scholarly journals Glucose-6-Phosphate Dehydrogenase of Trypanosomatids: Characterization, Target Validation, and Drug Discovery

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Shreedhara Gupta ◽  
Mariana Igoillo-Esteve ◽  
Paul A. M. Michels ◽  
Artur T. Cordeiro
Keyword(s):  
Oxidative Stress ◽  
Enzyme Activity ◽  
Trypanosoma Brucei ◽  
Redox State ◽  
Chemotherapeutic Agents ◽  
Dependent Manner ◽  
Target Validation ◽  
Leishmania Mexicana ◽  
State Dependent ◽  
Glucose 6 Phosphate Dehydrogenase

In trypanosomatids, glucose-6-phosphate dehydrogenase (G6PDH), the first enzyme of the pentosephosphate pathway, is essential for the defense of the parasite against oxidative stress. Trypanosoma brucei, Trypanosoma cruzi, and Leishmania mexicana G6PDHs have been characterized. The parasites' G6PDHs contain a unique 37 amino acid long N-terminal extension that in T. cruzi seems to regulate the enzyme activity in a redox-state-dependent manner. T. brucei and T. cruzi G6PDHs, but not their Leishmania spp. counterpart, are inhibited, in an uncompetitive way, by steroids such as dehydroepiandrosterone and derivatives. The Trypanosoma enzymes are more susceptible to inhibition by these compounds than the human G6PDH. The steroids also effectively kill cultured trypanosomes but not Leishmania and are presently considered as promising leads for the development of new parasite-selective chemotherapeutic agents.

scholarly journals Human Proximal Tubule Epithelial Cells (HK-2) as a Sensitive In Vitro System for Ochratoxin A Induced Oxidative Stress

Toxins ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 787
Author(s):  
Enrique García-Pérez ◽  
Dojin Ryu ◽  
Hwa-Young Kim ◽  
Hae Dun Kim ◽  
Hyun Jung Lee
Keyword(s):  
Oxidative Stress ◽  
Ochratoxin A ◽  
Cell Lines ◽  
Time Dependent ◽  
Mrna Levels ◽  
Dependent Manner ◽  
In Vitro System ◽  
Glutathione Peroxidase 1 ◽  
Glucose 6 Phosphate Dehydrogenase

Ochratoxin A (OTA) is a mycotoxin that is potentially carcinogenic to humans. Although its mechanism remains unclear, oxidative stress has been recognized as a plausible cause for the potent renal carcinogenicity observed in experimental animals. The effect of OTA on oxidative stress parameters in two cell lines of LLC-PK1 and HK-2 derived from the kidneys of pig and human, respectively, were investigated and compared. We found that the cytotoxicity of OTA on LLC-PK1 and HK-2 cells was dose- and time-dependent in both cell lines. Furthermore, increased intracellular reactive oxygen species (ROS) induced by OTA in both cell lines were observed in a time-dependent manner. Glutathione (GSH) was depleted by OTA at >48 h in HK-2 but not in LLC-PK1 cells. While the mRNA levels of glucose-6-phosphate dehydrogenase (G6PD) and glutathione peroxidase 1 (GPX1) in LLC-PK1 were down-regulated by 0.67- and 0.66-fold, respectively, those of catalase (CAT), glutathione reductase (GSR), and superoxide dismutase 1 (SOD) in HK-2 were up-regulated by 2.20-, 2.24-, and 2.75-fold, respectively, after 72 h exposure to OTA. Based on these results, we conclude that HK-2 cells are more sensitive to OTA-mediated toxicity than LLC-PK1, and OTA can cause a significant oxidative stress in HK-2 as indicated by changes in the parameter evaluated.

Efficacy of Alpha-Lipoic Acid in Iron-Induced Oxidative Stress.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3599-3599
Author(s):  
Ashutosh Lal ◽  
Jung H. Suh ◽  
Bruce N. Ames
Keyword(s):  
Oxidative Stress ◽  
Iron Overload ◽  
Lipoic Acid ◽  
Iron Content ◽  
Redox State ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Dependent Manner ◽  
Intracellular Iron ◽  
Dose Dependent

Abstract Antioxidant supplementation could reduce organ damage and premature death in patients with iron overload. We evaluated the improvement in iron-induced oxidative stress with α-Lipoic acid (LA), a multifunctional thiol antioxidant and inducer of phase II enzymes, and compared it with benzylhydroxylamine (BH), a reducing agent that protects against free radicals. Human fibroblasts (IMR-90) were grown in regular cell culture medium or with ferric ammonium citrate (FAC). The intracellular iron content was measured by inductively-coupled plasma spectrometry (ICP). Either LA or BH was added on day 2, and cells grown to confluence. Oxidative stress was assessed by dichlorodihydrofluorescein diacetate fluorescence (DCF-fl). GSH:GSSG was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The total intracellular iron content (mean±SEM, ng per 5x10^6 cells) increased from 66.95±6.51 in control cells to 262.26±4.69 after exposure to 25 μM FAC, and 556.26±21.15 after exposure to 125 μM FAC. The increase in iron-content of the IMR-90 fibroblasts caused significant rise in oxidant appearance at the highest concentration, as evidenced by 27.8±2.6% increase in steady-state DCF-fl compared with control cells (p <.001). Addition of increasing concentrations of LA attenuated iron-mediated rise in DCF-fl in dose dependent manner. LA at concentrations above 25 μM completely abolished the iron-dependent rise in DCF-fl (91.9±2.3% for FAC+LA, p <.001). BH treated cells also exhibited a dose-dependent decrease in DCF-fl, but a much higher concentration (>200 μM) was needed for complete attenuation of iron-induced rise in DCF-fl (108.3±3.4%, p <.001). These results suggest that LA is more effective than BH in ameliorating iron-mediated increase in oxidative stress. To further understand the basis for the efficacy of LA, intracellular GSH and GSSG were measured. Results show that LA improved the total GSH levels and its redox state in a dose dependent manner. LA and BH attenuated iron-mediated oxidant production, with LA exhibiting greater efficacy. This effect may be due to potent ability of LA to improve intracellular GSH levels and redox state. Our results suggest LA may be useful in reducing complications from iron overload.

scholarly journals Redox-coupled quinone dynamics in the respiratory complex I

2018 ◽  
Vol 115 (36) ◽  
pp. E8413-E8420 ◽  
Author(s):  
Judith Warnau ◽  
Vivek Sharma ◽  
Ana P. Gamiz-Hernandez ◽  
Andrea Di Luca ◽  
Outi Haapanen ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Sites ◽  
Complex I ◽  
Redox State ◽  
Effective Diffusion ◽  
Proton Pumping ◽  
Free Energy Calculations ◽  
Dependent Manner ◽  
Membrane Domain ◽  
State Dependent

Complex I couples the free energy released from quinone (Q) reduction to pump protons across the biological membrane in the respiratory chains of mitochondria and many bacteria. The Q reduction site is separated by a large distance from the proton-pumping membrane domain. To address the molecular mechanism of this long-range proton-electron coupling, we perform here full atomistic molecular dynamics simulations, free energy calculations, and continuum electrostatics calculations on complex I from Thermus thermophilus. We show that the dynamics of Q is redox-state-dependent, and that quinol, QH2, moves out of its reduction site and into a site in the Q tunnel that is occupied by a Q analog in a crystal structure of Yarrowia lipolytica. We also identify a second Q-binding site near the opening of the Q tunnel in the membrane domain, where the Q headgroup forms strong interactions with a cluster of aromatic and charged residues, while the Q tail resides in the lipid membrane. We estimate the effective diffusion coefficient of Q in the tunnel, and in turn the characteristic time for Q to reach the active site and for QH2 to escape to the membrane. Our simulations show that Q moves along the Q tunnel in a redox-state-dependent manner, with distinct binding sites formed by conserved residue clusters. The motion of Q to these binding sites is proposed to be coupled to the proton-pumping machinery in complex I.

scholarly journals Antioxidative Potential of Garlic on Lead-Induced Oxidative Stress and Effect on Enzyme Activity in Rice Plants

2018 ◽  
pp. 79-83
Author(s):  
Tugbobo Oladimeji S ◽  
Idowu Kayode S ◽  
Ajao Oluwaseyi I
Keyword(s):  
Oxidative Stress ◽  
Enzyme Activity ◽  
Antioxidant Enzymes ◽  
Lead Acetate ◽  
Lipid Peroxides ◽  
Garlic Extract ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Rice Plants ◽  
Antioxidant Defense Systems

Seedling of Ofada rice (Oryza sativum L) were raised in sand (swampy) and clay (upland) cultures under 500mg/kg lead acetate and 500mg/kg garlic aqueous extract for 40-days. The uptake and distribution pattern of lead with possible induction of oxidative stress and likely alteration in the inherent antioxidant defense systems of the rice plants were determined. The inhibitory potential of garlic against lead-induced oxidative stress in rice seedling was also assessed. From the results, rice seedlings grown for 10-40 days under 500mg/kg lead acetate showed significant (P<0.05) increase in level of lipid peroxides in roots, indicating enhanced lipid peroxidation compared to control. However, incubation of garlic extract with supernatants of rice root and shoot caused a significant (P<0.05) reduction in the accumulation of lipid peroxides in a concentration dependent manner. In addition, there was a marked increase in antioxidant enzymes activities in lead acetate treated seedlings, where the shoot maintained higher defensive enzyme activity than roots. The results suggest that lead-induced oxidative stress could be salvaged by garlic extract and antioxidant enzymes are biomarkers for lead-induced oxidative injury in rice plants.

scholarly journals Benzo[b]thiophenesulphonamide 1,1-dioxide derivatives inhibit tNOX activity in a redox state-dependent manner

2005 ◽  
Vol 92 (4) ◽  
pp. 690-695 ◽  
Author(s):  
I Encío ◽  
D J Morré ◽  
R Villar ◽  
M J Gil ◽  
V Martínez-Merino
Keyword(s):  
Redox State ◽  
Dependent Manner ◽  
State Dependent

Hybrid Compounds & Oxidative Stress Induced Apoptosis in Cancer Therapy

2020 ◽  
Vol 27 (13) ◽  
pp. 2118-2132 ◽  
Author(s):  
Aysegul Hanikoglu ◽  
Hakan Ozben ◽  
Ferhat Hanikoglu ◽  
Tomris Ozben
Keyword(s):  
Oxidative Stress ◽  
Drug Resistance ◽  
Side Effects ◽  
Cancer Therapy ◽  
Tumor Cells ◽  
Anticancer Drugs ◽  
Chemotherapeutic Agents ◽  
Oxidation Reactions ◽  
Hybrid Compounds ◽  
Induced Apoptosis

: Elevated Reactive Oxygen Species (ROS) generated by the conventional cancer therapies and the endogenous production of ROS have been observed in various types of cancers. In contrast to the harmful effects of oxidative stress in different pathologies other than cancer, ROS can speed anti-tumorigenic signaling and cause apoptosis of tumor cells via oxidative stress as demonstrated in several studies. The primary actions of antioxidants in cells are to provide a redox balance between reduction-oxidation reactions. Antioxidants in tumor cells can scavenge excess ROS, causing resistance to ROS induced apoptosis. Various chemotherapeutic drugs, in their clinical use, have evoked drug resistance and serious side effects. Consequently, drugs having single-targets are not able to provide an effective cancer therapy. Recently, developed hybrid anticancer drugs promise great therapeutic advantages due to their capacity to overcome the limitations encountered with conventional chemotherapeutic agents. Hybrid compounds have advantages in comparison to the single cancer drugs which have usually low solubility, adverse side effects, and drug resistance. This review addresses two important treatments strategies in cancer therapy: oxidative stress induced apoptosis and hybrid anticancer drugs.

Non-canonical Functions of Telomerase Reverse Transcriptase: Emerging Roles and Biological Relevance

2020 ◽  
Vol 20 (6) ◽  
pp. 498-507 ◽  
Author(s):  
Connor A.H. Thompson ◽  
Judy M.Y. Wong
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Reverse Transcriptase ◽  
Cancer Cells ◽  
Telomere Length ◽  
Telomere Maintenance ◽  
Telomerase Reverse Transcriptase ◽  
Alternative Mechanism ◽  
Dependent Manner ◽  
Mitochondrial Integrity

Increasing evidence from research on telomerase suggests that in addition to its catalytic telomere repeat synthesis activity, telomerase may have other biologically important functions. The canonical roles of telomerase are at the telomere ends where they elongate telomeres and maintain genomic stability and cellular lifespan. The catalytic protein component Telomerase Reverse Transcriptase (TERT) is preferentially expressed at high levels in cancer cells despite the existence of an alternative mechanism for telomere maintenance (alternative lengthening of telomeres or ALT). TERT is also expressed at higher levels than necessary for maintaining functional telomere length, suggesting other possible adaptive functions. Emerging non-canonical roles of TERT include regulation of non-telomeric DNA damage responses, promotion of cell growth and proliferation, acceleration of cell cycle kinetics, and control of mitochondrial integrity following oxidative stress. Non-canonical activities of TERT primarily show cellular protective effects, and nuclear TERT has been shown to protect against cell death following double-stranded DNA damage, independent of its role in telomere length maintenance. TERT has been suggested to act as a chromatin modulator and participate in the transcriptional regulation of gene expression. TERT has also been reported to regulate transcript levels through an RNA-dependent RNA Polymerase (RdRP) activity and produce siRNAs in a Dicer-dependent manner. At the mitochondria, TERT is suggested to protect against oxidative stress-induced mtDNA damage and promote mitochondrial integrity. These extra-telomeric functions of TERT may be advantageous in the context of increased proliferation and metabolic stress often found in rapidly-dividing cancer cells. Understanding the spectrum of non-canonical functions of telomerase may have important implications for the rational design of anti-cancer chemotherapeutic drugs.

Combination of Histone Deacetylase Inhibitor with Cu(II) 5,5- diethylbarbiturate Complex Induces Apoptosis in Breast Cancer Stem Cells: A Promising Novel Approach

2020 ◽  
Vol 21 ◽  
Author(s):  
Merve Erkisa ◽  
Nazlihan Aztopal ◽  
Elif Erturk ◽  
Engin Ulukaya ◽  
Veysel T. Yilmaz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Histone Deacetylases ◽  
Caspase 3 ◽  
Cancer Cell Line ◽  
Annexin V ◽  
Tumor Formation ◽  
Dependent Manner

Background: Cancer stem cells (CSC) are subpopulation within the tumor that acts a part in the initiation, progression, recurrence, resistance to drugs and metastasis of cancer. It is well known that epigenetic changes lead to tumor formation in cancer stem cells and show drug resistance. Epigenetic modulators and /or their combination with different agents have been used in cancer therapy. Objective: In our study we scope out the effects of combination of a histone deacetylases inhibitor, valproic acid (VPA), and Cu(II) complex [Cu(barb-κN)(barb-κ2N,O)(phen-κN,N’)]·H2O] on cytotoxicity/apoptosis in a stem-cell enriched population (MCF-7s) obtained from parental breast cancer cell line (MCF-7). Methods: Viability of the cells was measured by the ATP assay. Apoptosis was elucidated via the assessment of caspase-cleaved cytokeratin 18 (M30 ELISA) and a group of flow cytometry analysis (caspase 3/7 activity, phosphatidylserine translocation by annexin V-FITC assay, DNA damage and oxidative stress) and 2ˈ,7ˈ–dichlorofluorescein diacetate staining. Results: The VPA combined with Cu(II) complex showed anti proliferative activity on MCF-7s cells in a dose- and time-dependently. Treatment with combination of 2.5 mM VPA and 3.12 μM Cu(II) complex induces oxidative stress in a time-dependent manner, as well as apoptosis that is evidenced by the increase in caspase 3/7 activity, positive annexin-V-FITC, and increase in M30 levels. Conclusion: The results suggest that the combination therapy induces apoptosis following increased oxidative stress, thereby making it a possible promising therapeutic strategy that further analysis is required.

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