Ros mediated cell death

It has long been recognized that an increase of reactive oxygen species ROS can modify the cell-signaling proteins and have functional consequences, which successively mediate pathological processes such as atherosclerosis, diabetes, unchecked growth, neurodegeneration, inflammation, and aging. While numerous articles have demonstrated the impacts of ROS on various signaling pathways and clarify the mechanism of action of cell-signaling proteins, their influence on the level of intracellular ROS, and their complex interactions among multiple ROS associated signaling pathways, the systemic summary is necessary.

Reactive oxygen species ROSgenerated through a variety of extracellular and intracellular actions, have drawn attention as novel signal mediators which are involved in growth, differentiation, progression, and death of the cell [ 12 ]. As a group of chemical species that include at least one oxygen atom in each molecule but display stronger reactivity than molecular oxygen, ROS comprise free radicals such as superoxide, hydroxyl radical, and singlet oxygen, as well as nonradical species such as hydrogen peroxide formed by the partial reduction of oxygen [ 3 — 5 ].

Oxygen free radicals are highly reactive and have the capacity to damage cellular components such as proteins, lipids, and nucleic acids.

Mitochondria, Apoptosis, and Oxidative Stress

Classically, ROS were regarded as host defending molecule released by neutrophil for destructing exogenous pathogens such as bacteria; however, accumulated evidence indicates that ROS play central roles in determination of cell fate as second messengers and modifying of various signaling molecules [ 6 — 9 ].

It has been demonstrated that ROS have impacts on several signaling pathways and the mechanisms of how ROS act on cell-signaling proteins, how the cell-signaling proteins influence the level of intracellular ROS in turn, and if there are complex interactions between different ROS associated signaling pathways have been clarified, but the systemic summary is necessary. Under a physiological state, the level of cellular ROS is stable in a dynamic equilibrium, and this balance is modulated by cellular processes that produce ROS and eliminate them Figure 1.

The resource of cellular ROS could be broadly divided into two main categories: firstly, there are those biological processes, mainly the mitochondrial oxidative metabolism, that release ROS as a byproduct, or a waste product, of various other necessary reactions and, secondly, there are those processes, in cellular response to xenobiotics, cytokines, and bacterial invasion, that generate ROS intentionally, either in molecular synthesis or in breakdown, as part of a signal transduction pathway, or as part of a cell defense mechanism [ 10 — 12 ].

The initial product of the mitochondrial respiratory chain is mainly generated by complexes I and III and could be quickly transformed into H 2 O 2 by the enzyme superoxide dismutase SOD and then could be reduced to water by catalase or glutathione peroxidase [ 13 — 16 ]. And, as a critical role to withstand the excessive formation of intracellular ROS, series of antioxidant proteins have been found.

SOD2, in the matrix, converts superoxide, which cannot diffuse across membranes, to H 2 O 2 which then is reduced to water by catalase. MEKK1 is a redox-sensitive kinase that could be glutathionylated at C leading to its inactivation [ 44 ]. Furthermore, NIK, the upstream kinase in the noncanonical pathway, is believed to be activated by ROS through inhibition of phosphatases and oxidation of cysteine residues [ 4546 ]. Meanwhile, in some cells, treatment with H 2 O 2 leads to the phosphorylation and activation of phospholipase C- PLC- gamma which results in the generation of inositol trisphosphate IP3 and diacylglycerol DAG [ 59 ].

IP3 could increase the intracellular calcium by inducing the release of calcium from intracellular stores that can mediate activation of ERK pathway and generation of DAG and increases in intracellular calcium which results in the activation of several forms of protein kinase C PKC leading to Ras and Raf activation [ 6061 ]. TNF receptor-associated JNK activation is thought to be mediated in part by oxygen radicals because superoxide anion and lipid peroxide-scavengers inhibit JNK activation.

Furthermore, it is possible that low levels of ROS intermediates leave phosphatase activity intact, leading to a transient activation of JNK. The TNF receptors switch on the p38 pathway via the activation of cdc42, whereas growth factor receptors switch on the p38 pathway by the sequential activation of Ras and Rac1 [ 67 ].

The BMK1 also known as ERK5 pathway, which has been involved in cell survival, antiapoptotic signaling, angiogenesis, cell motility, differentiation, and cell proliferation, is one of the least studied members of the MAPK family [ 70 ]. This pathway consists of three main cellular components: Kelch-like ECH-associated protein 1 Keap1nuclear factor erythroid 2-related factor 2 Nrf2and antioxidant response elements ARE [ 71 — 76 ].

Under normal physiological conditions, Keap1, which is also called an inhibitor of Nrf2 INrf2is associated with Nrf2 the majority of which resides in the cytoplasm and recruits and interacts with the cullin-3 E3-ubiquitin ligase Cul3 [ 77 ].One of the important initial events upon recognition of a plant pathogen is the changes in the redox status of the infected cells due to the accumulation of Reactive Oxygen Species ROS.

Though plants have evolved an array of defensive strategies to resist stresses, including those from attack by pathogens, but the changed redox cue of the infected cells are often exploited by the plant for specific purpose as well.

It is becoming evident gradually that ROS or the redox cue, which are generated during pathogen attack are recognized by plant as a signaling agent for triggering responses. The necrosis of infected tissue caused by ROS during pathogen infection increases host susceptibility to necrotrophic pathogen, but exhibit resistance to biotrophic pathogen. Avirulent pathogens often induce a biphasic ROS accumulation with a weak transient first phase, followed by a more intense continuous phase.

In this review we provide the relevant findings of signaling role of ROS in plant defence responses. Biotic stresses caused by pathogenic infection spur the generation of ROS in plants through distinct pathways involving specific ROS-producing enzymatic systems that results in accumulation of cellular or intercellular prooxidants [1].

Biotrophic pathogen prefer living, while necrotrophic one prefer dead cells for nutritional purposes. Therefore, tissue necrosis caused by ROS during pathogen infection increases host susceptibility to necrotrophic but resistance to biotrophic pathogen.

Many pathogen infections to plant induce a radical burst. It is one of the earliest events in the plant defence response [1]. ROS play pivotal role in survival and death of the plants. Many regulators are not only involved in growth and development but are also involved in limiting pathogen ingression, induction of apoptosis and signal transduction of several defence processes, thereby playing pivotal role in both cell survival and death [2].

Pathogen-induced burst of ROS production, particularlyHydrogen peroxide HH 2 O 2at the plant cell surface drives rapid peroxidase-mediated oxidative cross-linking of structural proteins of cell wall, thereby strengthening this physical barrier against pathogen ingress [3]. The burst of ROS production has been implicated in diverse physiological processes including resistance to biotic and abiotic stress [5].

Deciphering the physiology and implication of oxidative burst associated with stress elicitation in plants has been the subject of investigation for quite a long time. The necessity for ROS appears to be diverse for resistance to different pathogens [6,7]. ROS seems to play a critical role as signalling intermediates during the defence responses to bacterial pathogens [8].

In non-stressed plant tissues both enzymatic and non-enzymatic antioxidants are able to maintain redox homeostasis by neutralizing the harmful effects of ROS. In fact, the greater kinetics of ROS generation and poor antioxidant efficiency in severe biotic sstresses accelerates cellular necrosis and PCD [9].

ROS has been found to be closely integrated with the damage of the tissue observed during pathogenic infection. Previous studies exhibited that ROS are produced by plant cells on invasion of the pathogens [10,11]. The change in redox status of the infected tissue due to accelerated generation of ROS following the infection by pathogenic organism is one of the fastest plant responses to infection.

As a result, HH 2 O 2 is detected in significantly greater amount within minutes following the addition of elicitor prepared from walls of the pathogen Verticillium dahliae to soybean cell cultures.Reactive oxygen species ROS are well known for being both beneficial and deleterious.

Much evidences has accumulated over the past decade, suggesting that patients infected with RNA viruses are under chronic oxidative stress. Changes to the body's antioxidant defense system, in relation to SOD, ascorbic acid, selenium, carotenoids, and glutathione, have been reported in various tissues of RNA-virus infected patients.

Oxidative stress via RNA virus infections can contribute to several aspects of viral disease pathogenesis including apoptosis, loss of immune function, viral replication, inflammatory response, and loss of body weight. We focus on how ROS production is correlated with host cell death. Moreover, ROS may play an important role as a signal molecule in the regulation of viral replication and organelle function, potentially providing new insights in the prevention and treatment of RNA viruses and retrovirus infections.

Cellular metabolisms produce different varieties of reactive oxygen species ROS as byproducts. These ROS play an important role in cell signaling and regulate hormone action, growth factors, cytokines, transcription, apoptosis, ion transport, immunomodulation, and neuromodulation [ 12 ].

They lend fundamental aid to the normal functioning of the body's immune system and proliferate T-cells that provide immunological defense adaptive immunity [ 34 ]. Any imbalance in the production of ROS and the body's inability to detoxify these ROS is referred to as oxidative stress [ 6 ]. The research has shown that children suffering from hepatitis B or C exhibit increased levels of lipid peroxidation, which indicates weak antioxidant defense due to low catalase and SOD activity [ 9 ].

Earlier and recent studies have suggested that ROS induces apoptosis [ 10 — 12 ], and that the agents that cause apoptosis are either oxidants or generate the ROS.

ros mediated cell death

This hypothesis was later shown to be correct when researchers demonstrated the role of proto-oncogene BCL-2 in preventing apoptosis in an antioxidant way [ 13 ]. Peterhan and his coworkers were the first to demonstrate that a virus could generate ROS from phagocytes [ 14 ]. Later research showed that many retroviruses, DNA viruses and RNA viruses can cause cell death by generating oxidative stress in infected cells [ 15 — 17 ]. Inthe scientific community held its first conference to discuss the possible interaction between viral infection and ROS in detail [ 18 ].

These viruses posses the highest mutation rates among every living creature [ 19 — 22 ]. Therefore, it is not always easy to develop successful and effective vaccines and drugs against these viruses. Oxidative stress always plays a dominant pathogenic role in HIV and hepatitis infections. A decrease in antioxidants indicates the weakening of the immune system, as immune cells require more antioxidants to maintain their function and integrity.

This in turn leads to decreases in zinc and vitamin E antioxidants. The decrease in zinc results in the inhibition of intracellular virus replication [ 26 ], and the selenium decrease indicates the progression of HIV toward AIDS. After suffering the primary illness, patients do not show any symptoms for up to more than 10 years, during which the virus load falls but the virus does not stop replicating.

Researchers first exhibited the occurrence of oxidative stress during chronic hepatitis C in [ 32 ]. This OS is associated with hepatic damage, a decrease in GHS, an increase in serum malondialdrhyde MDA4-hydroxynonenal HNE and caspase activity, and decreases in plasma and hepatic zinc concentrations [ 33 — 35 ].

Zinc therapy increases the functioning of surviving liver tissue [ 35 ]. However, zinc and selenium deficiencies affect DNA repair and the immune system, increasing the chances of chronicity and malignancy [ 36 ]. HCV replication takes place in hepatocytes, which potentially attack and propagate in immune system cells.Thank you for visiting nature.

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A Nature Research Journal. Some insects, such as dragonflies, have evolved nanoprotrusions on their wings that rupture bacteria on contact. This has inspired the design of antibacterial implant surfaces with insect-wing mimetic nanopillars made of synthetic materials.

Here, we characterise the physiological and morphological effects of mimetic titanium nanopillars on bacteria. The nanopillars induce deformation and penetration of the Gram-positive and Gram-negative bacterial cell envelope, but do not rupture or lyse bacteria. They can also inhibit bacterial cell division, and trigger production of reactive oxygen species and increased abundance of oxidative stress proteins.

It is now well established that insect wings, including the cicada and dragonfly, possess antibacterial and antifungal properties. Previous studies indicate that this process is mediated by the physical nanoprotrusions found on the wing surface, which ultimately stretch and damage the microbial cell upon contact, leading to lysis and death 123456. Bactericidal effects were also described for other Gram-negative bacteria, including Branhamella catarrhalis, Escherichia coli and Pseudomonas fluorescens 6.

Alongside cicada, dragonfly wings have been shown to possess efficient bactericidal properties. Diplacodes bipunctata wings were found to mediate killing of both Gram-negative P. The capillary architecture of D. The unique bactericidal properties of cicada and dragonfly wings have drawn significant research interest 78910as the physical nature of bacterial killing could provide an effective strategy to prevent biofilm formation, and infection of indwelling and implantable devices, while negating the current need to use materials impregnated with antibiotics.

To date, a wide range of nanofabrication techniques have been utilised to generate bactericidal nanotopographies on synthetic materials, including black silicon bSi 2titanium 11titanium alloy 12 and polymers Several models for the process of contact killing have been proposed.

The biophysical model suggested that cicada wing nanopillars induce physical stretching of the cell membrane upon contact, leading to bacterial rupture and death, and cell rigidity was reported to be an important determinant of susceptibility In support of this, the elastic mechanical model proposed that Gram-positive bacteria are less susceptible to nanopillar deformation and rupture owing to their lower maximum stretching capacity.

However, by increasing nanopillar sharpness and spacing, the antibacterial properties may be enhanced A quantitative thermodynamic model proposed that the bactericidal activity of nanopatterned surfaces is directly related to the balance between adhesion energy and deformation energy.

Multiple factors are reported to influence the antimicrobial efficacy of natural and synthetic nanopillars. Of note, the microbial adhesion force to a nanotopography has been shown to directly influence viability. Saccharomyces cerevisiae rupturing was greatest in strains that adhered most strongly to cicada wing nanopillars 5.

Similarly, the strong adhesion between dragonfly nanopillars and E. The rigidity of bacterial cells has also been found to influence their susceptibility to mechanical rupture 614whereby Gram-negative bacteria were more sensitive to nanopillar-mediated stretching.

ros mediated cell death

This observation most likely reflects variations in envelope architecture. In addition to this, nanotopography geometries, including aspect ratio and nanopillar density, have been shown to influence the efficiency of bactericidal activity 3513 Although the bactericidal activity of natural and synthetic nanopillars has been widely reported, no consensus has been reached on the precise mechanism that leads to the microbial cell death and importantly, while many studies infer that nanopillars mediate mechanical rupture of bacterial cells, this has not been shown conclusively.

In addition to their capacity to rupture and lyse bacteria, nanostructured surfaces are reported to alter the genomic and proteomic profile of bacteria.Thank you for visiting nature.

You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. A Nature Research Journal. The effectiveness of current gene-targeting therapeutic strategies is limited by the drug resistance and the genomic instability that cancer cells acquire.

Most cancer cells exhibit increased aerobic glycolysis and oxidative stress — features that could be important in the development new anticancer strategies.

An increase in reactive oxygen species ROS is associated with abnormal cancer cell growth and reflects a disruption of redox homeostasis, due either to an elevation of ROS production or to a decline of ROS-scavenging capacity. If the increase of ROS reaches a certain threshold level that is incompatible with cellular survival, ROS may exert a cytotoxic effect, leading to the death of malignant cells and thus limiting cancer progression. However, under persistent intrinsic oxidative stress, many cancer cells become well-adapted to such stress and develop an enhanced, endogenous antioxidant capacity.

Abrogation of this adaptation mechanism with 'pro-oxidant' agents could be an attractive strategy to preferentially affect cancer cells and could have significant therapeutic implications. Because radiation and many conventional cytotoxic anticancer drugs can also directly or indirectly increase ROS levels in cancer cells, combination of radiotherapy or standard chemotherapy with agents that abrogate antioxidant systems in cancer cells should also be explored. Finally, the undefined, possibly unique, redox biology of cancer stem cells suggests that redox-modulating strategies could represent an effective strategy to combat this highly drug-resistant population of cells.

Increased generation of reactive oxygen species ROS and an altered redox status have long been observed in cancer cells, and recent studies suggest that this biochemical property of cancer cells can be exploited for therapeutic benefits.

Cancer cells in advanced stage tumours frequently exhibit multiple genetic alterations and high oxidative stress, suggesting that it might be possible to preferentially eliminate these cells by pharmacological ROS insults. However, the upregulation of antioxidant capacity in adaptation to intrinsic oxidative stress in cancer cells can confer drug resistance. Abrogation of such drug-resistant mechanisms by redox modulation could have significant therapeutic implications. We argue that modulating the unique redox regulatory mechanisms of cancer cells might be an effective strategy to eliminate these cells.

Druker, B. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. Comoglio, P. Drug development of MET inhibitors: targeting oncogene addiction and expedience.

Nature Rev. Drug Discov. Couzin, J. Cancer drugs. Smart weapons prove tough to design. Science— Accessed November 22, Saudi J Gastroenterol. Nat Rev Dis Primers. Sreevalsan S and Safe S: Reactive oxygen species and colorectal cancer. Curr Colorectal Cancer Rep. View Article : Google Scholar.

Nat Rev Drug Discov.

ros mediated cell death

PLoS One. Cell Death Dis. Int J Biochem Cell Biol. Free Radic Biol Med. Eur J Med Chem. BMC Cancer. Onco Targets Ther. Semin Cancer Biol. Cold Spring Harb Perspect Biol. Genes Cancer. Biochem J. Anticancer Drugs. J Am Chem Soc. Mol Cancer. Gastrointest Cancer Res. Cancer Res. Br J Cancer. Clin Cancer Res. Dig Dis Sci. ACS Chem Biol. Expert Opin Biol Ther. Curr Pharm Des.Thank you for visiting nature. You are using a browser version with limited support for CSS.

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Novel drugs are urgently needed for gastric cancer GC treatment. Chaetocin therefore may be a potential agent for GC treatment. Gastric cancer GC is the fifth most common cancer and the third leading cause of cancer-related death worldwide 1.

ros mediated cell death

The traditional treatment options for GC include surgery and chemotherapy. However, the 5-year survival rates of patients receiving these therapies are still very low.

The targeting of specific molecules could be an efficient strategy for the treatment of GC. Recently, some novel molecular targeted agents have been used to treat GC, including trastuzumab which targets the epidermal growth factor receptor and bevacizumab which targets the vascular endothelial growth factor. However, the efficiency of these drugs is limited 23.

Induction of ROS‑mediated cell death and activation of the JNK pathway by a sulfonamide derivative

Thus, the identification of new molecular targets and the development of novel targeted therapeutic agents, which can be highly efficacious in treating GC, are urgently needed.

Reduced TRXs function as antioxidants by donating reducing equivalents to reactive oxygen species ROS scavenging enzymes such as peroxiredoxins. By regulating cell redox events, the TRX-TRXR system influences various cellular functions including proliferation, differentiation and death 4567.

However, the TRX-TRXR system has recently been found to be upregulated in a variety of human cancers including gastric, colorectal, lung and liver cancers, and overexpression of specific components of this system is linked to tumor cell proliferation, invasion, metastasis, and drug resistance 8910 Chaetocin is a small-molecule thiodioxopiperazine natural product isolated from the Chaetomium species of fungi 15 Recently, some studies have shown that chaetocin has a potent inhibitory effect on cancer cells 1718192021indicating that chaetocin may be a potential agent for cancer therapy.

Molecular mechanisms associated with the anticancer effect of chaetocin are still vague. Most importantly, chaetocin was shown to inhibit the activity of TRXR-1 in the cell-free system, which may be related to its anticancer effect However, the pharmacological effect and underlying mechanism of action of chaetocin in GC cells remains unclear.

In the present study, we investigated the antiGC effects of chaetocin both in vitro and in vivo and determined whether chaetocin exerts its anticancer effects in GC by inhibiting TRXR Chaetocin was purchased from Sigma-Aldrich St.

Reactive oxygen species

Anti-mouse immunoglobulin G and anti-rabbit immunoglobulin G horseradish peroxidase-conjugated secondary antibodies were purchased from Sigma-Aldrich. Stable cell lines were established by puromycin selection. Experiments were performed using a standard protocol developed by Roche Applied Science. Cell proliferation was monitored by measuring electrical impedance across microelectrodes on the bottom of the E-Plate.

Impedance was expressed as the normalized cell index, which is an arbitrary unit. The results were analyzed using the real-time cell analysis software supplied by the company.

After chaetocin treatment, cells were washed with PBS, fixed in ice-cold methanol, and stained with crystal violet. An Epson scanner Suwa, Nagano, Japan was used to image the colonies.

The next day, membranes were washed with PBST, incubated with a horseradish peroxidase-conjugated secondary antibody and finally detected using enhanced chemiluminescence. After chaetocin treatment, HGC and AGS cell lysates were denatured and precipitated by trichloroacetic acid at a final concentration of 7. The structure of chaetocin was assembled using Chemoffice. The complex of TRXR-1 protein and chaetocin obtained from the docking simulation were used as the initial coordinates for MD simulations.

TRXR-1 and chaetocin were assessed using ff99sb force field and general amber force field, respectively. Reads were aligned to the human RefSeq hg38 reference genome using Bowtie2. Briefly, a total of 1.


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