Overproduction of the reactive oxygen species (ROS) superoxide (O
2
−) and hydrogen peroxide (H
2O
2) are increasingly implicated in human disease and aging. ROS are also being explored as important ...modulating agents in a number of cell signaling pathways. Earlier work has focused on development of small catalytic scavengers of O
2
−, commonly referred to as superoxide dismutase (SOD) mimetics. Many of these compounds also have substantial abilities to catalytically scavenge H
2O
2 and peroxynitrite (ONOO
−). Peroxides have been increasingly shown to disrupt cell signaling cascades associated with excessive inflammation associated with a wide variety of human diseases. Early studies with enzymatic scavengers like SOD frequently reported little or no beneficial effect in biologic models unless SOD was combined with catalase or a peroxidase. Increasing attention has been devoted to developing catalase or peroxidase mimetics as a way to treat overt inflammation associated with the pathophysiology of many human disorders. This review will focus on recent development of catalytic scavengers of peroxides and their potential use as therapeutic agents for pulmonary, cardiovascular, neurodegenerative and inflammatory disorders.
Thiocyanate (−SCN) is the primary determinant of hypothiocyanous acid (HOSCN) formation during inflammation. Under normal physiological levels of chloride, bromide, and −SCN in the plasma there is ...almost equal amounts of hypochlorous acid (HOCl) and HOSCN formed by myeloperoxidase (MPO). When −SCN transport is limited as observed in cystic fibrosis a larger proportion of HOCl is generated. Pharmacologic administration of −SCN can shift the proportion of HOSCN generated to almost 100% at concentrations around 400 μM 22.
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Animals often lick their wounds to promote healing. Saliva is thought to have healing properties due to it containing many agents that have antimicrobial properties. A number of these components make up the innate immune system’s oxidant generating network. One of these components is the saliva peroxidase also known as lactoperoxidase (LPO). LPO utilizes hydrogen peroxide (H2O2) and the pseudohalide thiocyanate (−SCN) to generate a broad-spectrum antimicrobial oxidant hypothiocyanous acid (HOSCN). HOSCN has antimicrobial activity against viruses, fungi, and bacteria. Although saliva contains the highest levels of −SCN and HOSCN in the body, this network operates in all extracellular fluids in the body including the blood, tears, nasal and lung fluids, gastric fluid, milk and semen. Another unique property of this system is that −SCN can react directly with all hypohalous acids and haloamines to funnel the oxidants to HOSCN that can be selectively detoxified by the host’s thioredoxin reductase but not by pathogen’s thioredoxin reductases due to evolutionary divergence. New understanding of this system many allow us to develop novel approaches to simultaneously treat inflammation while preventing infections.
Mitochondria are considered major generators of cellular reactive oxygen species (ROS) which are implicated in the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). We have ...recently shown that isolated mitochondria consume hydrogen peroxide (H₂O₂) in a substrate- and respiration-dependent manner predominantly via the thioredoxin/peroxiredoxin (Trx/Prx) system. The goal of this study was to determine the role of Trx/Prx system in dopaminergic cell death. We asked if pharmacological and lentiviral inhibition of the Trx/Prx system sensitized dopaminergic cells to mitochondrial dysfunction, increased steady-state H₂O₂ levels and death in response to toxicants implicated in PD. Incubation of N27 dopaminergic cells or primary rat mesencephalic cultures with the Trx reductase (TrxR) inhibitor auranofin in the presence of sub-toxic concentrations of parkinsonian toxicants paraquat; PQ or 6-hydroxydopamine; 6OHDA (for N27 cells) resulted in a synergistic increase in H₂O₂ levels and subsequent cell death. shRNA targeting the mitochondrial thioredoxin reductase (TrxR2) in N27 cells confirmed the effects of pharmacological inhibition. A synergistic decrease in maximal and reserve respiratory capacity was observed in auranofin treated cells and TrxR2 deficient cells following incubation with PQ or 6OHDA. Additionally, TrxR2 deficient cells showed decreased basal mitochondrial oxygen consumption rates. These data demonstrate that inhibition of the mitochondrial Trx/Prx system sensitizes dopaminergic cells to mitochondrial dysfunction, increased steady-state H₂O₂, and cell death. Therefore, in addition to their role in the production of cellular H₂O₂ the mitochondrial Trx/Prx system serve as a major sink for cellular H₂O₂ and its disruption may contribute to dopaminergic pathology associated with PD.
There is considerable evidence that chromosome structure plays important roles in gene control, but we have limited understanding of the proteins that contribute to structural interactions between ...gene promoters and their enhancer elements. Large DNA loops that encompass genes and their regulatory elements depend on CTCF-CTCF interactions, but most enhancer-promoter interactions do not employ this structural protein. Here, we show that the ubiquitously expressed transcription factor Yin Yang 1 (YY1) contributes to enhancer-promoter structural interactions in a manner analogous to DNA interactions mediated by CTCF. YY1 binds to active enhancers and promoter-proximal elements and forms dimers that facilitate the interaction of these DNA elements. Deletion of YY1 binding sites or depletion of YY1 protein disrupts enhancer-promoter looping and gene expression. We propose that YY1-mediated enhancer-promoter interactions are a general feature of mammalian gene control.
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•YY1 generally occupies active enhancers and promoters across cell types•YY1 can form dimers and promote DNA interactions•Perturbation of YY1 binding disrupts enhancer-promoter looping and gene expression•YY1’s structural role accounts for diverse functions reported previously
YY1 is a structural regulator of enhancer-promoter interactions and facilitates gene expression.
Super-enhancers (SEs) are clusters of enhancers that cooperatively assemble a high density of the transcriptional apparatus to drive robust expression of genes with prominent roles in cell identity. ...Here we demonstrate that the SE-enriched transcriptional coactivators BRD4 and MED1 form nuclear puncta at SEs that exhibit properties of liquid-like condensates and are disrupted by chemicals that perturb condensates. The intrinsically disordered regions (IDRs) of BRD4 and MED1 can form phase-separated droplets, and MED1-IDR droplets can compartmentalize and concentrate the transcription apparatus from nuclear extracts. These results support the idea that coactivators form phase-separated condensates at SEs that compartmentalize and concentrate the transcription apparatus, suggest a role for coactivator IDRs in this process, and offer insights into mechanisms involved in the control of key cell-identity genes.
Evolution has favored the utilization of dioxygen (O2) in the development of complex multicellular organisms. O2 is actually a toxic mutagenic gas that is highly oxidizing and combustible. It is ...thought that plants are largely to blame for polluting the earth's atmosphere with O2 owing to the development of photosynthesis by blue-green algae over 2 billion years ago. The rise of the plants and atmospheric O2 levels placed evolutionary stress on organisms to adapt or become extinct. This implies that all the surviving creatures on our planet are mutants that have adapted to the "abnormal biology" of O2. Much of the adaptation to the presence of O2 in biological systems comes from well-coordinated antioxidant and repair systems that focus on converting O2 to its most reduced form, water (H2O), and the repair and replacement of damaged cellular macromolecules. Biological systems have also harnessed O2's reactive properties for energy production, xenobiotic metabolism, and host defense and as a signaling messenger and redox modulator of a number of cell signaling pathways. Many of these systems involve electron transport systems and offer many different mechanisms by which antioxidant therapeutics can alternatively produce an antioxidant effect without directly scavenging oxygen-derived reactive species. It is likely that each agent will have a different set of mechanisms that may change depending on the model of oxidative stress, organ system, or disease state. An important point is that all biological processes of aerobes have coevolved with O2 and this creates a Pandora's box for trying to understand the mechanism(s) of action of antioxidants being developed as therapeutic agents.
Nuclear and chemical weapons of mass destruction share both a tragic and beneficial legacy in mankind’s history and health. The horrific health effects of ionizing radiation and mustard gas exposures ...unleashed during disasters, wars, and conflicts have been harnessed to treat human health maladies. Both agents of destruction have been transformed into therapies to treat a wide range of cancers. The discovery of therapeutic uses of radiation and sulfur mustard was largely due to observations by clinicians treating victims of radiation and sulfur mustard gas exposures. Clinicians identified vulnerability of leukocytes to these agents and repurposed their use in the treatment of leukemias and lymphomas. Given the overlap in therapeutic modalities, it goes to reason that there may be common mechanisms to target as protective strategies against their damaging effects. This commentary will highlight oxidative stress as a common mechanism shared by both radiation and sulfur mustard gas exposures and discuss potential therapies targeting oxidative stress as medical countermeasures against the devastating lung diseases wrought by these agents.
The evolution of the plant immune response has culminated in a highly effective defense system that is able to resist potential attack by microbial pathogens. The primary immune response is referred ...to as PAMP-triggered immunity (PTI) and has evolved to recognize common features of microbial pathogens. In the coevolution of host-microbe interactions, pathogens acquired the ability to deliver effector proteins to the plant cell to suppress PTI, allowing pathogen growth and disease. In response to the delivery of pathogen effector proteins, plants acquired surveillance proteins (R proteins) to either directly or indirectly monitor the presence of the pathogen effector proteins. In this review, taking an evolutionary perspective, we highlight important discoveries over the last decade about the plant immune response.
Interstitial lung disease encompasses a large group of chronic lung disorders associated with excessive tissue remodeling, scarring, and fibrosis. The evidence of a redox imbalance in lung fibrosis ...is substantial, and the rationale for testing antioxidants as potential new therapeutics for lung fibrosis is appealing. Current animal models of lung fibrosis have clear involvement of ROS in their pathogenesis. New classes of antioxidant agents divided into catalytic antioxidant mimetics and antioxidant scavengers are being developed. The catalytic antioxidant class is based on endogenous antioxidant enzymes and includes the manganese-containing macrocyclics, porphyrins, salens, and the non-metal-containing nitroxides. The antioxidant scavenging class is based on endogenous antioxidant molecules and includes the vitamin E analogues, thiols, lazaroids, and polyphenolic agents. Numerous studies have shown oxidative stress to be associated with many interstitial lung diseases and that these agents are effective in attenuating fibroproliferative responses in the lung of animals and humans.
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