The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

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Nitric Oxide and Peroxynitrite in Health and Disease

Inflammation and Alzheimer's disease.

Multicolor nonlinear microscopy of living tissue using two- and three-photon-excited intrinsic fluorescence combined with second harmonic generation by supermolecular structures produces images with the resolution and detail of standard histology without the use of exogenous stains. Imaging of intrinsic indicators within tissue, such as nicotinamide adenine dinucleotide, retinol, indoleamines, and collagen provides crucial information for physiology and pathology. The efficient application of multiphoton microscopy to intrinsic imaging requires knowledge of the nonlinear optical properties of specific cell and tissue components. Here we compile and demonstrate applications involving a range of intrinsic molecules and molecular assemblies that enable direct visualization of tissue morphology, cell metabolism, and disease states such as Alzheimer's disease and cancer.

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Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation

Oxidative stress has long been linked to the neuronal cell death that is associated with certain neurodegenerative conditions. Whether it is a primary cause or merely a downstream consequence of the neurodegenerative process is still an open question, however. The advent of a growing number of in vitro and in vivo models that emulate human disease pathology is aiding scientists in deciphering just where oxidative stress intersects with other cellular events in the emerging roadmap leading to neurodegeneration. Here I review the evidence for oxidative stress in neurodegeneration and how this relates to other cellular events.

Oxidative stress in neurodegeneration: cause or consequence?

Free radicals and other so-called 'reactive species' are constantly produced in the brain in vivo. Some arise by 'accidents of chemistry', an example of which may be the leakage of electrons from the mitochondrial electron transport chain to generate superoxide radical (O2*-). Others are generated for useful purposes, such as the role of nitric oxide in neurotransmission and the production of O2*- by activated microglia. Because of its high ATP demand, the brain consumes O2 rapidly, and is thus susceptible to interference with mitochondrial function, which can in turn lead to increased O2*- formation. The brain contains multiple antioxidant defences, of which the mitochondrial manganese-containing superoxide dismutase and reduced glutathione seem especially important. Iron is a powerful promoter of free radical damage, able to catalyse generation of highly reactive hydroxyl, alkoxyl and peroxyl radicals from hydrogen peroxide and lipid peroxides, respectively. Although most iron in the brain is stored in ferritin, 'catalytic' iron is readily mobilised from injured brain tissue. Increased levels of oxidative damage to DNA, lipids and proteins have been detected by a range of assays in post-mortem tissues from patients with Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis, and at least some of these changes may occur early in disease progression. The accumulation and precipitation of proteins that occur in these diseases may be aggravated by oxidative damage, and may in turn cause more oxidative damage by interfering with the function of the proteasome. Indeed, it has been shown that proteasomal inhibition increases levels of oxidative damage not only to proteins but also to other biomolecules. Hence, there are many attempts to develop antioxidants that can cross the blood-brain barrier and decrease oxidative damage. Natural antioxidants such as vitamin E (tocopherol), carotenoids and flavonoids do not readily enter the brain in the adult, and the lazaroid antioxidant tirilazad (U-74006F) appears to localise in the blood-brain barrier. Other antioxidants under development include modified spin traps and low molecular mass scavengers of O2*-. One possible source of lead compounds is the use of traditional remedies claimed to improve brain function. Little is known about the impact of dietary antioxidants upon the development and progression of neurodegenerative diseases, especially Alzheimer's disease. Several agents already in therapeutic use might exert some of their effects by antioxidant action, including selegiline (deprenyl), apomorphine and nitecapone.

Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment.

HPLC with electrochemical array detection (HPLC-ECD) was used to quantify 3,3'-dityrosine (diTyr) and 3-nitrotyrosine (3-NO2-Tyr) in four regions of the human brain that are differentially affected in Alzheimer's disease (AD). DiTyr and 3-NO2-Tyr levels were elevated consistently in the hippocampus and neocortical regions of the AD brain and in ventricular cerebrospinal fluid (VF), reaching quantities five- to eightfold greater than mean concentrations in brain and VF of cognitively normal subjects. Uric acid, a proposed peroxynitrite scavenger, was decreased globally in the AD brain and VF. The results suggest that AD pathogenesis may involve the activation of oxidant-producing inflammatory enzyme systems, including nitric oxide synthase.

https://www.jneurosci.org/content/jneuro/18/20/8126.full.pdf

Electrochemical Analysis of Protein Nitrotyrosine and Dityrosine in the Alzheimer Brain Indicates Region-Specific Accumulation

Pirfenidone (PFD) was the first approved drug by FDA for the treatment of idiopathic pulmonary fibrosis (IPF). However, the rapid metabolism of 5-methyl of PFD increases the risk of side effects in clinics. Thus, in this paper, a common practice that a stable amide bond linking various groups used to replace 5-methyl of PFD in medicinal chemistry was applied, and total 18 PFD derivatives were synthesized. All compounds were investigated for their antiproliferation activities against NIH3T3 cells and the structure-activity relationships of the target compounds were also discussed. Among them, YZQ17 possessed potent antiproliferation activity compared to PFD and better potency in inhibiting TGF-β-induced migration of NIH3T3 cells at a much lower concentration than that of PFD. In addition, YZQ17 dramatically inhibited the expression levels of fibrotic markers α-SMA, collagen I, and fibronectin. Moreover, further mechanistic studies confirmed that YZQ17 exhibited this considerable anti-fibrosis activity via the TGF-β/Smad2/3 dependent pathway. Finally, the results of human and rat liver microsomes assay in vitro and pharmacokinetic assay in rats confirmed that YZQ17 showed better pharmacokinetics than that of PFD. Collectively, the preliminary study of PFD derivatives modified by the amide group indicated that YZQ17 could be regarded as a lead compound for further investigation and optimization.

Synthesis and structure-activity relationships of pirfenidone derivatives as anti-fibrosis agents in vitro.

At present, machine translation in the market depends on parallel sentence corpus, and the number of parallel sentences will affect the performance of machine translation, especially in low resource corpus. In recent years, the use of non parallel corpora to learn cross language word representation as low resources and less supervision to obtain bilingual sentence pairs provides a new idea. In this paper, we propose a new method. First, we create cross domain mappings in a small number of single languages. Then a classifier is constructed to extract bilingual parallel sentence pairs. Finally, we prove the effectiveness of our method in Uygur Chinese low resource language by using machine translation, and achieve good results.

Extracting Parallel Sentences from Low-Resource Language Pairs with Minimal Supervision

Machine translation makes it easy for people to communicate across languages. Multimodal machine translation is also one of the important directions of research in machine translation, which uses feature information such as images and audio to assist translation models in obtaining higher quality target languages. However, in the vast majority of current research work has been conducted on the basis of commonly used corpora such as English, French, German, less research has been done on low-resource languages, and this has left the translation of low-resource languages relatively behind. This paper selects the English-Hindi and English-Hausa corpus, researched on low-resource language translation. The different models we use for image feature information extraction are fusion of image features with text information in the text encoding process of translation, using image features to provide additional information, and assisting the translation model for translation. Compared with text-only machine translation, the experimental results show that our method improves 3 BLEU in the English-Hindi dataset and improves 0.47 BLEU in the English-Hausa dataset. In addition, we also analyze the effect of image feature information extracted by different feature extraction models on the translation results. Different models pay different attention to each region of the image, and ResNet model is able to extract more feature information compared to VGG model, which is more effective for translation.

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Adding Visual Information to Improve Multimodal Machine Translation for Low-Resource Language

The atomic mechanism of phase transformation under high pressure has been the focus of researches. In the present study, the roles of hydrostatic pressure (P) on phase transformation temperature and microstructural evolution in aluminum (Al) during cyclic thermal loading are studied from molecular dynamics simulations. The FCC → Liquid → FCC, FCC → liquid → FCC + BCC, FCC → BCC → Liquid → BCC and BCC → Liquid → BCC transformation pathways were observed under 0 ≤ P ≤ 14 GPa, 15 ≤ P ≤ 21 GPa, 22 ≤ P ≤ 25 GPa and 26 ≤ P ≤ 100 GPa, respectively, during cyclic thermal loading. It should be noted that the melting temperature predicted by the used potential at high P is obviously lower than experimental results. The FCC → BCC transformation involves nucleation and growth of BCC phase. The nucleation of BCC phase undergoes by the continuous deformation of FCC lattice, corresponding to the Bain transformation path. The growth of BCC phase is completed by the atomic diffusion. With increasing P, the 111<112̅> twin and {111} stacking fault in FCC phase evolve to five-fold twin and HCP phase, respectively. The microstructure of BCC phase is dominated by the {112}<110> twin. Insight obtained in this work paves the way for understanding the atomic mechanism of high pressure phase transformation. 

Zhenqiang Yu

Papers

Electrochemical Analysis of Protein Nitrotyrosine and Dityrosine in the Alzheimer Brain Indicates Region-Specific Accumulation

Synthesis and structure-activity relationships of pirfenidone derivatives as anti-fibrosis agents in vitro.

Extracting Parallel Sentences from Low-Resource Language Pairs with Minimal Supervision

Adding Visual Information to Improve Multimodal Machine Translation for Low-Resource Language

Phase transformation behavior of aluminum under high hydrostatic pressure: A molecular dynamics study