Breakthroughs in cancer immunotherapies have demonstrated considerable success, though not without limitations. Non‐thermal plasma (NTP) for cancer therapy has been emerging as a potential adjuvant treatment via induction of immunogenic cell death (ICD). Cancer cells undergoing ICD stimulate a patient's immune system to mount an anticancer response. While promising, the underlying mechanisms of NTP‐induced ICD must be closely examined. Here, the interaction between non‐thermal plasma and cancerous cells is studied. The short‐lived reactive oxygen and nitrogen species (e.g., hydroxyl radicals, atomic oxygen, nitric oxide) produced by plasma are the main effectors that elicit ICD in melanoma while, surprisingly, persistent species do not. This is demonstrated in vitro using a dielectric barrier discharge plasma system and is validated in a vaccination assay in vivo. Plasma generation of reactive species appears to be dictated by the total energy. Collectively, this work provides fundamental insight into plasma interactions with biological material. Furthermore, it lays the foundation for future development of NTP systems for clinical translation. The addition of plasma systems into the existing arsenal of cancer therapies opens the possibility for new combination strategies for safer and more robust control of cancer.
The identification of unknown molecules has been one of the cornerstone applications of mass spectrometry for decades. This tutorial reviews the basics of the interpretation of electrospray ionization‐based MS and MS/MS spectra in order to identify small‐molecule analytes (typically below 2000 Da). Most of what is discussed in this tutorial also applies to other atmospheric pressure ionization methods like atmospheric pressure chemical/photoionization. We focus primarily on the fundamental steps of MS‐based structural elucidation of individual unknown compounds, rather than describing strategies for large‐scale identification in complex samples. We critically discuss topics like the detection of protonated and deprotonated ions ([M + H]+ and [M − H]−) as well as other adduct ions, the determination of the molecular formula, and provide some basic rules on the interpretation of product ion spectra. Our tutorial focuses primarily on the fundamental steps of MS‐based structural elucidation of individual unknown compounds (eg, contaminants in chemical production, pharmacological alteration of drugs), rather than describing strategies for large‐scale identification in complex samples. This tutorial also discusses strategies to obtain useful orthogonal information (UV/Vis, H/D exchange, chemical derivatization, etc) and offers an overview of the different informatics tools and approaches that can be used for structural elucidation of small molecules. It is primarily intended for beginning mass spectrometrists and researchers from other mass spectrometry sub‐disciplines that want to get acquainted with structural elucidation are interested in some practical tips and tricks.
On the basis of the original lead neocryptolepine or 5-methyl-5H-indolo[2,3-b]quinoline, an alkaloid from Cryptolepis sanguinolenta, derivatives were prepared using a biradical cyclization methodology. Starting from easily accessible educts, this approach allowed the synthesis of hitherto unknown compounds with a varied substitution pattern. As a result of steric hindrance, preferential formation of the 3-substituted isomers over the 1-substituted isomers was observed when cyclizing N-(3-substituted-phenyl)-N'-[2-(2-trimethylsilylethynyl)phenyl]carbodiimides. All compounds were evaluated for their activity against chloroquine-sensitive as well as chloroquine-resistant Plasmodium falciparum strains, for their activity against Trypanosoma brucei and T. cruzi, and for their cytotoxicity on human MRC-5 cells. Mechanisms of action were investigated by testing heme complexation using ESI-MS, inhibition of beta-hematin formation, DNA interactions (DNA-methyl green assay and linear dichroism), and inhibition of human topoisomerase II. Neocryptolepine derivatives with a higher antiplasmodial activity and a lower cytotoxicity than the original lead have been obtained. This selective antiplasmodial activity was associated with inhibition of beta-hematin formation. 2-Bromoneocryptolepine was the most selective compound with an IC(50) value against chloroquine-resistant P. falciparum of 4.0 microM in the absence of cytotoxicity (IC(50) > 32 microM). Although cryptolepine, a known lead for antimalarials also originally isolated from Cryptolepis sanguinolenta, was more active (IC(50) = 2.0 microM), 2-bromoneocryptolepine showed a low affinity for DNA and no inhibition of human topoisomerase II, in contrast to cryptolepine. Although some neocryptolepine derivatives showed a higher antiplasmodial activity than 2-bromocryptolepine, these compounds also showed a higher affinity for DNA and/or a more pronounced cytotoxicity. Therefore, 2-bromoneocryptolepine is considered as the most promising lead from the present work for new antimalarial agents. In addition, 2-bromo-, 2-nitro-, and 2-methoxy-9-cyanoneocryptolepine exhibited antitrypanosomal activity in the micromolar range in the absence of obvious cytotoxicity.
Although access to high-resolution mass spectrometry (MS), especially in the field of biomolecular MS, is becoming readily available due to recent advances in MS technology, the accompanied information on isotopic distribution in high-resolution spectra is not used at its full potential, mainly because of lack of knowledge and/or awareness. In this review, we give an insight into the practical problems related to calculating the isotopic distribution for large biomolecules, and present an overview of methods for the calculation of the isotopic distribution. We discuss the key events that triggered the development of various algorithms and explain the rationale of how and why the various isotopic-distribution calculations were performed. The review is focused around the developmental stages as briefly outlined below, starting with the first observation of an isotopic distribution. The observations of Beynon in the field of organic MS that chlorine appeared in a mass spectrum as two variants with odds 3:1 lie at the basis of the first wave of algorithms for the calculation of the isotopic distribution, based on the atomic composition of a molecule. From here on, we explain why more complex biomolecules such as peptides exhibit a highly complex isotope pattern when assayed by MS, and we discuss how combinatorial difficulties complicate the calculation of the isotopic distribution on computers. For this purpose, we highlight three methods, which were introduced in the 1980s. These are the stepwise procedure introduced by Kubinyi, the polynomial expansion from Brownawell and Fillippo, and the multinomial expansion from Yergey. The next development was instigated by Rockwood, who suggested to decompose the isotopic distribution in terms of their nucleon count instead of the exact mass. In this respect, we could claim that the term "aggregated" isotopic distribution is more appropriate. Due to the simplification of the isotopic distribution to its aggregated counterpart, Rockwood was able to use the convolution for the calculation of the "aggregated" isotopic distribution. Convolution methods are computationally efficient and economic in their memory usage. We spend a section on the work introduced by Rockwood during the 1990s. Due to recent breakthroughs in mass spectrometric technology and the widespread high-resolution instruments (e.g., FTICR-MS, FTOrbitrap-MS, and TOF-MS) that provide high-resolution, isotope-resolved, accurate mass data, there is an emerging need for algorithms that can calculate isotopic distributions for large biomolecules. The number of recent publications on this topic does witness this trend. The new methods are mostly based on complex mathematical developments such as, for example, cellular automata (Meija and Caruso [2004]. J Am Soc Mass Spectrom, 15(5):654-658), dynamic programming (Snider [2007]. J Am Soc Mass Spectrom, 18:1511-1515), and hierarchical models (Li et al. [2008] J Am Soc Mass Spectrom, 19:1867-1874). We also comment on the ideas to use Punnet squares and Pascal's triangle to...
Please cite this article as: Vandegehuchte, Michiel B., Lemière, Filip, Vanhaecke, Lynn, Vanden Berghe, Wim, Janssen, Colin R., Direct and transgenerational impact on Daphnia magna of chemicals with a known effect on DNA methylation, Comparative Biochemistry and Physiology (2009), doi: 10.1016/j.cbpc.2009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.A C C E P T E D M A N U S C R I P T A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT2 Abstract 25The purpose of this study is to investigate (1) the induction of epigenetic effects in the 26 crustacean Daphnia magna using DNA methylation as an epigenetic mark and (2) the 27 potential stable transfer of such an epigenetic effect to non-exposed subsequent generations. 28Daphnids were exposed to chemical substances known to affect DNA methylation in 29 mammals: vinclozolin, 5-azacytidine, 2'-deoxy-5-azacytidine, genistein and biochanin A. 30Effects on overall DNA cytosine methylation, body length and reproduction were evaluated 31 in 21 day experiments. Using a multi-generational experimental design these endpoints 32 were also evaluated in the F 1 and F 2 generation of both exposed and non-exposed offspring
14Cellular Biology, University of Leeds, LS2 9JT, UK Electrospray ion mobility-mass spectrometry (IM-MS) data show that for some small 21 molecules, two (or even more) ions with identical sum formula and mass, but distinct drift 22
For the first time estrogen DNA-adducts were identified in DNA human breast tumor tissue using nano-LC coupled to nano-Electrospray Tandem Mass Spectrometry. Normal breast tissue was analyzed analogously. The data obtained in the five breast tumor and five adjacent normal tissue samples were compared qualitatively, but no straightforward difference was observed. Prior to LC-MS analysis the DNA was enzymatically hydrolyzed to a nucleoside pool. The DNA-hydrolysates were directly injected onto a column switching system developed for on-line sample clean-up and subsequent analysis of the DNA-adducts. In four patients using Premarin, DNA-adducts of 4-hydroxy-equilenin (4OHEN) were detected. All except three samples contained DNA-adducts from 4-hydroxy-estradiol or 4-hydroxy-estrone. Also DNA isolated from eight alcohol fixed and paraffin embedded breast tumor tissue showed the presence of different estrogen DNA-adducts. Worthwhile mentioning is the presence of adducts responding to m/z 570 Ͼ m/z 454 transition. This is a well-known SRM-transition indicative for the presence of the 2'-deoxyguanosine (dGuo) adduct of Benzo H ormone treatment is widespread for women of all ages. In the United States, for instance, 30% of post-menopausal women use hormone eeplacement therapy (HRT) [1], e.g., Premarin. Studies in which the development of breast and endometrial cancer was associated with estrogen therapy [2][3][4][5][6] were supported by a more recent follow-up study in which it was demonstrated that post-menopausal women have an increased risk of breast cancer when using estrogens, especially in combination with progestin [7]. In animals, too, a relationship between the administration of estrogens and the development of cancer was shown [8].The carcinogenic properties of estrogens are explained by direct stimulation of cell proliferation via estrogen receptor mediated mechanisms [9,10] and by mechanisms based on metabolic activation [11][12][13][14], leading to DNA damage such as oxidative damage [15][16][17][18] and the formation of DNA-adducts [19 -28], which can cause mutations and induce cancer [29].The latter pathways are the result of metabolic activation of estrogens by the cytochrome P-450 system leading to 2-and 4-hydroxy derivatives. The 2-hydroxy estrogens are excreted in the urine as a result of their fast transformation to water-soluble compounds [13,14]. The 4-hydroxy form, however, has a longer half-life
Five geranylflavonoids, one prenylated flavonoid, and a simple flavanone were isolated from an ethanolic extract of Paulownia tomentosa fruit. Tomentodiplacol (1), 3'-O-methyl-5'-methoxydiplacol (2), 6-isopentenyl-3'-O-methyltaxifolin (3), and dihydrotricin (4) are reported from a natural source for the first time and 3'-O-methyldiplacone (6) for the first time from the genus Paulownia. The structures of the compounds were determined by mass spectrometry, including HRMS, and by 1D and 2D NMR spectroscopy. The cytotoxicity and DPPH (2,2-diphenyl-1-picrylhydrazyl)-quenching activity of some of these compounds were tested, with diplacone proving to be the best antioxidant, although the most cytotoxic compound.
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