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The source and clearance of ROS. (a) Three major origins of ROS. The sources of ROS can be roughly classified into three major categories: exogenous, endogenous, and transition metal ion-catalyzed. Exogenous sources of ROS can elicit radical chain reactions, contain/produce ROS, or stimulate enzymatic ROS production. Endogenous sources of ROS include the various enzymes that produce ROS as by-products or as signaling mediators or as antimicrobial agents during inflammation. Many of these enzymes can be activated by stimulation by cytokines and growth factors, such as NOX, LOX, XO, and MPO. Some CYPs are inducible and can be upregulated by environmental pollutants, dietary phytocompounds, or drugs. The transition metal ion-catalyzed Fenton-reaction produces highly reactive hydroxyl radical from hydrogen peroxide. (b) Layers of antioxidant defense. There are several layers of antioxidant defense. Basal level antioxidant defenses provide buffering capacity upon ROS challenge. Radical scavengers can directly quench ROS, and metal-chelating proteins can block ROS generation catalyzed by the Fenton or Fenton-like reactions. Further antioxidant capacity is provided by inducible antioxidant enzymes that are mostly under the regulation of Nrf2/ARE signaling (see Figure 4). ROS can oxidize the thiol group of amino acid residues leading to intermolecular or intramolecular disulfide bond formation. These disulfide bonds that are caused by oxidation can lead to structural/functional alteration of proteins. These disulfide bonds can be reduced by the glutathione system and the thioredoxin system allowing resumption of protein function. NADPH plays an indispensable role in the recycling of glutathione and thioredoxin, and therefore metabolic enzymes that are involved in NADPH generation also account for antioxidant defense.
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Accumulation of oxidized nucleic acids causes genomic instability leading to senescence, apoptosis, and tumorigenesis. Phytoagents are known to reduce the risk of cancer development; whether such effects are through regulating the extent of nucleic acid oxidation remains unclear. Here, we outlined the role of reactive oxygen species in nucleic acid...
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... Phytochemicals are biologically active compounds that possess potent anti-tumor properties [76]. They participate in slowing or preventing carcinogenesis by mobbing free radicals, suppressing the survival and spreading of malignant cells, and reducing the invasiveness and angiogenesis of tumors [77][78][79]. Phytochemicals prevent cancer progression by acting on several molecular targets and signal transduction pathways, such as membrane receptors, downstream tumor-activator or suppressor proteins, kinases, transcription factors, caspases, microRNAs, and cyclins [76]. ...
Synthesized in plants, polyphenols are powerful antioxidants and protect against stressful conditions. We aimed to identify different kinds of phytochemicals in fruits and provide detailed information on the roles they play in promoting good health in the human body. We also discussed the biological activities of phytochemicals found in several fruits. Google Scholar and PubMed databases were used to search for relevant information that could assist in answering our research questions. We selected and reviewed both research and review articles related to the purpose of our study. Fruits contain numerous antioxidants which neutralize the negative impact of free radicals on the body. Free radicals are destructive species that can be produced during normal body metabolism or come from exogenous sources such as smoking or exposure to radiation. Due to their unstable nature, they can cause damage to cellular macromolecules, resulting in the development of degenerative diseases. Phytochemicals are diverse groups of bioactive compounds found in fruits that have
potent antioxidant activity and exhibit several health-promoting properties in both in vivo and in vitro studies. There are two
major groups of antioxidants: natural (or dietary) antioxidants and synthetic antioxidants. Natural antioxidants have gained
much popularity in recent times because of the safety concerns surrounding the use of synthetic antioxidants. The consumption of fruits plays a critical role in disease prevention, especially diseases resulting from oxidative damage to cells. The inclusion of fruits in one’s daily diet helps improve their overall wellbeing.
... These phytochemicals have been tested for anti-cancer efficacy both in vitro and in vivo. Such compounds possess complementary and overlapping mechanisms to slow down the cancer progression by scavenging free radicals (Lee et al., 2013), suppressing cell survival and proliferation to prevent malignancy (Yan et al., 2018), as well as reducing tumor invasiveness and angiogenesis (Lu et al., 2018). Furthermore, these phytochemicals are reported to exert a wide and complex range of actions on different molecular targets and signal transduction pathways, including membrane receptors (Deng et al., 2017), kinases (Dou et al., 2018), downstream tumor-activator or -suppressor proteins (Adams et al., 2010), transcription factors (Zhang et al., 2017), microRNAs (miRNAs) (Cojocneanu Petric et al., 2015), cyclins, and caspases (Yan et al., 2018). ...
... Several plant compounds, including primary and secondary metabolites, have been shown to reduce tumor development and progression in vivo. Phytochemicals can act on cancer cells and decrease tumor formation and spread through a variety of mechanisms such as stabilizing molecules that can stimulate cancer growth, boost the immune system, stop the formation of carcinogenic substances, protect healthy cells from carcinogens, reduce inflammation that can lead to cancer development, regulating hormones, inducing autophagy of damaged cells, preventing DNA damage in healthy cells, and scavenging free radicals (Lee, Huang, & Shyur, 2013). To accomplish this, phytochemicals either inhibit cancer cell activating proteins, enzymes, and signaling pathways [Cdc2, CDK2, and CDK4 kinases, topoisomerase enzyme, cyclooxygenase and COX-2 (Cycloxigenase), Bcl-2, cytokines, PI3K, Akt, MAPK/ERK, MMP, TNK, mechanistic target of rapamycin (mTOR), or by activating DNA repair mechanisms (p21, p27, p51, p53 genes, and their protein products), Bax, Bid, Bak proteins, stimulating the formation of protective enzymes 7,8,9,10,12), inducing antioxidant action (antioxidant enzymes such as GSH, GST, and GPxn), exhibiting strong anticancer effects in terms of their efficacy on the aforementioned proteins, enzymes, and signaling pathways] (Ayaz et al., 2022;Iqbal et al., 2017). ...
Cancer is a disease caused by a combination of factors that induce excessive cell proliferation and spread to other parts of the body. Traditional cancer therapy methods have several limitations, including toxicity to normal cells, low absorption, quick clearance, resistance, non-specificity, and high cost. As a result, there is an increased desire for alternative treatments based on natural products, with plants serving as the primary source. Anticancer medicines from plants have natural properties that allow them to transcend such constraints since they are more effective, safer, widely available, and less costly. Indeed, screening medicinal plants has resulted in the development of outstanding cytotoxic medications for modern medicine. Currently, more than 60% of clinically approved anticancer agents are derived from herbs. Furthermore, each year, hundreds of possible anticancer phytochemicals are discovered in plants, opening up new avenues for cancer treatment. Many of the plant species researched are native to developing countries in Africa and Asia, where herbal therapy is practiced and medicinal herbs are utilized as first-line treatment. Several studies have displayed improved effectiveness of conventional chemotherapeutics when coupled with phytochemicals; it appears to reduce drug resistance and side effects while improving therapeutic response. Despite these achievements, converting bioactive phytochemicals into pharmaceuticals has remained challenging, owing in part to large-scale separation challenges, mechanistic knowledge, and pharmacological development. This chapter focuses on proven anticancer phytochemicals, in preclinical and clinical trials, to offer insights into useful botanicals in anticancer drug development. Strategies for overcoming hurdles in the development of plant-based anticancer medicines are also discussed.
... Changes in the aquatic environment caused by external environmental pollution, such as microplastic exposure, increase the production of reactive oxygen species (ROS), which cause oxidative stress in marine organisms (Jin et al., 2022). ROS include superoxide (O 2 − ), hydrogen peroxide (H 2 O 2 ), and hydroxyl radicals (OH − ), which are excessively generated in fish exposed to stress, and a large amount of ROS oxidizes nucleic acids in cells, lipids and proteins, resulting in DNA damage and apoptosis (Lee et al., 2013). Therefore, organisms, including fish, use antioxidant defense systems to protect themselves against diverse stresses and maintain physiological homeostasis. ...
We confirmed antioxidant-related gene expression, bioaccumulation, and cell damage following exposure to various microplastics in vivo and in vitro in the goldfish Carassius auratus. Exposure of C. auratus to a 500 µm fiber-type microplastic environment (MF; 10 and 100 fibers/L) and two sizes (0.2 and 1.0 µm) of beads (MB; 10 and 100 beads/L) for 120 h increased superoxide dismutase (SOD) mRNA expression in the liver until 24 h followed by a decrease. Whereas, catalase (CAT) mRNA expression increased from 12 h to the end of the in vivo experiment. In vitro experiments were conducted with diluted microfibers (1 and 5 fibers/L) and microbeads (1 and 5 beads/L) using cultured liver cells. The results of SOD and CAT mRNA expression analysis conducted in vitro showed a tendency similar to those of experiments conducted in vivo. The H2O2 level increased in the high-concentration experimental groups compared with that in the low-concentration groups of 0.2-µm beads. In addition, the H2O2 level increased in both MF and MB groups from 12 h of exposure. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in plasma were used as indicators of liver damage in fish. The ALT and AST levels increased up to 120 h after exposure. Caspase-3 (casp-3) mRNA expression was higher in the MB group than in the MF group. We visually confirmed liver casp-3 mRNA signals using in situ hybridization. The degree of DNA damage in the MF and MB high-concentration groups increased with the exposure time. The tail length and percent of DNA in the tail of the MB group were significantly higher than those of the MF group, confirming that DNA damage was greater in the MB group. Both fiber- and bead-type microplastics induced oxidative stress in C. auratus, but the bead-type induced greater stress than the fiber-type.
... In the case of GSH, a similar pattern of relative GSH fluorescence was observed in both plasma and S9 (Figure 4), but higher GSH levels were recorded in S9 when comparing between the fractions because the cell is richer with GSH than plasma (Lu, 2009;Wu et al., 2004). When comparing ROS levels between the fractions, higher levels in plasma could be due to the external pollutants affecting the ROS production and leading to increase in extracellular ROS (Lee et al., 2013). Considering the obtained results, it can be again concluded that plasma samples might be more suitable for the assessment of both GSH and ROS levels in biomonitoring of pollution effects. ...
... Although generally associated with mitochondria and electron flux, ROS may be generated by plasma membrane (Lee et al., 2017) or induced by external sources, namely pollutants and/or drugs (Lee et al., 2013), resulting in higher fluorescence detection of extracellular ROS in plasma compared to S9 (Fig. 6, Table SI2). Significant spatial variations were not observed regarding ROS concentration (Fig. 6, Table SI2). ...
... Although generally associated with mitochondria and electron flux, ROS may be generated by plasma membrane (Lee et al., 2017) or induced by external sources, namely pollutants and/or drugs (Lee et al., 2013), resulting in higher fluorescence detection of extracellular ROS in plasma compared to S9 (Fig. 6, Table SI2). Significant spatial variations were not observed regarding ROS concentration (Fig. 6, Table SI2). ...
The goal of the present study was to investigate differences in biomarker responses related to metal(loid)s in white stork Ciconia ciconia) nestling's blood from continental Croatia. To achieve this, a battery of biomarkers that can be affected by environmental pollutants, including metal(loid)s, was assessed (esterase activity, fluorescence-based oxidative stress biomarkers, metallothionein levels, glutathione-dependent enzyme activity). The research was conducted during the white stork breeding season in diverse areas (a landfill, industrial and agricultural sites, and an unpolluted area). White storks' nestlings near the landfill exhibited reduced carboxylesterase (CES) activity, elevated glutathione (GSH) concentration, as well as high Pb content in the blood. Increased As and Hg concentrations in blood were attributable to environmental contamination in agricultural area and an assumed unpolluted area, respectively. Furthermore, agricultural practices appeared to affect CES activity, as well as elevate Se levels. In addition to the successful implementation of biomarkers, present research showed that agricultural areas and a landfill are areas with increased metal(loid) levels possibly causing adverse effects on the white storks. This first-time heavy metal and metalloid analyses in the white stork nestlings from Croatia point to the necessary monitoring and future assessments of pollution impact to prevent irreversible adverse effects.
... 170,171 The thiol (SH) plays a significant role in the antioxidant properties of the resulting metal complex, while the disulfide linkages account for their prooxidant properties. 172,173 The varying capabilities for these compounds' intracellular transport and binding to critical conformational and functional components of the cells may cause metabolic changes and physiological alterations. These in turn may result in the death of cells, resulting in tissue or organ-specific adverse effects. ...
The platinum drug, cisplatin, is considered as among the most successful medications in cancer treatment. However, due to its inherent toxicity and resistance limitations, research into other metal-based non-platinum anticancer medications with diverse mechanisms of action remains an active field. In this regard, copper complexes feature among non-platinum compounds which have shown promising potential as effective anticancer drugs. Moreover, the interesting discovery that cancer cells can alter their copper homeostatic processes to develop resistance to platinum-based treatments leads to suggestions that some copper compounds can indeed re-sensitize cancer cells to these drugs. In this work, we review copper and copper complexes bearing dithiocarbamate ligands which have shown promising results as anticancer agents. Dithiocarbamate ligands act as effective ionophores to convey the complexes of interest into cells thereby influencing the metal homeostatic balance and inducing apoptosis through various mechanisms. We focus on copper homeostasis in mammalian cells and on our current understanding of copper dysregulation in cancer and recent therapeutic breakthroughs using copper coordination complexes as anticancer drugs. We also discuss the molecular foundation of the mechanisms underlying their anticancer action. The opportunities that exist in research for these compounds and their potential as anticancer agents, especially when coupled with ligands such as dithiocarbamates, are also reviewed.
... Nrf2 deficiency worsened disease activity in experimental arthritis models, whereas its activation exhibited immunoregulatory and anti-inflammatory effects. Thus, the pharmacologic regulation of Nrf2 has gained increasing interest as a strategy to target ROS [63]. ...
... Two other reports for serum silicon levels in patients with RA and vitamin K1 (10 mg daily for 8 weeks) showed controversial results [118,119]. Vitamin A (retinol) detoxifies H 2 O 2 through ascorbate peroxidase [63]. Vitamin E (tocopherol and tocotrienols) guards against and detoxifies the products of membrane lipid peroxidation. ...
Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that causes progressive joint damage and can lead to lifelong disability. Numerous studies support the hypothesis that reactive oxygen species (ROS) are associated with RA pathogenesis. Recent advances have clarified the anti-inflammatory effect of antioxidants and their roles in RA alleviation. In addition, several important signaling pathway components, such as nuclear factor kappa B, activator-protein-1, nuclear factor (erythroid-derived 2)-like 2/kelch-like associated protein, signal transducer and activator of transcription 3, and mitogen-activated protein kinases, including c-Jun N-terminal kinase, have been identified to be associated with RA. In this paper, we outline the ROS generation process and relevant oxidative markers, thereby providing evidence of the association between oxidative stress and RA pathogenesis. Furthermore, we describe various therapeutic targets in several prominent signaling pathways for improving RA disease activity and its hyper oxidative state. Finally, we reviewed natural foods, phytochemicals, chemical compounds with antioxidant properties and the association of microbiota with RA pathogenesis.
... Intriguingly, it has been recently demonstrated that polyphenols may also have pro-oxidant properties by increasing ROS levels, and this has opened another unexpected opportunity to use these compounds as a potential therapeutic strategy against cancer. The use of dietary agents, such as curcumin and resveratrol, has been demonstrated to promote the production of hydrogen peroxide and to efficiently kill tumor cells without affecting normal cells [46]. ...
Oleuropein plays a key role as a pro-oxidant as well as an antioxidant in cancer. In this study, the activity of oleuropein, in an in vitro model of ovarian (OCCs) and breast cancer cells (BCCs) was investigated. Cell viability and cell death were analyzed. Oxidative stress was measured by CM-H2DCFDA flow cytometry assay. Mitochondrial dysfunction was evaluated based on mitochondrial reactive oxygen species (ROS) and GPX4 protein levels. Further, the effects on iron metabolism were analyzed by measuring the intracellular labile iron pool (LIP). We confirmed that high doses of oleuropein show anti-proliferative and pro-apoptotic activity on HEY and MCF-7 cells. Moreover, our results indicate that low doses of oleuropein impair cell viability without affecting the mortality of cells, and also decrease the LIP and ROS levels, keeping them unchanged in MCF-7 cells. For the first time, our data show that low doses of oleuropein reduce erastin-mediated cell death. Interestingly, oleuropein decreases the levels of intracellular ROS and LIP in OCCs treated with erastin. Noteworthily, we observed an increased amount of ROS scavenging enzyme GPX4 together with a consistent reduction in mitochondrial ROS, confirming a reduction in oxidative stress in this model.
... Multiple phytochemicals have been tested for anti-cancer efficacy both in vitro and in vivo. They make use of complementary mechanisms to decelerate the process of developing a tumor by making free radicals as their targets [21], freezing proliferation and survival of cancerous cells [22], as well as the angiogenesis of tumors [23]. A complex range of actions are exhibited on several molecular targets and signal transduction pathways that include membrane receptors [24], kinases [25], downstream tumor-activator or suppressor proteins [26], transcriptional factors [27], microRNAs (miRNAs) [28], cyclins, and caspases [22]. ...
