical results of these deliberations affected the historical trajectory of the respective student struggles, is the main concern of this study
A study of the behaviour of L - Glutamic acid in the course of and after γ - Ray treatment
No full textThe aim of current study is quality control of L - Glutamic acid in supplement mixture before and after treatment with γ - ray. Microbiological methods, included in European Pharmacopoeia were used for examination of microbial purity of substance L - Glutamic acid. Abnormal content (1.5.10 -4 g) of bacteria and contaminants were identified mostly as non patogenic bacilli of Subtilis group. Patogenic contaminants as Enterobacteriaceae and Staphylococcus aureus were not found. Resistency factors show moderate ray sensitivity of the microorganisms. HPLC method was developed and applied and analytical parameters repeatability, limit of detection (LOD), limit of quantitation (LOQ) and linearity were studied and determined in accordance with ICH and European Pharmacopoeia requirements. For repeatability SD = 1.43, RDS = + 0.44. The obtained LOD is 10 μg and LOQ is 40 μg. The correlation coefficients is found to be 0.99746 at SD = + 3914.60 AU. There are no significant difference between content of L - Glutamic acid in supplement mixtures before (RDS = + 0.44 %) and after γ - ray treatment (RDS = + 0.082 %)
Detection of Reactive Oxygen and Nitrogen Species by Electron Paramagnetic Resonance (EPR) Technique
No full textDuring the last decade there has been growing interest in physical-chemical oxidation processes and the behavior of free radicals in living systems. Radicals are known as intermediate species in a variety of biochemical reactions. Numerous techniques, assays and biomarkers have been used to measure reactive oxygen and nitrogen species (ROS and RNS), and to examine oxidative stress. However, many of these assays are not entirely satisfactory or are used inappropriately. The purpose of this chapter is to review current EPR (Electron Paramagnetic Resonance) spectroscopy methods for measuring ROS, RNS, and their secondary products, and to discuss the strengths and limitations of specific methodological approaches
Oxidative Stress: A Key Modulator in Neurodegenerative Diseases
No full textOxidative stress is proposed as a regulatory element in ageing and various neurological disorders. The excess of oxidants causes a reduction of antioxidants, which in turn produce an oxidation–reduction imbalance in organisms. Paucity of the antioxidant system generates oxidative-stress, characterized by elevated levels of reactive species (oxygen, hydroxyl free radical, and so on). Mitochondria play a key role in ATP supply to cells via oxidative phosphorylation, as well as synthesis of essential biological molecules. Various redox reactions catalyzed by enzymes take place in the oxidative phosphorylation process. An inefficient oxidative phosphorylation may generate reactive oxygen species (ROS), leading to mitochondrial dysfunction. Mitochondrial redox metabolism, phospholipid metabolism, and proteolytic pathways are found to be the major and potential source of free radicals. A lower concentration of ROS is essential for normal cellular signaling, whereas the higher concentration and long-time exposure of ROS cause damage to cellular macromolecules such as DNA, lipids and proteins, ultimately resulting in necrosis and apoptotic cell death. Normal and proper functioning of the central nervous system (CNS) is entirely dependent on the chemical integrity of brain. It is well established that the brain consumes a large amount of oxygen and is highly rich in lipid content, becoming prone to oxidative stress. A high consumption of oxygen leads to excessive production of ROS. Apart from this, the neuronal membranes are found to be rich in polyunsaturated fatty acids, which are highly susceptible to ROS. Various neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), among others, can be the result of biochemical alteration (due to oxidative stress) in bimolecular components. There is a need to understand the processes and role of oxidative stress in neurodegenerative diseases. This review is an effort towards improving our understanding of the pivotal role played by OS in neurodegenerative disorders
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