Generation Of Oxidative Stress Research Articles

Palladium hydride nanourchins with amplified photothermal therapeutic effects through controlled hydrogen release and antigen-assisted immune activation

Traditional photothermal therapy (PTT) is still hindered by the high-temperature tolerance caused by heat shock proteins (HSPs) and weak immune responses. Herein, palladium hydride nanourchins (PdHs) are synthesized by a two-step hydrothermal method for photothermal immunotherapy. The prepared PdHs with dendritic urchin structures not only are able to load ovalbumin (OVA) and tumor cells fragments (TF) as antigen with ultra-high efficiency (35.7% and 43.1%), but also present significantly enhanced photothermal conversion efficiency (36%) and hydrogen release under 808 nm laser irradiation. The released hydrogen further induces oxidative stress and intracellular reactive oxygen species (ROS) generation, and hinders mitochondrial respiratory, finally, resulting the down-regulation of HSPs to make cells sensitive to PTT. Additionally, the obtained PdHs-TF nanourchins under 808 nm laser irradiation can inhibit tumor growth more effectively by combining PTT and TF antigens release to induce immunotherapy. This work provided a new pathway for the development of PTT and multifunctional applications of palladium nanoparticles in tumor therapy.

Multicentric Standardization of Protocols for the Diagnosis of Human Mitochondrial Respiratory Chain Defects.

The quantification of mitochondrial respiratory chain (MRC) enzymatic activities is essential for diagnosis of a wide range of mitochondrial diseases, ranging from inherited defects to secondary dysfunctions. MRC lesion is frequently linked to extended cell damage through the generation of proton leak or oxidative stress, threatening organ viability and patient health. However, the intrinsic challenge of a methodological setup and the high variability in measuring MRC enzymatic activities represents a major obstacle for comparative analysis amongst institutions. To improve experimental and statistical robustness, seven Spanish centers with extensive experience in mitochondrial research and diagnosis joined to standardize common protocols for spectrophotometric MRC enzymatic measurements using minimum amounts of sample. Herein, we present the detailed protocols, reference ranges, tips and troubleshooting methods for experimental and analytical setups in different sample preparations and tissues that will allow an international standardization of common protocols for the diagnosis of MRC defects. Methodological standardization is a crucial step to obtain comparable reference ranges and international standards for laboratory assays to set the path for further diagnosis and research in the field of mitochondrial diseases.

Co-treatment with vactosertib, a novel, orally bioavailable activin receptor-like kinase 5 inhibitor, suppresses radiotherapy-induced epithelial-to-mesenchymal transition, cancer cell stemness, and lung metastasis of breast cancer.

BackgroundAcquired metastasis and invasion of cancer cells during radiotherapy are in part due to induction of epithelial-to-mesenchymal transition (EMT) and cancer stem cell (CSC) properties, which are mediated by TGF-β signaling. Here we evaluated the anti-metastatic therapeutic potential of vactosertib, an orally bioavailable TGF-β type I receptor (activin receptor-like kinase 5, ALK5) inhibitor, via suppression of radiation-induced EMT and CSC properties, oxidative stress generation, and breast to lung metastasis in a breast cancer mouse model and breast cancer cell lines.Materials and methodsCo-treatment of vactosertib with radiation was investigated in the 4T1-Luc allografted BALB/c syngeneic mouse model and in 4T1-Luc and MDA-MB-231 cells. The anti-metastatic therapeutic potential of vactosertib in breast cancer was investigated using fluorescence immunohistochemistry, real-time quantitative reverse transcription-polymerase chain reaction, western blotting, wound healing assay, mammosphere formation assay, and lung metastasis analysis in vitro and in vivo.ResultsRadiation induced TGF-β signaling, EMT markers (Vimentin, Fibronectin, Snail, Slug, Twist, and N-cadherin), CSC properties (expression of pluripotent stem cell regulators, mammosphere forming ability), reactive oxygen species markers (NOX4, 4-HNE), and motility of breast cancer cells in vitro and in vivo. Vactosertib attenuated the radiation-induced EMT and CSC properties by inhibiting ROS stress in breast cancer. Moreover, vactosertib combined with radiation showed a significant anti-metastatic effect with suppression of breast to lung metastasis in vivo.ConclusionsThese results indicate that inhibition of TGF-β signaling with vactosertib in breast cancer patients undergoing radiotherapy would be an attractive strategy for the prevention of cancer metastasis and recurrence.

Lack of Functional Trehalase Activity in Candida parapsilosis Increases Susceptibility to Itraconazole.

Central metabolic pathways may play a major role in the virulence of pathogenic fungi. Here, we have investigated the susceptibility of a Candida parapsilosis mutant deficient in trehalase activity (atc1Δ/ntc1Δ strain) to the azolic compounds fluconazole and itraconazole. A time-course exposure to itraconazole but not fluconazole induced a significant degree of cell killing in mutant cells compared to the parental strain. Flow cytometry determinations indicated that itraconazole was able to induce a marked production of endogenous ROS together with a simultaneous increase in membrane potential, these effects being irrelevant after fluconazole addition. Furthermore, only itraconazole induced a significant synthesis of endogenous trehalose. The recorded impaired capacity of mutant cells to produce structured biofilms was further increased in the presence of both azoles, with itraconazole being more effective than fluconazole. Our results in the opportunistic pathogen yeast C. parapsilosis reinforce the study of trehalose metabolism as an attractive therapeutic target and allow extending the hypothesis that the generation of internal oxidative stress may be a component of the antifungal action exerted by the compounds currently available in medical practice.

Effect of Fe3+ on Na,K-ATPase: Unexpected activation of ATP hydrolysis.

Iron is a key element in cell function; however, its excess in iron overload conditions can be harmful through the generation of reactive oxygen species (ROS) and cell oxidative stress. Activity of Na,K-ATPase has been shown to be implicated in cellular iron uptake and iron modulates the Na,K-ATPase function from different tissues. In this study, we determined the effect of iron overload on Na,K-ATPase activity and established the role that isoforms and conformational states of this enzyme has on this effect. Total blood and membrane preparations from erythrocytes (ghost cells), as well as pig kidney and rat brain cortex, and enterocytes cells (Caco-2) were used. In E1-related subconformations, an enzyme activation effect by iron was observed, and in the E2-related subconformations enzyme inhibition was observed. The enzyme's kinetic parameters were significantly changed only in the Na+ curve in ghost cells. In contrast to Na,K-ATPase α2 and α3 isoforms, activation was not observed for the α1 isoform. In Caco-2 cells, which only contain Na,K-ATPase α1 isoform, the FeCl3 increased the intracellular storage of iron, catalase activity, the production of H2O2 and the expression levels of the α1 isoform. In contrast, iron did not affect lipid peroxidation, GSH content, superoxide dismutase and Na,K-ATPase activities. These results suggest that iron itself modulates Na,K-ATPase and that one or more E1-related subconformations seems to be determinant for the sensitivity of iron modulation through a mechanism in which the involvement of the Na, K-ATPase α3 isoform needs to be further investigated.

The linkage between mercury-caused neuro- and genotoxicity via the inhibition of DNA repair machinery: fish brain model

Heavy metals in model conditions as well as industrial pollution launch disturbances in neural cells of different animals and human beings. The neurotoxicity of mercury, which is one of the most toxic heavy metals, has been studied for several decades. However, its low doses chronic exposure effects for neural tissue cells are still poorly understood. Therefore, the basic molecular mechanisms of mercury should be clarified. The purpose of our research is to clarify the mechanism of mercury genotoxicity, the role of the DNA repair protein apurinic/apyrimidinic endonuclease 1 (APE1) in neural tissue cells, and the response to inorganic mercury-induced neurotoxicity. In our model, we used juvenile rainbow trout exposed to mercury chloride with a range of doses 9‑36 µg/L for 60 days to study the cytotoxicity of chronic exposure. We detected the reactive oxygen species (ROS) production as an index of oxidative stress and APE1 as a marker of cellular DNA damage response in a neural cell. The ROS level was measured by using the fluorometric method based on 2',7'-dichlorofluorescein diacetate reaction. The analyses of markers of the DNA repair (APE1) and apoptosis (B cell lymphoma-2 anti-apoptotic protein – Bcl-2) were carried out with western blotting. The mercury chloride chronic exposure induced statistically significant upregulation of the ROS production in the fish brain. Contrary, the mercury low doses stimulated the downregulation of APE1 expression in the brain tissue. Furthermore, mercury chronic exposure inhibited the expression of Bcl-2 in the animals treated with 18 and 36 µg/L mercury chloride. The harmful effect of mercury could be promoted by oxidative stress generation. The downregulation of APE1 expression could lead to a lack of DNA damage response efficacy and initiate the decline in neural cell functioning. Obtained data on the APE1 expression have shown that the neurotoxic effect of mercury could be mediated, at least partially, by the decline in cellular DNA damage response in the brain. The evaluation of decrease in DNA repair response via detection of the APE1 expression can be a prospective tool to reveal the deleterious effects of toxicants in terms of their neuro- and genotoxicity.

Influence of arsenate imposition on modulation of antioxidative defense network and its implication on thiol metabolism in some contrasting rice (Oryza sativa L.) cultivars.

Globally, many people have been suffering from arsenic poisoning. Arsenate (AsV) exposure to twelve rice cultivars caused growth retardation, triggered production of As-chelatin biopeptides and altered activities of antioxidants along with increase in ascorbate (AsA)-glutathione (GSH) contents as a protective measure. The effects were more conspicuous in cvs. Swarnadhan, Tulaipanji, Pusa basmati, Badshabhog, Tulsibhog and IR-20 to attenuate oxidative-overload mediated adversities. Contrastingly, in cvs. Bhutmuri, Kumargore, Binni, Vijaya, TN-1 and IR-64, effects were less conspicuous in terms of alterations in the said variables due to reduced generation of oxidative stress. Under As(V) imposition, the protective role of phytochelatins (PCs) were recorded where peaks height and levels of PCs (PC2, PC3 and PC4) were elevated significantly in the test seedlings with an endeavour to detoxify cells by sequestering arsenic-phytochelatin (As-PC) complex into vacuole that resulted in reprogramming of antioxidants network. Additionally, scatter plot correlation matrices, color-coded heat map analysis and regression slopes demonstrated varied adaptive responses of test cultivars, where cvs. Bhutmuri, Kumargore, Binni, Vijaya, TN-1 and IR-64 found tolerant against As(V) toxicity. Results were further justified by hierarchical clustering. These findings could help to grow identified tolerant rice cultivars in As-prone soil with sustainable growth and productivity after proper agricultural execution.

Role of up-regulation of oxidative stress biomarkers in thrombotic transformation of atherosclerotic plaque in Acute Coronary Syndrome (ACS) patients from a lower middle income country

Background: In response to oxidative stress, reactive oxygen species aggravate and activate different signaling mechanism and stimulate the release of different inflammatory mediators, and provoke the generation of oxidative stress, all of which can promote the development of acute coronary syndrome. Methodology: The study sample comprised of 76 ACS patients and 76 healthy controls. Blood samples of ACS patients and controls were collected to determine the serum concentration of antioxidants, and the serum levels of inflammatory biomarkers. Spectrophotometric method and ELISA kit method was used to measure these variables accordingly. Results: The results indicated a significant rise in the levels of IL-1, IL-6, IL-8, TNF-α, MMP-11, ICAM-1 and VCAM-1 in ACS patients compared to controls whereas significant decrease was recorded in GSH, CAT, SOD, GRx and HDL levels in patients with ACS compared to controls. Conclusion: The present study indicated that the increased serum concentration of inflammatory cytokines and antioxidant reduction may influence the pathogenesis of ACS. Keywords: Acute coronary syndrome, oxidative stress , antioxidants

Pro-inflammatory effects of silver nanoparticles in the intestine.

Nanotechnology is a promising technology of the twenty-first century, being a rapidly evolving field of research and industrial innovation widely applied in our everyday life. Silver nanoparticles (AgNP) are considered the most commercialized nanosystems worldwide, being applied in diverse sectors, from medicine to the food industry. Considering their unique physical, chemical and biological properties, AgNP have gained access into our daily life, with an exponential use in food industry, leading to an increased inevitable human oral exposure. With the growing use of AgNP, several concerns have been raised, in recent years, about their potential hazards to human health, more precisely their pro-inflammatory effects within the gastrointestinal system. Therefore a review of the literature has been undertaken to understand the pro-inflammatory potential of AgNP, after human oral exposure, in the intestine. Despite the paucity of information reported in the literature about this issue, existing studies indicate that AgNP exert a pro-inflammatory action, through generation of oxidative stress, accompanied by mitochondrial dysfunction, interference with transcription factors and production of cytokines. However, further studies are needed to elucidate the mechanistic pathways and molecular targets involved in the intestinal pro-inflammatory effects of AgNP.

Impact of Nickel Oxide Nanoparticles (NiO) on Oxidative Stress Biomarkers and Hemocyte Counts of Mytilus galloprovincialis.

In this study, the toxic effects of nickel oxide nanoparticles (NiO-NPs) on the model organism Mediterranean mussel (Mytilus galloprovincialis) gill, digestive gland, and hemolymph tissues for 96h were investigated. Lipid peroxidation (MDA) determination was performed to reveal the oxidative stress generation potential of nanoparticles, and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST) enzyme levels were measured to determine antioxidant responses. Lysosomal membrane stability and total hemocyte counts were performed to determine cytotoxic effects. All parameters were altered in different concentrations of NiO-NPs (2, 20, and 200mg L-1). The SOD levels increased depending on the concentration (p < 0.05), and the increases in CAT, GPx, and GST levels were lower at 20mg L-1 concentration (p < 0.05). There was a slight difference between the exposure and the control groups in terms of GR enzyme. The MDA level increased in parallel with the concentration (p < 0.05), the stability of the cell membrane (p < 0.05), and the number of hemocyte cells decreased as a result of exposure (p < 0.05). The results emphasize that NiO-NPs may have negative effects on the aquatic environment.

Neuroprotective effects of ATPase inhibitory factor 1 preventing mitochondrial dysfunction in Parkinson's disease

Mitochondrial dysfunction is a key element in the progression of Parkinson’s disease (PD). The inefficient operation of the electron transport chain (ETC) impairs energy production and enhances the generation of oxidative stress contributing to the loss of dopaminergic cells in the brain. ATPase inhibitory factor 1 (IF1) is a regulator of mitochondrial energy metabolism. IF1 binds directly to the F1Fo ATP synthase and prevents ATP wasting during compromised energy metabolism. In this study, we found treatment with IF1 protects mitochondria against PD-like insult in vitro. SH-SY5Y cells treated with IF1 were resistant to loss of ATP and mitochondrial inner membrane potential during challenge with rotenone, an inhibitor of complex I in the ETC. We further demonstrated that treatment with IF1 reversed rotenone-induced superoxide production in mitochondria and peroxide accumulation in whole cells. Ultimately, IF1 decreased protein levels of pro-apoptotic Bax, cleaved caspase-3, and cleaved PARP, rescuing SH-SY5Y cells from rotenone-mediated apoptotic death. Administration of IF1 significantly improved the results of pole and hanging tests performed by PD mice expressing human α-synuclein. This indicates that IF1 mitigates PD-associated motor deficit. Together, these findings suggest that IF1 exhibits a neuroprotective effect preventing mitochondrial dysfunction in PD pathology.

Graphene oxide chronic exposure enhanced perfluorooctane sulfonate mediated toxicity through oxidative stress generation in freshwater clam Corbicula fluminea

Graphene oxide (GO), a frequently utilized graphene family nanomaterial, is inevitably released into the aquatic environment and interacts with organic pollutants, including perfluorooctane sulfonate (PFOS), a well-known persistent organic pollutant. To determine the adverse effects of GO chronic exposure on PFOS bioaccumulation and toxicity, adult freshwater bivalves, namely Asian clams (Corbicula fluminea) were treated for 28 days with PFOS (500 ng/L) and different concentrations of GO (0.2, 1, 5 mg/L) as PFOS single and GO single exposure groups, as well as PFOS-GO mixture exposure groups. Our results demonstrated that the bioaccumulation of PFOS was significantly enhanced by co-exposure in gills and visceral masses, which was 1.64–2.91 times higher in gills than in visceral masses. Both single, as well as co-exposure, caused a significant reduction in clams’ siphoning behavior, compared to the controls. Further, the co-exposure significantly increased the production of reactive oxygen species (ROS), exacerbating malondialdehyde (MDA) content, enhancing superoxide dismutase (SOD) and catalase (CAT), while decreasing glutathione reductase (GR) and glutathione S-transferase (GST) enzymatic activities in clam tissues. And co-exposure significantly altered the expressions of se-gpx, sod, cyp30, hsp40, and hsp22 genes (associated with oxidative stress and xenobiotic metabolism) both in gills and visceral masses. Moreover, co-exposure caused significant histopathological changes such as cilia degradation in the gills, expansion of tubule lumens in digestive glands, and oocyte shrinkage in gonads. Finally, the enhanced integrated biomarker response (EIBR) index revealed that co-exposure to 500 ng/L PFOS + 1 mg/L/5 mg/L GO was the most stressful circumstance. Overall, our findings suggested that the presence of GO increased PFOS bioaccumulation in tissues, inducing multifaceted negative implications at molecular and behavioral levels through oxidative stress generation in Asian clams.

Ageing, Neurodegeneration and Parkinson's Disease

For the human development aging is one of the important aspect among which on cellular processes and functions are predispose to neurodegeneration and synthetic changes in the body are involved in the pathogenesis of Parkinson’s. The accumulation of the cellular development and their function leads to the progression of Parkinson’s. The formation of ROS, generation of oxidative stress, disruptions in inflammatory pathways like COX, LOX, formation of lewy bodies, protein degradation, genetic mutations, mitochondrial depletion and several other pathways involved in the pathogenies. These may be due to age related decline in acetylcholine and dopamine levels. On medical findings from survey it's been discovered Parkinson’s is age associated ailment and quite a times irreversible yet curable on early stages and can be treated with dopamine and acetylcholine analogues, where levodopa and carbidopa is considered to be the drug of choice at different doses for the inhibiting progression of Parkinson’s.

Synthesis and study of the trypanocidal activity of catechol-containing 3-arylcoumarins, inclusion in β-cyclodextrin complexes and combination with benznidazole

American trypanosomiasis or Chagas disease is caused by the protozoan parasite Trypanosoma cruzi , and is considered a neglected disease, being an important problem for public health. Benznidazole (BZN) is the drug used to treat the disease. However, it has limited efficacy and adverse side effects. Therefore, the development of new therapeutic alternatives is necessary. In this work, the trypanocidal activity and cytotoxicity of a series of catechol-containing 3-arylcoumarins, their combination with BZN, and the inclusion in β-cyclodextrins (β-CDs), were evaluated. The results obtained showed that the entire series has moderate trypanocidal activity on the trypomastigote form of the parasite, being the 3-(4′-bromophenyl)-6,7-dihydroxycoumarin ( 8 ) the most active compound (IC 50 = 34 μM) and the most cytotoxic in Vero cells (IC 50 = 162 μM) as well. By forming the inclusion complex 8 -β-CDs, the trypanocidal activity and cytotoxicity decreased. In addition, the formation of inclusion complexes increased the solubility. The possible mechanism of action of 8 was evaluated and proved to be through the generation of oxidative stress. The combination with BZN presented a synergistic effect on the trypanocidal activity, reducing the necessary dose of BZN. The presence of a catechol in the studied scaffold seems to modulate the trypanocidal activity, and the combination of drugs proved to be a promising alternative strategy for treating the disease.

Antidiabetic-activity sulfated polysaccharide from Chaetomorpha linum: Characteristics of its structure and effects on oxidative stress and mitochondrial function

A water-soluble polysaccharide from the green alga Chaetomorpha linum, designated CHS2, was obtained by water extraction, preparative anion-exchange and size-exclusion chromatography. Results of chemical and spectroscopic analyses showed that CHS2 was a sulfated rhamnogalactoarabinan, and its backbone was mainly constituted by 4-linked and 3,4-linked β-l-arabinopyranose with sulfate groups at C-2/C-3 of 4-linked β-l-arabinopyranose. The branching contained 4-linked, 6-linked β-d-galactopyranose and terminal rhamnose residues. Based on the inhibition of human islet amyloid polypeptide (hIAPP) aggregation and morphology change of hIAPP aggregates in in vitro tests, it was proved that CHS2 effectively inhibited the hIAPP aggregation and possessed strong antidiabetic activity. CHS2 was nearly no toxicity in NIT-1 cells and could attenuate hIAPP-induced cytotoxicity. CHS2 may significantly reduce the generation of intracellular reactive oxygen species and hIAPP aggregation-induced oxidative stress in NIT-1 cells. CHS2 was co-localized with mitochondria, and largely protected mitochondria function from hIAPP aggregation-induced damage through stabilizing mitochondrial membrane potential and enhancing the mitochondrial complex I, II or III activity and ATP level. The data demonstrated that CHS2 could have potential prospect to become an antidiabetic drug for type 2 diabetes mellitus treatment.

Effects of perfluorooctanoic acid in oxidative stress generation, DNA damage in cumulus cells, and its impact on in vitro maturation of porcine oocytes.

Perfluorooctanoic acid is a synthetic compound mostly used in a wide range of consumer products with several adverse effects on somatic cells and gametes. It has been linked to hepatotoxic and carcinogenic effects, alterations in the immune system, endocrine, and reproductive alterations. In vivo studies show an increase in reactive oxygen species and DNA damage. However, the mechanisms by which this compound affects fertility, remain contradictory. Therefore, the aim of the present study was to evaluate the effect of perfluorooctanoic acid on oocyte viability and maturation, as well as the viability, generation of oxidative stress, and genotoxic damage in the cumulus cells exposed during in vitro maturation. This compound had a negative effect on oocyte viability (lethal concentration, LC50 =269 μM) and maturation (inhibition maturation concentration IM50 =75 μM), while in cumulus cells the LC50 was 158 μM. The generation of reactive oxygen species evaluated in cumulus cells, protein carbonylation, and DNA damage, was significantly increased at 40 μM perfluorooctanoic acid. This study provides evidence that perfluorooctanoic acid causes reactive oxygen species generation, protein oxidation, and DNA damage in cumulus cells, compromising the maturation and viability of porcine oocyte, which may affect fertility.

The Role of Lipid Rafts and Membrane Androgen Receptors in Androgen's Neurotoxic Effects.

Sex differences have been observed in multiple oxidative stress–associated neurodegenerative diseases. Androgens, such as testosterone, can exacerbate oxidative stress through a membrane androgen receptor (mAR), AR45, localized to lipid rafts in the plasma membrane. The goal of this study is to determine if interfering with mAR localization to cholesterol-rich lipid rafts decreases androgen induced neurotoxicity under oxidative stress environments. We hypothesize that cholesterol-rich caveolar lipid rafts are necessary for androgens to induce oxidative stress generation in neurons via the mAR localized within the plasma membrane. Nystatin was used to sequester cholesterol and thus decrease cholesterol-rich caveolar lipid rafts in a neuronal cell line (N27 cells). Nystatin was applied prior to testosterone exposure in oxidatively stressed N27 cells. Cell viability, endocytosis, and protein analysis of oxidative stress, apoptosis, and mAR localization were conducted. Our results show that the loss of lipid rafts via cholesterol sequestering blocked androgen-induced oxidative stress in cells by decreasing the localization of mAR to caveolar lipid rafts.

Effect of Consumption of Sphenostylis stenocarpa Seed-formulated Diet on Oxidative Stress Biomarkers of Dexamethasone-treated Pregnant Rats

Aim: The present study tends to examine the effect of consumption of Sphenostylis stenocarpa-formulated diet on oxidative stress biomarkers of dexamethasone-treated pregnant rats.&#x0D; Methodology: Sphenostylis stenocarpa was obtained locally from a market in Ado Ekiti. They were ground into powder and used to make feed for laboratory animals. Fifteen pregnant female rats were divided into three groups of five. Animals in group A were only fed standard animal feed. This served as the control group. Those in group B were exposed to Sphenostylis stenocarpa-formulated diet + 0.3 mg/kg body weight of dexamethasone, while those in group C were exposed to Sphenostylis stenocarpa-formulated diet. At the end of the eight days treatment, animals were sacrificed and blood sample, liver and kidney were collected.&#x0D; Results: The results revealed that treatment of animals with dexamethasone significantly increased (P&lt;0.05) the activities of SOD and CAT and the concentration of MDA but decreased the concentration of GSH in plasma, liver homogenate and kidney homogenate respectively when compared with those in animals in the control group as well as those fed with S. stenocarpa-formulated diet only. The result further showed that feeding of animals with S. stenocarpa-formulated diet only had no significant effect on oxidative stress biomarkers investigated when compared with those in the control group.&#x0D; Conclusion: It can be concluded that exposure of animals to dexamethasone induced oxidative stress in animals while S. stenocarpa-formulated diet possesses the potential to alleviate the effect of oxidative stress generation.

Cytotoxic mechanisms of doxorubicin at clinically relevant concentrations in breast cancer cells.

Doxorubicin (DOX) is a chemotherapeutic agent frequently used for the treatment of a variety of tumor types, such as breast cancer. Despite the long history of DOX, the mechanistic details of its cytotoxic action remain controversial. Rather than one key mechanism of cytotoxic action, DOX is characterized by multiple mechanisms, such as (1) DNA intercalation and adduct formation, (2) topoisomerase II (TopII) poisoning, (3) the generation of free radicals and oxidative stress, and (4) membrane damage through altered sphingolipid metabolism. Many past reviews of DOX cytotoxicity are based on supraclinical concentrations, and several have addressed the concentration dependence of these mechanisms. In addition, most reviews lack a focus on the time dependence of these processes. We aim to update the concentration and time-dependent trends of DOX mechanisms at representative clinical concentrations. Furthermore, attention is placed on DOX behavior in breast cancer cells due to the frequent use of DOX to treat this disease. This review provides insight into the mechanistic pathway(s) of DOX at levels found within patients and establishes the magnitude of effect for each mechanism.

Involvement of Oxidative Stress in the Development of Subcellular Defects and Heart Disease.

It is now well known that oxidative stress promotes lipid peroxidation, protein oxidation, activation of proteases, fragmentation of DNA and alteration in gene expression for producing myocardial cell damage, whereas its actions for the induction of fibrosis, necrosis and apoptosis are considered to result in the loss of cardiomyocytes in different types of heart disease. The present article is focused on the discussion concerning the generation and implications of oxidative stress from various sources such as defective mitochondrial electron transport and enzymatic reactions mainly due to the activation of NADPH oxidase, nitric oxide synthase and monoamine oxidase in diseased myocardium. Oxidative stress has been reported to promote excessive entry of Ca2+ due to increased permeability of the sarcolemmal membrane as well as depressions of Na+-K+ ATPase and Na+-Ca2+ exchange systems, which are considered to increase the intracellular of Ca2+. In addition, marked changes in the ryanodine receptors and Ca2+-pump ATPase have been shown to cause Ca2+-release and depress Ca2+ accumulation in the sarcoplasmic reticulum as a consequence of oxidative stress. Such alterations in sarcolemma and sarcoplasmic reticulum are considered to cause Ca2+-handling abnormalities, which are associated with mitochondrial Ca2+-overload and loss of myofibrillar Ca2+-sensitivity due to oxidative stress. Information regarding the direct effects of different oxyradicals and oxidants on subcellular organelles has also been outlined to show the mechanisms by which oxidative stress may induce Ca2+-handling abnormalities. These observations support the view that oxidative stress plays an important role in the genesis of subcellular defects and cardiac dysfunction in heart disease.