Organismal life encounters reactive oxidants from internal metabolism and environmental toxicant exposure. Reactive oxygen and nitrogen species cause oxidative stress and are traditionally viewed as ...being harmful. On the other hand, controlled production of oxidants in normal cells serves useful purposes to regulate signaling pathways. Reactive oxidants are counterbalanced by complex antioxidant defense systems regulated by a web of pathways to ensure that the response to oxidants is adequate for the body's needs. A recurrent theme in oxidant signaling and antioxidant defense is reactive cysteine thiol-based redox signaling. The nuclear factor erythroid 2-related factor 2 (Nrf2) is an emerging regulator of cellular resistance to oxidants. Nrf2 controls the basal and induced expression of an array of antioxidant response element-dependent genes to regulate the physiological and pathophysiological outcomes of oxidant exposure. This review discusses the impact of Nrf2 on oxidative stress and toxicity and how Nrf2 senses oxidants and regulates antioxidant defense.
Polarization of immune cells is commonly observed in host responses associated with microbial immunity, inflammation, tumorigenesis, and tissue repair and fibrosis. In this process, immune cells ...adopt distinct programs and perform specialized functions in response to specific signals. Accumulating evidence indicates that inhalation of micro- and nano-sized particulates activates barrier immune programs in the lung in a time- and context-dependent manner, including type 1 and type 2 inflammation, and T helper (Th) 17 cell, regulatory T cell (Treg), innate lymphoid cell (ILC), and myeloid-derived suppressor cell (MDSC) responses, which highlight the polarization of several major immune cell types. These responses facilitate the pulmonary clearance and repair under physiological conditions. When exposure persists and overwhelms the clearance capacity, they foster the chronic progression of inflammation and development of progressive disease conditions, such as fibrosis and cancer. The pulmonary response to insoluble particulates thus represents a distinctive disease process wherein non-infectious, persistent exposures stimulate the polarization of immune cells to orchestrate dynamic inflammatory and immune reactions, leading to pulmonary and pleural chronic inflammation, fibrosis, and malignancy. Despite large variations in particles and their associated disease outcomes, the early response to inhaled particles often follows a common path. The initial reactions entail a barrier immune response dominated by type 1 inflammation that features active phagocytosis by M1 macrophages and recruitment of neutrophils, both of which are fueled by Th1 and proinflammatory cytokines. Acute inflammation is immediately followed by resolution and tissue repair mediated through specialized pro-resolving mediators (SPMs) and type 2 cytokines and cells including M2 macrophages and Th2 lymphocytes. As many particles and fibers cannot be digested by phagocytes, resolution is often extended and incomplete, and type 2 inflammation becomes heightened, which promotes interstitial fibrosis, granuloma formation, and tumorigenesis. Recent studies also reveal the involvement of Th17-, Treg-, ILC-, and MDSC-mediated responses in the pathogenesis caused by inhaled particulates. This review synopsizes the progress in understanding the interplay between inhaled particles and the pulmonary immune functions in disease pathogenesis, with focus on particle-induced polarization of immune cells and its role in the development of chronic inflammation, fibrosis, and cancer in the lung.
The utilization of molecular oxygen as the terminal electron acceptor for energy production has in many ways shaped the evolution of complex life, physiology, and certain disease processes. The ...generation of reactive oxygen species (ROS), either as by-products of O(2) metabolism or by specialized enzymes, has the potential to damage cellular components and functions. Exposure to a variety of exogenous toxicants also promotes ROS production directly or through indirect means to cause toxicity. Oxidative stress activates the expression of a wide range of genes that mediate the pathogenic effect of ROS or are required for the detection and detoxification of the oxidants. In many cases, these are mediated by specific transcription factors whose expression, structure, stability, nuclear targeting, or DNA-binding affinity is regulated by the level of oxidative stress. This review examines major transcription factors that mediate transcriptional responses to oxidative stress, focusing on recent progress in the signaling pathways and mechanisms of activation of transcription factors by oxidative stress and the implications of this regulation in the development of disease and chemical toxicity.
We investigated the potential regulatory role of miR-219-5p in esophageal squamous cell carcinoma (ESCC) and looked at the underlying mechanisms in ESCC.
Real-time PCR was used to determine the ...levels of miR-219-5p in ESCC tissues and cell lines. The effects of miR-219-5p and cyclin A2 (CCNA2) on cell proliferation and cell cycle progression were evaluated using MTT, colony formation and flow cytometry assays with ESCC cell lines EC9706 and TE-9. Bioinformatics techniques and the luciferase reporter assay were applied to validate CCNA2 as the miR-219-5p target in ESCC cells. The mRNA and protein levels of CCNA2 were measured using real-time PCR and western blotting.
MiR-219-5p expression was significantly lower in ESCC tissues and cells than in healthy tissues. Upregulation of miR-219-5p repressed cell proliferation and induced cell cycle arrest at the G2/M phase. CCNA2 was identified and confirmed as a direct downstream target of miR-219-5p and its expression negatively correlated with miR-219-5p profiles in ESCC tissues. Knockdown of CCNA2 potentiated the effects of miR-219-5p on cell proliferation and cell cycle distribution.
Our results demonstrate that miR-219-5p might function as a tumor suppressor by directly targeting CCNA2 expression. It could serve as a new therapeutic target for ESCC.
Eastern China provides a precious opportunity to explore how subduction drives evolution of the overlying continental lithosphere and to understand the fate of subducted plates. In this study, a ...synthesis of geochronological, whole-rock geochemical and zircon Hf isotopic data is used to examine temporal and spatial variations in distribution, composition and generation of Mesozoic magmas in the northern North China Craton. A compilation of age data reveals over 1000 km of inland-ward migration of a magmatic belt during 185– 145 Ma and then back again after 145– 140 Ma, coincident with the transition from contractional to extensional deformation regime in the very early Cretaceous. Distinct trends in lithologies, geochemistry and NdHf isotopes as a function of age and location are also observed in these magmas. The Mesozoic magmatism and deformation, as well as the lithospheric destruction, across the northern North China Craton is interpreted as the consequence of a change in subduction geodynamic regime of the Paleo-Pacific slab and its interaction with overlying continental lithosphere, which involves an active continental arc at Korean and Liaodong Peninsulas in the early-middle Jurassic, progressive shallowing of the subducting Paleo-Pacific plate in the middle-late Jurassic, and subsequent slab rollback in the early Cretaceous. Considering that trench retreat and slab-roll back are demonstrated as the pre-request of slab stagnation in the mantle transition zone, we further propose that the big mantle wedge structure in East Asia was probably initiated at 145– 140 Ma and was likely fully developed by ~120 Ma. Such a peculiar deep mantle structure governed the post-Cretaceous evolution of the Asian continental lithosphere by mediating the chemical and physical properties of upper mantle.
Stroke and myocardial infarction are among the most common causes of mortality and disability in the world. The ischemic injury underlying these illnesses is complex, involving intricate interplays ...among many biological functions including energy metabolism, vascular regulation, hemodynamics, oxidative stress, inflammation, platelet activation, and tissue repair that take place in a context- and time-dependent manner. The current drug therapy of choice is to timely resupply the blood to the ischemic tissue; but reperfusion may introduce additional harm to the tissue through a process known as ischemia/reperfusion injury. As such, new drugs that would complement reperfusion by providing neural and cardiovascular protection and by targeting multiple abnormalities in ischemia are receiving increased attention. Scutellarin is an herbal flavonoid glucuronide with multiple pharmacological activities. Owing to its multiple beneficial effects, such as anti-oxidant, anti-inflammation, vascular relaxation, anti-platelet, anti-coagulation, and myocardial protection, scutellarin has been used clinically to treat stroke, myocardial infarction, and diabetic complications. Over the past three decades, clinical and pharmacological studies have accumulated a body of evidence that not only demonstrated these therapeutic effects, but also provided significant insights into the pharmacokinetic behavior, therapeutic profile, and mode of action of scutellarin in humans and animal models. Medicinal modification and new drug delivery methods have led to the development of new derivatives and formulations of scutellarin with improved bioavailability, efficacy, and safety. Here we review the current literature on scutellarin to provide a comprehensive understanding of the pharmacological activity, mechanism of action, toxicity, and therapeutic potential of scutellarin for the treatment of ischemia, diabetic complications, and other chronic diseases.
We examine a method to detect the light speed variation from gamma ray burst data observed by the Fermi Gamma-ray Space Telescope (FGST). We suggest new criteria to determine the characteristic time ...for low energy photons by the energy curve and the average energy curve respectively, and obtain similar results compared with those from the light curve. We offer a new criterion with both the light curve and the average energy curve to determine the characteristic time for low energy photons. We then apply the new criteria to the GBM NaI data, the GBM BGO data, and the LAT LLE data, and obtain consistent results for three different sets of low energy photons from different FERMI detectors.
Tea plant (Camellia sinensis) is an economically important beverage crop. Drought stress (DS) seriously limits the growth and development of tea plant, thus affecting crop yield and quality. To ...elucidate the molecular mechanisms of tea plant responding to DS, we performed transcriptomic analysis of tea plant during the three stages control (CK) and during DS, and recovery (RC) after DS using RNA sequencing (RNA-Seq). Totally 378.08 million high-quality trimmed reads were obtained and assembled into 59,674 unigenes, which were extensively annotated. There were 5,955 differentially expressed genes (DEGs) among the three stages. Among them, 3,948 and 1,673 DEGs were up-regulated under DS and RC, respectively. RNA-Seq data were further confirmed by qRT-PCR analysis. Genes involved in abscisic acid (ABA), ethylene, and jasmonic acid biosynthesis and signaling were generally up-regulated under DS and down-regulated during RC. Tea plant potentially used an exchange pathway for biosynthesis of indole-3-acetic acid (IAA) and salicylic acid under DS. IAA signaling was possibly decreased under DS but increased after RC. Genes encoding enzymes involved in cytokinin synthesis were up-regulated under DS, but down-regulated during RC. It seemed probable that cytokinin signaling was slightly enhanced under DS. In total, 762 and 950 protein kinases belonging to 26 families were differentially expressed during DS and RC, respectively. Overall, 547 and 604 transcription factor (TF) genes belonging to 58 families were induced in the DS vs. CK and RC vs. DS libraries, respectively. Most members of the 12 TF families were up-regulated under DS. Under DS, genes related to starch synthesis were down-regulated, while those related to starch decomposition were up-regulated. Mannitol, trehalose and sucrose synthesis-related genes were up-regulated under DS. Proline was probably mainly biosynthesized from glutamate under DS and RC. The mechanism by which ABA regulated stomatal movement under DS and RC was partly clarified. These results document the global and novel responses of tea plant during DS and RC. These data will serve as a valuable resource for drought-tolerance research and will be useful for breeding drought-resistant tea cultivars.
With the rapid development of nanotechnology, nanoparticles have been widely used in many applications such as phototherapy, cell imaging, and drug/gene delivery. A better understanding of how ...nanoparticles interact with bio‐system (especially cells) is of great importance for their potential biomedical applications. In this review, the current status and perspective of theoretical and computational investigations is presented on the nanoparticle‐biomembrane interactions in cellular delivery. In particular, the determining parameters (including the properties of nanoparticles, cell membranes and environments) that govern the cellular uptake of nanoparticles (direct penetration and endocytosis) are discussed. Further, some special attention is paid to their interactions beyond the translocation of nanoparticles across membranes (e.g., nanoparticles escaping from endosome and entering into nucleus). Finally, a summary is given, and the challenging problems of this field in the future are identified.
Nanoparticles have recently been widely used as drug delivery carriers. This review summarizes the recent progresses on the theoretical and computational investigations of nanoparticle‐biomembrane interactions in cellular delivery. The factors that govern cellular uptake of nanoparticles are discussed in detail, and their interactions in intracellular trafficking are also illustrated. Finally, the challenging problems of this field in the future are given.
It is postulated in Einstein's relativity that the speed of light in vacuum is a constant for all observers. However, the effect of quantum gravity could bring an energy dependence of light speed. ...Even a tiny speed variation, when amplified by the cosmological distance, may be revealed by the observed time lags between photons with different energies from astrophysical sources. From the newly detected long gamma ray burst GRB 160509A, we find evidence to support the prediction for a linear form modification of light speed in cosmological space.
PDF
