Search Results (10)

Background: Standard treatment for patients with early-stage estrogen receptor-positive (ER+) breast cancer often includes sequential adjuvant radiation and endocrine therapies. Unfortunately, ~1/3 of patients eventually experience disease recurrence, partly due to residual disease in the form of drug-tolerant persister cancer cells. The anti-cancer efficacy of radiation therapy is partly attributable to the production of oxyradicals that damage biomolecules. We previously showed that endocrine therapy increases mitochondrial content in ER+ breast cancer cells; we postulated that this may also increase oxidative stress. Methods: Herein, we tested the efficacy of concurrent endocrine and radiation therapies, including both conventional (CDR) and ultra-high dose rate (UHDR) radiation. Results: We found that estrogen deprivation and radiation inhibit cell growth, induce apoptosis, and force cells into an oxidatively stressed state. DNA damage was almost exclusive to cells treated with the combination of endocrine and radiation therapy. Radiation slowed tumor growth in two xenograft models, and combination with estrogen deprivation prolonged the time to regrowth in ZR75-1 tumors. Conclusions: These findings indicate that simultaneous treatment with endocrine and radiation therapies can be advantageous, warranting further evaluation to identify tumor features predictive of response to individual and combination treatments. Full article

Delayed reperfusion of the ischemic heart (I/R) is known to impair the recovery of cardiac function and produce a wide variety of myocardial defects, including ultrastructural damage, metabolic alterations, subcellular Ca²⁺-handling abnormalities, activation of proteases, and changes in cardiac gene expression. Although I/R injury has been reported to induce the formation of reactive oxygen species (ROS), inflammation, and intracellular Ca²⁺ overload, the generation of oxidative stress is considered to play a critical role in the development of cardiac dysfunction. Increases in the production of superoxide, hydroxyl radicals, and oxidants, such as hydrogen peroxide and hypochlorous acid, occur in hearts subjected to I/R injury. In fact, mitochondria are a major source of the excessive production of ROS in I/R hearts due to impairment in the electron transport system as well as activation of xanthine oxidase and NADPH oxidase. Nitric oxide synthase, mainly present in the endothelium, is also activated due to I/R injury, leading to the production of nitric oxide, which, upon combination with superoxide radicals, generates nitrosative stress. Alterations in cardiac function, sarcolemma, sarcoplasmic reticulum Ca²⁺-handling activities, mitochondrial oxidative phosphorylation, and protease activation due to I/R injury are simulated upon exposing the heart to the oxyradical-generating system (xanthine plus xanthine oxidase) or H₂O₂. On the other hand, the activation of endogenous antioxidants such as superoxide dismutase, catalase, glutathione peroxidase, and the concentration of a transcription factor (Nrf2), which modulates the expression of various endogenous antioxidants, is depressed due to I/R injury in hearts. Furthermore, pretreatment of hearts with antioxidants such as catalase plus superoxide dismutase, N-acetylcysteine, and mercaptopropionylglycerine has been observed to attenuate I/R-induced subcellular Ca²⁺ handling and changes in Ca²⁺-regulatory activities; additionally, it has been found to depress protease activation and improve the recovery of cardiac function. These observations indicate that oxidative stress is intimately involved in the pathological effects of I/R injury and different antioxidants attenuate I/R-induced subcellular alterations and improve the recovery of cardiac function. Thus, we are faced with the task of developing safe and effective antioxidants as well as agents for upregulating the expression of endogenous antioxidants for the therapy of I/R injury. Full article

Retinal pigment epithelial (RPE) is an oxidation-resistant cell. But if it is subjected to various harmful stimuli for a prolonged period, an excessive amount of oxyradical will be generated to cause retinal dysfunction. We investigated and elucidated the protective mechanism of Sea buckthorn proanthocyanidins (SBP) against oxidative damage in RPE. In this study, we established an oxidative damage model of adult retinal pigment epithelial cell line-19 (ARPE-19) using hydrogen peroxide (H₂O₂), followed by different concentrations of SBP for 24 h. The finding demonstrated that SBP effectively inhibited the generation of malondialdehyde (MDA), restored the activity of superoxide dismutase (SOD) and content of glutathione (GSH), and significantly eliminated the level of reactive oxygen species (ROS) and oxidative stress. It was revealed that 100 µg/mL of SBP was more suitable for restoring oxidative damage in ARPE-19, which enhanced cell activity and migration ability and maintained normal cell morphology. In addition, SBP increased the expression of Bcl-2, decreased the expression of Bax and caspase-3, and activated the Nrf2/HO-1 signaling pathway to protect ARPE-19 from oxidative stress. Moreover, SBP could restore the morphology and quantity of mitochondria and inhibit mitochondrial permeability and swelling. The present results provide a theoretical basis for the protective and restorative effect of SBP in retinopathy caused by oxidative stress. Full article

Anthocyanins are a class of natural pigments that accumulate transiently or permanently in plant tissues, often in response to abiotic and biotic stresses. They play a photoprotective role by attenuating the irradiance incident on the photochemical apparatus and quenching oxyradicals through their powerful anti-oxidative function. The objective of the current study is to understand the impact of introducing Vitis vinifera mybA1 (VvmybA1) in ‘Hamlin’ sweet orange trees on various aspects, including photosynthetic performance, pigment composition, and gene expression related to photosynthesis and light harvesting. We describe the relationship between anthocyanin accumulation and photosynthetic measurements in genetically modified ‘Hamlin’ sweet orange trees expressing the grapevine-derived Vitis vinifera mybA1 (VvmybA1). The juvenile leaves of transgenic plants displayed an intense purple color compared to the mature leaves, and microscopic visualization showed anthocyanin accumulation primarily in the leaf epidermal cells. Under optimal growth conditions, there were no significant differences in leaf gas exchange variables, suggesting normal photosynthetic performance. The chlorophyll fluorescence maximum quantum yield of PSII was slightly reduced in VvmybA1 transgenic leaves compared to the performance of the control leaves, while the total performance index per absorbance remained unaffected. Comparison of the chlorophyll and carotenoid pigment contents revealed that chlorophyllide a and carotenoid pigments, including trans-neoxanthin, trans-violaxanthin, cis-violaxanthin, zeaxanthin, antheraxanthin, and total xanthophylls were enhanced in VvmybA1 transgenic leaves. Although there were no significant changes in the rates of the gas exchange parameters, we recorded a high relative expression of the ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit (RuBP) and rubisco activase (RCA) in the mature leaves of transgenic plants, indicating activation of Rubisco. Our findings confirm an efficient photoacclimation of the photosynthetic apparatus, allowing the transgenic line to maintain a photosynthetic performance similar to that of the wild type. Full article

Susceptibility to phosphine was compared in 15 populations of lesser grain borer (Rhyzopertha dominica) collected from grain storage godowns across India. A high level of resistance to phosphine was noticed in R. dominica collected from northern India compared to those collected from northeastern regions of India. The median lethal concentration values varied from 0.024 mg/L to 1.991 mg/L, with 1.63 to 82.96-fold resistance compared to laboratory susceptible checks. Antioxidant enzymes have been reported to negate the reactive oxygen species generated upon encountering the fumigant phosphine. Distinct differences in the activity of antioxidant enzymes were noticed in the field populations exposed to phosphine. Peroxidase activity varied between 1.28 and 336.8 nmol H₂O₂ reduced/min/mg protein. The superoxide dismutase inhibition rate was between 81.29 and 99.66%, and catalase activity varied between 6.28 and 320.13 nmol H₂O₂ reduced/min/mg protein. The findings of our investigation show that the activities of peroxidase and superoxide dismutase are positively linked (p < 0.01) with an increase in resistance ratios, whereas catalase was found to have a negative association with resistance to phosphine. The reported results elucidate the differential activities of principal antioxidant enzymes in scavenging the oxyradicals (O₂^•−, H₂O_2,^•OH) associated with tolerance to phosphine in R. dominica. Full article

Diabetes mellitus leads to cellular damage and causes apoptosis by oxidative stress. Heartwood extract of Pterocarpus marsupium has been used in Ayurveda to treat various diseases such as leprosy, diabetes, asthma, and bronchitis. In this study, we worked out the mechanism of the antidiabetic potential of methanolic heartwood extract of Pterocarpus marsupium (MPME). First, metabolic profiling of MPME was done using gas chromatography-mass spectrometry (GCMS), ultra-performance liquid chromatography-mass spectroscopy (UPLC-MS), and high-performance thin-layer chromatography (HPTLC) to identify phenols, flavonoids, and terpenoids in MPME. Biological studies were carried out in vitro using the HepG2 cell line. Many antidiabetic compounds were identified including Quercetin. Methanolic extract of MPME (23.43 µg/mL–93.75 µg/mL) was found to be safe and effective in reducing oxyradicals in HepG2 cells. A concentration of 93.75 µg/mL improved glucose uptake efficiently. A significant decrease in oxidative stress, cell damage, and apoptosis was found in MPME-treated HepG2 cells. The study suggests that the heartwood of Pterocarpus marsupium offers good defense in HepG2 cells against oxidative stress and improves glucose uptake. The results show the significant antidiabetic potential of MPME using a HepG2 cell model. The effect seems to occur by reducing oxidative stress and sensitizing the cells towards glucose uptake, hence lowering systemic glucose levels, as well as rescuing ROS generation. Full article

Ischemia-reperfusion (I/R) injury is well-known to be associated with impaired cardiac function, massive arrhythmias, marked alterations in cardiac metabolism and irreversible ultrastructural changes in the heart. Two major mechanisms namely oxidative stress and intracellular Ca²⁺-overload are considered to explain I/R-induced injury to the heart. However, it is becoming apparent that oxidative stress is the most critical pathogenic factor because it produces myocardial abnormalities directly or indirectly for the occurrence of cardiac damage. Furthermore, I/R injury has been shown to generate oxidative stress by promoting the formation of different reactive oxygen species due to defects in mitochondrial function and depressions in both endogenous antioxidant levels as well as regulatory antioxidative defense systems. It has also been demonstrated to adversely affect a wide variety of metabolic pathways and targets in cardiomyocytes, various resident structures in myocardial interstitium, as well as circulating neutrophils and leukocytes. These I/R-induced alterations in addition to myocardial inflammation may cause cell death, fibrosis, inflammation, Ca²⁺-handling abnormalities, activation of proteases and phospholipases, as well as subcellular remodeling and depletion of energy stores in the heart. Analysis of results from isolated hearts perfused with or without some antioxidant treatments before subjecting to I/R injury has indicated that cardiac dysfunction is associated with the development of oxidative stress, intracellular Ca²⁺-overload and protease activation. In addition, changes in the sarcolemma and sarcoplasmic reticulum Ca²⁺-handling, mitochondrial oxidative phosphorylation as well as myofibrillar Ca²⁺-ATPase activities in I/R hearts were attenuated by pretreatment with antioxidants. The I/R-induced alterations in cardiac function were simulated upon perfusing the hearts with oxyradical generating system or oxidant. These observations support the view that oxidative stress may be intimately involved in inducing intracellular Ca²⁺-overload, protease activation, subcellular remodeling, and cardiac dysfunction as a consequence of I/R injury to the heart. Full article

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. Full article

Although heart failure due to a wide variety of pathological stimuli including myocardial infarction, pressure overload and volume overload is associated with cardiac hypertrophy, the exact reasons for the transition of cardiac hypertrophy to heart failure are not well defined. Since circulating levels of several vasoactive hormones including catecholamines, angiotensin II, and endothelins are elevated under pathological conditions, it has been suggested that these vasoactive hormones may be involved in the development of both cardiac hypertrophy and heart failure. At initial stages of pathological stimuli, these hormones induce an increase in ventricular wall tension by acting through their respective receptor-mediated signal transduction systems and result in the development of cardiac hypertrophy. Some oxyradicals formed at initial stages are also involved in the redox-dependent activation of the hypertrophic process but these are rapidly removed by increased content of antioxidants in hypertrophied heart. In fact, cardiac hypertrophy is considered to be an adaptive process as it exhibits either normal or augmented cardiac function for maintaining cardiovascular homeostasis. However, exposure of a hypertrophied heart to elevated levels of circulating hormones due to pathological stimuli over a prolonged period results in cardiac dysfunction and development of heart failure involving a complex set of mechanisms. It has been demonstrated that different cardiovascular abnormalities such as functional hypoxia, metabolic derangements, uncoupling of mitochondrial electron transport, and inflammation produce oxidative stress in the hypertrophied failing hearts. In addition, oxidation of catecholamines by monoamine oxidase as well as NADPH oxidase activation by angiotensin II and endothelin promote the generation of oxidative stress during the prolonged period by these pathological stimuli. It is noteworthy that oxidative stress is known to activate metallomatrix proteases and degrade the extracellular matrix proteins for the induction of cardiac remodeling and heart dysfunction. Furthermore, oxidative stress has been shown to induce subcellular remodeling and Ca²⁺-handling abnormalities as well as loss of cardiomyocytes due to the development of apoptosis, necrosis, and fibrosis. These observations support the view that a low amount of oxyradical formation for a brief period may activate redox-sensitive mechanisms, which are associated with the development of cardiac hypertrophy. On the other hand, high levels of oxyradicals over a prolonged period may induce oxidative stress and cause Ca²⁺-handling defects as well as protease activation and thus play a critical role in the development of adverse cardiac remodeling and cardiac dysfunction as well as progression of heart failure. Full article

The development of controlled drug delivery systems based on bio-renewable materials is an emerging strategy. In this work, a controlled drug delivery system based on mesoporous oxidized cellulose beads (OCBs) was successfully developed by a facile and green method. The introduction of the carboxyl groups mediated by the TEMPO(2,2,6,6-tetramethylpiperidine-1-oxyradical)/NaClO/NaClO₂ system presents the pH-responsive ability to cellulose beads, which can retain the drug in beads at pH = 1.2 and release at pH = 7.0. The release rate can be controlled by simply adjusting the degree of oxidation to achieve drug release at different locations and periods. A higher degree of oxidation corresponds to a faster release rate, which is attributed to a higher degree of re-swelling and higher hydrophilicity of OCBs. The zero-order release kinetics of the model drugs from the OCBs suggested a constant drug release rate, which is conducive to maintaining blood drug concentration, reducing side effects and administration frequency. At the same time, the effects of different model drugs and different drug-loading solvents on the release behavior and the physical state of the drugs loaded in the beads were studied. In summary, the pH-responsive oxidized cellulose beads with good biocompatibility, low cost, and adjustable release rate have shown great potential in the field of controlled drug release. Full article