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1.
Hemidesmus indicus induces apoptosis via proteasome inhibition and generation of reactive oxygen species.
Turrini, E, Catanzaro, E, Ferruzzi, L, Guerrini, A, Tacchini, M, Sacchetti, G, Paganetto, G, Maffei, F, Pellicioni, V, Poli, F, et al
Scientific reports. 2019;(1):7199
Abstract
Proteasome inhibition represents an important anticancer strategy. Here, we studied the mechanisms at the basis of the pro-apoptotic activity of the standardized decoction of Hemidesmus indicus, a plant evoking a complex anticancer activity, and explored its inhibition of proteasome activity in human leukemia cells. Additionally, we preliminary tested the cytotoxicity of some H. indicus's phytochemicals on leukemia cells and their intestinal absorption on a human intestinal epithelium model consisting of a monolayer of differentiated Caco2 cells. We observed a potent antileukemic effect for H. indicus, imputable to the modulation of different critical targets at protein and mRNA levels and the reduction of the 26S proteasome expression. We found that some phytomarkers of H. indicus decoction passed through the enterocyte monolayer. Overall, our study supports the pharmacological potential of H. indicus, which can represent an interesting botanical drug in the oncological area.
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2.
Oxidative stress in hemodialysis: Causative mechanisms, clinical implications, and possible therapeutic interventions.
Liakopoulos, V, Roumeliotis, S, Zarogiannis, S, Eleftheriadis, T, Mertens, PR
Seminars in dialysis. 2019;(1):58-71
Abstract
Oxidative stress (OS) is the result of prooxidant molecules overwhelming the antioxidant defense mechanisms. Hemodialysis (HD) constitutes a state of elevated inflammation and OS, due to loss of antioxidants during dialysis and activation of white blood cells triggering production of reactive oxygen species. Dialysis vintage, dialysis methods, and type and condition of vascular access, biocompatibility of dialyzer membrane and dialysate, iron administration, and anemia all can play a role in aggravating OS, which in turn has been associated with increased morbidity and mortality. Oral or intravenous administration of antioxidants may detoxify the oxidative molecules and at least in part repair OS-mediated tissue damage. Lifestyle interventions and optimization of a highly biocompatible HD procedure might ameliorate OS development in dialysis.
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3.
The Role of Oxidative Stress, Adhesion Molecules and Antioxidants in Preeclampsia.
Haram, K, Mortensen, JH, Myking, O, Magann, EF, Morrison, JC
Current hypertension reviews. 2019;(2):105-112
Abstract
Oxidative stress is a consequence of reduction in the antioxidant capacity and excessive production of reactive oxygen and nitrogen species (ROS). Oxidative agents, which are overproduced due to ischemic-reperfusion injury in the placenta, may overwhelm the normal antioxidant activity. This imbalance is a key feature in the pathogenesis of preeclampsia. A decrease in glutathione peroxidase (GPX) activity is associated with the synthesis of vasoconstrictive eicosanoids such as F2-isoprostanes and thromboxane, which are known to be upregulated in preeclampsia. Biochemical markers of lipid peroxidation, such as malondialdehyde and F2-isoprostane in the placenta, are also increased. Adhesion molecules participate in the pathophysiology of preeclampsia by contributing to a reduced invasion by the trophoblast and increased vascular endothelial damage. Superoxide dismutase (SOD), catalase (CAT) and GPX play important roles counteracting oxidative stress. Other antioxidant factors participate in the etiology of preeclampsia. Levels of antioxidants such as Lycopene, Coenzyme 10, as well as some vitamins, are reduced in preeclamptic gestations.
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Dietary phytochemicals with anti-oxidant and pro-oxidant activities: A double-edged sword in relation to adjuvant chemotherapy and radiotherapy?
Fernando, W, Rupasinghe, HPV, Hoskin, DW
Cancer letters. 2019;:168-177
Abstract
Many advances have been made in the development and introduction of new anti-cancer drugs to the clinic. However, limited attention has been paid to improving the efficacy of currently available treatments through complementary phytochemical interventions that affect cellular reactive oxygen species (ROS) levels, which are important for the etiology of certain cancers and the effectiveness of radiotherapy and some chemotherapy. In this regard, the maintenance of redox homeostasis may be influenced by the intake of anti-oxidant and pro-oxidant compounds from dietary sources. Interestingly, certain dietary phytochemicals exhibit both anti-oxidant and pro-oxidant activities, depending on their concentration and cellular microenvironment. There is evidence that concurrent administration of some dietary phytochemicals enhances the efficacy of certain cancer treatments by increasing intracellular ROS accumulation. Paradoxically, consumption of the same dietary phytochemicals under conditions that result in the scavenging of ROS might also negatively affect the outcome of ROS-dependent cancer treatments. This review discusses the potential impact of consuming dietary phytochemicals with anti-oxidant and/or pro-oxidant activities on the effectiveness of concurrent chemotherapy and/or radiotherapy in cancer patients.
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5.
Pre-diagnostic derivatives of reactive oxygen metabolites and the occurrence of lung, colorectal, breast and prostate cancer: An individual participant data meta-analysis of two large population-based studies.
Gào, X, Wilsgaard, T, Jansen, EH, Holleczek, B, Zhang, Y, Xuan, Y, Anusruti, A, Brenner, H, Schöttker, B
International journal of cancer. 2019;(1):49-57
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Abstract
Oxidative stress may be involved in carcinogenesis and biomarkers of oxidative stress like derivatives of reactive oxygen metabolites (d-ROM) may be useful for cancer prediction. However, no previous study assessed the association of pre-diagnostic d-ROM measurements with cancer incidence. We measured serum d-ROM levels in a cohort sample of n = 4,345 participants of the German ESTHER study and in a case-cohort sample of the Norwegian Tromsø study (cancer cases: n = 941; subcohort: n = 1,000). Moreover, d-ROM was repeatedly measured at follow-ups of both studies. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were derived by (weighted) multivariable-adjusted Cox regression with time-dependent modeling of d-ROM levels for incident lung, colorectal, breast and prostate cancer. Individual study results were pooled by random effects meta-analysis. The HRs (95% CI) for comparison of top and bottom d-ROM tertile were statistically significant for lung (1.90 [1.25-2.89]), colorectal (1.70 [1.15-2.51]) and breast cancer incidence (1.45 [1.01-2.09]) but not for prostate cancer incidence (1.20 [0.84-1.72]). In conclusion, this individual participant data meta-analysis of two large population-based cohort studies with repeated d-ROM measurements yielded evidence for an involvement of high oxidative stress in carcinogenesis. Given the observed associations of pre-diagnostic d-ROM measurements with lung, colorectal and breast cancer incidence, subjects with increased serum d-ROM levels should be recommended to reduce these levels by lifestyle changes including smoking cessation, a healthy diet and an increase in physical activity.
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Reactive oxygen species as mediators of oxygen signaling during fetal-to-neonatal circulatory transition.
Villamor, E, Moreno, L, Mohammed, R, Pérez-Vizcaíno, F, Cogolludo, A
Free radical biology & medicine. 2019;:82-96
Abstract
Reactive oxygen species (ROS) are frequently seen as pathological agents of oxidative stress. However, ROS are not always deleterious and can also act as cell signaling molecules. Vascular oxygen sensing and signaling during fetal-to-neonatal circulatory transition is a remarkable example of the physiological regulatory actions of ROS. The fetal relative hypoxic environment induces hypoxic pulmonary vasoconstriction (HPV) and ductus arteriosus (DA) relaxation favoring the presence of high pulmonary vascular resistance and right-to-left ductal shunt. At birth, the increase in oxygen tension causes relaxation of pulmonary arteries (PAs) and normoxic DA vasoconstriction (NDAV), thus diverting blood flow to the lungs. Although the response to changes in oxygen tension is diametrically opposite, the mechanisms responsible for HPV and NDAV appear to be the result of a similar interaction between triggering and modulating factors that lead to an increase in cytosolic Ca2+ concentration and Ca2+ sensitization of the contractile apparatus. Growing evidence points to an increase in ROS (mitochondria- and/or NADPH-derived superoxide and/or H2O2), leading to inhibition of voltage-gated K+ channels, membrane depolarization, and activation of voltage-gated L-type Ca2+ channels as critical events in the signaling pathway of both HPV and NDAV. Several groups of investigators have completed this pathway adding other elements such as neutral sphingomyelinase-derived ceramide, the sarcoplasmic/endoplasmic reticulum (through ryanodine and inositol 1,4,5-trisphosphate receptors), Rho kinase-mediated Ca2+ sensitization, or transient receptor potential channels. The present review focus on the role of ROS as mediators of the homeostatic oxygen sensing system during fetal and neonatal life not only in the PAs and DA but also in systemic arteries.
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Reaction-Based Fluorescent Probes for the Detection and Imaging of Reactive Oxygen, Nitrogen, and Sulfur Species.
Wu, L, Sedgwick, AC, Sun, X, Bull, SD, He, XP, James, TD
Accounts of chemical research. 2019;(9):2582-2597
Abstract
This Account describes a range of strategies for the development of fluorescent probes for detecting reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive (redox-active) sulfur species (RSS). Many ROS/RNS have been implicated in pathological processes such as Alzheimer's disease, cancer, diabetes mellitus, cardiovascular disease, and aging, while many RSS play important roles in maintaining redox homeostasis, serving as antioxidants and acting as free radical scavengers. Fluorescence-based systems have emerged as one of the best ways to monitor the concentrations and locations of these often very short lived species. Because of the high levels of sensitivity and in particular their ability to be used for temporal and spatial sampling for in vivo imaging applications. As a direct result, there has been a huge surge in the development of fluorescent probes for sensitive and selective detection of ROS, RNS, and RSS within cellular environments. However, cellular environments are extremely complex, often with more than one species involved in a given biochemical process. As a result, there has been a rise in the development of dual-responsive fluorescent probes (AND-logic probes) that can monitor the presence of more than one species in a biological environment. Our aim with this Account is to introduce the fluorescent probes that we have developed for in vitro and in vivo measurement of ROS, RNS, and RSS. Fluorescence-based sensing mechanisms used in the construction of the probes include photoinduced electron transfer, intramolecular charge transfer, excited-state intramolecular proton transfer (ESIPT), and fluorescence resonance energy transfer. In particular, probes for hydrogen peroxide, hypochlorous acid, superoxide, peroxynitrite, glutathione, cysteine, homocysteine, and hydrogen sulfide are discussed. In addition, we describe the development of AND-logic-based systems capable of detecting two species, such as peroxynitrite and glutathione. One of the most interesting advances contained in this Account is our extension of indicator displacement assays (IDAs) to reaction-based indicator displacement assays (RIAs). In an IDA system, an indicator is allowed to bind reversibly to a receptor. Then a competitive analyte is introduced into the system, resulting in displacement of the indicator from the host, which in turn modulates the optical signal. With an RIA-based system, the indicator is cleaved from a preformed receptor-indicator complex rather than being displaced by the analyte. Nevertheless, without a doubt the most significant result contained in this Account is the use of an ESIPT-based probe for the simultaneous sensing of fibrous proteins/peptides AND environmental ROS/RNS.
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Annurca apple polyphenol extract selectively kills MDA-MB-231 cells through ROS generation, sustained JNK activation and cell growth and survival inhibition.
Martino, E, Vuoso, DC, D'Angelo, S, Mele, L, D'Onofrio, N, Porcelli, M, Cacciapuoti, G
Scientific reports. 2019;(1):13045
Abstract
Polyphenols represent the most studied class of nutraceuticals that can be therapeutics for a large spectrum of diseases, including cancer. In this study, we investigated for the first time the antitumor activities of polyphenol extract from Annurca apple (APE) in MDA-MB-231 triple negative breast cancer cells, and we explored the underlying mechanisms. APE selectively inhibited MDA-MB-231 cell viability and caused G2/M phase arrest associated with p27 and phospho-cdc25C upregulation and with p21 downregulation. APE promoted reactive oxygen species (ROS) generation in MDA-MB-231 cells while it acted as antioxidant in non-tumorigenic MCF10A cells. We demonstrated that ROS generation represented the primary step of APE antitumor activity as pretreatment with antioxidant N-acetylcysteine (NAC) prevented APE-induced G2/M phase arrest, apoptosis, and autophagy. APE downregulated Dusp-1 and induced a significant increase in JNK/c-Jun phosphorylation that were both prevented by NAC. Moreover, downregulation of JNK by its specific inhibitor SP600125 significantly diminished the anticancer activity of APE indicating that ROS generation and sustained JNK activation represented the main underlying mechanism of APE-induced cell death. APE also inhibited AKT activation and downregulated several oncoproteins, such as NF-kB, c-myc, and β-catenin. In light of these results, APE may be an attractive candidate for drug development against triple negative breast cancer.
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Crosstalk between Calcium and ROS in Pathophysiological Conditions.
Feno, S, Butera, G, Vecellio Reane, D, Rizzuto, R, Raffaello, A
Oxidative medicine and cellular longevity. 2019;:9324018
Abstract
Calcium ions are highly versatile intracellular signals that regulate many cellular processes. The key to achieving this pleiotropic role is the spatiotemporal control of calcium concentration evoked by an extensive molecular repertoire of signalling components. Among these, reactive oxygen species (ROS) signalling, together with calcium signalling, plays a crucial role in controlling several physiopathological events. Although initially considered detrimental by-products of aerobic metabolism, it is now widely accepted that ROS, in subtoxic levels, act as signalling molecules. However, dysfunctions in the mechanisms controlling the physiological ROS concentration affect cellular homeostasis, leading to the pathogenesis of various disorders.
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NEET Proteins: A New Link Between Iron Metabolism, Reactive Oxygen Species, and Cancer.
Mittler, R, Darash-Yahana, M, Sohn, YS, Bai, F, Song, L, Cabantchik, IZ, Jennings, PA, Onuchic, JN, Nechushtai, R
Antioxidants & redox signaling. 2019;(8):1083-1095
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Abstract
SIGNIFICANCE Cancer cells accumulate high levels of iron and reactive oxygen species (ROS) to promote their high metabolic activity and proliferation rate. However, high levels of iron and ROS can also lead to enhanced oxidative stress and the activation of cell death pathways such as apoptosis and ferroptosis. This has led to the proposal that different drugs that target iron and/or ROS metabolism could be used as anticancer drugs. However, due to the complex role iron and ROS play in cells, the majority of these drugs yielded mixed results, highlighting a critical need to identify new players in the regulation of iron and ROS homeostasis in cancer cells. Recent Advances: NEET proteins belong to a newly discovered class of iron-sulfur proteins (2Fe-2S) required for the regulation of iron and ROS homeostasis in cells. Recent studies revealed that the NEET proteins NAF-1 (CISD2) and mitoNEET (CISD1) play a critical role in promoting the proliferation of cancer cells, supporting tumor growth and metastasis. Moreover, the function of NEET proteins in cancer cells was found to be dependent of the degree of lability of their 2Fe-2S clusters. CRITICAL ISSUES NEET proteins could represent a key regulatory link between the maintenance of high iron and ROS in cancer cells, the activation of cell death and survival pathways, and cellular proliferation. FUTURE DIRECTIONS Because the function of NEET proteins depends on the lability of their clusters, drugs that target the 2Fe2S clusters of NEET proteins could be used as promising anticancer drugs.