Nanoparticles as Drug Delivery System against Tuberculosis in Zebrafish Embryos: Direct Visualization and Treatment

Fenaroli, Federico; Westmoreland, David; Benjaminsen, Jørgen; Kolstad, Terje R Selnes; Skjeldal, Frode Miltzow; Meijer, Annemarie H.; Vaart, Michiel van der; Ulanova, Lilia S.; Roos, Norbert; Nyström, Bo; Hildahl, Jon; Griffiths, Gareth

doi:10.1021/nn5019126

Cited by 135 publications

(119 citation statements)

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“…Thus, in our hands chemical preparation coupled to flat embedding has been beneficial for the analysis of both Drosophila wing imaginal discs and ovarian chambers (Kolotuev and Le Borgne, unpublished data). Our data complement previous developments that enabled the Tokuyasu-based analysis of vertebrate tissue such as zebrafish embryos (37,38) and expand a toolkit for those interested in processing polarized, multi-cellular samples. While the Tokuyasu preparation, the flat-embedding and orientation approach were applied in the same way for all these sample types, the fixation of the specimens had to be individually adapted, as not all specimens are compatible with HPF for immuno-labeling.…”

Section: Discussionsupporting

confidence: 75%

Adaptation of Cryo‐Sectioning for IEM Labeling of Asymmetric Samples: A Study Using Caenorhabditis elegans

Nicolle

Burel

Griffiths

et al. 2015

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Cryo-sectioning procedures, initially developed by Tokuyasu, have been successfully improved for tissues and cultured cells, enabling efficient protein localization on the ultrastructural level. Without a standard procedure applicable to any sample, currently existing protocols must be individually modified for each model organism or asymmetric sample.Here, we describe our method that enables reproducible cryo-sectioning of Caenorhabditis elegans larvae/adults and embryos. We have estab- Modern cell and developmental biology requires sophisticated high-resolution imaging. Be it light or electron microscopy, recent progress in technology has made it possible to apply a wide variety of methods to study processes such as molecular dynamics, protein localization and interactions between cellular components. While live imaging light microscopy (LM) allows visualization of the dynamics of molecular and cellular processes, it lacks high resolution of the structural context, even using the recently developed super-resolution LM techniques. Transmission electron microscopy (TEM), though static, gives access to high-resolution ultrastructure within the cellular context. Immuno-labeling of TEM samples is a powerful approach to localize antigens precisely at the ultrastructural level. The major disadvantage of immuno-electron microscopy (IEM) resides in the fact that it is performed on thin slices of specimens -that represent only a tiny fragment of the entire antigen-containing structures. As a result of sample dehydration and masking of active sites by resins, techniques that use resin embedding for IEM frequently lead to poor immuno-labeling signal. In contrast, the cryo-sectioning method developed by Tokuyasu www.traffic.dk 893

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Section: Discussionsupporting

confidence: 75%

Adaptation of Cryo‐Sectioning for IEM Labeling of Asymmetric Samples: A Study Using Caenorhabditis elegans

Nicolle

Burel

Griffiths

et al. 2015

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“…Alizarin red and Alcian blue staining was performed as described previously (38). Zebrafish were maintained as described (39). For compound treatment, DMSO and BET inhibitors were added as indicated at 1 dpf.…”

Section: Methodsmentioning

confidence: 99%

Bromodomain and Extra-terminal (BET) Protein Inhibitors Suppress Chondrocyte Differentiation and Restrain Bone Growth

Niu

Shao

Yan

et al. 2016

Journal of Biological Chemistry

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Edited by Xiao-Fan WangSmall molecule inhibitors for bromodomain and extra-terminal (BET) proteins have recently emerged as potential therapeutic agents in clinical trials for various cancers. However, to date, it is unknown whether these inhibitors have side effects on bone structures. Here, we report that inhibition of BET bromodomain proteins may suppress chondrocyte differentiation and restrain bone growth. We generated a luciferase reporter system using the chondrogenic cell line ATDC5 in which the luciferase gene was driven by the promoter of Col2a1, an elementary collagen of the chondrocyte. The Col2a1-luciferase ATDC5 system was used for rapidly screening both activators and repressors of human collagen Col2a1 gene expression, and we found that BET bromodomain inhibitors reduce the Col2a1-luciferase. Consistent with the luciferase assay, BET inhibitors decrease the expression of Col2a1. Bromodomain and extra-terminal (BET)2 proteins (containing four mammalian members, BRD2, BRD3, BRD4, and BRDT) function as key epigenetic readers by recognizing histone acetylation through binding to ⑀-N-lysine acetylation motifs of histone, such as Lys-5, Lys-12, and Lys-16 residues of H4 histone (1, 2) and Lys-27 residues of H3 histone (3). The BET proteins interact with the positive transcription elongation factor P-TEF␤ and RNA polymerase II (Pol II) to facilitate gene transcription (4 -6). A list of drugs, such as I-BET151, I-BET762, PFI-1, and (ϩ)-JQ1, were discovered to target BET proteins and block the interaction between BET proteins and acetyl-lysine of histones (2, 7).BET proteins and BET inhibitors have been reported to be involved in a variety of biological processes. Pharmacological inhibition of BET proteins lowers the expression of key transcription factors such as oncogene c-MYC (8), clamps the transductions of PI3K signaling (9), inhibits Gli1 transcription and Hedgehog pathway (10), blocks transcription in neurons (11), represses VEGF-induced angiogenesis and vascular permeability (12), reduces cell viability of osteosarcoma cells and inhibits osteoblastic differentiation (13), and restrains osteoclastogenesis (14). Meanwhile, potent BET inhibitors have been identified as showing antitumor efficacy in a number of preclinical cancer models in recent years, including leukemia, multiple myeloma, lymphoma, melanoma, and gastric cancer (15,16). This led to clinical studies focusing mostly on the treatment of leukemia and lymphoma. As a result of these studies, the first encouraging signs of efficacy have already been reported (17). Furthermore, previous studies showed that BET inhibitors also control neuronal differentiation and cause an autism-like syndrome (18). However, BET inhibitors were not examined extensively in these studies to determine their side effects on skeletal bone structures.The long bone is mainly formed through endochondral bone formation, which starts with the formation of a cartilage template from condensed mesenchymal cells. The chondrocytes of the cartilage template proliferate axial...

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“…This was further demonstrated by the same group in a transparent zebra-fish embryo model. [29] With a noninvasive imaging technique, nanoparticles were visualized being taken up by both infected and noninfected macrophages. Noninfected macrophages were actively recruited to the site of infection, where they phagocytosed their infected counterparts.…”

Section: Polymer Nanoparticles As Anti-tb Drug Delivery Carriersmentioning

confidence: 99%

Nanomaterials in the Prevention, Diagnosis, and Treatment of Mycobacterium Tuberculosis Infections

Liang

Ding

et al. 2017

Adv Healthcare Materials

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worldwide was estimated at a staggering 10.4 million, with a significant percentage (10%) resulting from concomitant HIV-TB coinfections. [1] Given the closely knitted association between TB infections and poor sanitation/poverty, it thus comes with no surprise that an overwhelming majority of disease burden (60%) is actually shouldered by countries from the developing world (Figure 1). [1] TB infections are compounded by the emergence of multidrug resistance (MDR). In spite of the tremendous amount of resources and research dollars that have been devoted to TB research, TB diagnostics and treatment outcomes still remain startlingly poor. TB remains worryingly underreported, under-diagnosed and undertreated. A 4.3 million gap was reported between incident and notified TB cases, chiefly in developing countries; majority of TB infections remain latent and unreported, and only 30% of new incident TB cases were subjected to drug susceptibility testing. [1] The Xpert Mycobacterium Tuberculosis (MTB)/RIF assay remains the only available WHOrecommended rapid diagnostic platform for detection of TB and drug (rifampicin) resistance. Treatment success rates are highly variable, ranging from 28% (extensively drug-resistant strains) to 83% (garden strains) of TB. The rate of decline in TB incidence has remained stagnant at 1.5% annually over the past decade, far lagging behind the 5% projected by the WHO's End TB Strategy. Against such a backdrop, TB remains firmly entrenched among the top 10 causes of death worldwide. [2] To this end, the WHO has since 2015, adopted the End TB Strategy in an effort to stem this burgeoning epidemic. Major diagnostic and treatment gaps in TB management still remain, and these need to be addressed to effectively curtail TB spread and its impact on global health. Pathogenesis of TB InfectionsMTB is the infectious agent responsible for TB infections. It originates from the family Mycobacteriaceae and is an obligate bacteria chiefly spread via air droplets.

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Nanoparticles as Drug Delivery System against Tuberculosis in Zebrafish Embryos: Direct Visualization and Treatment

Cited by 135 publications

References 53 publications

Adaptation of Cryo‐Sectioning for IEM Labeling of Asymmetric Samples: A Study Using Caenorhabditis elegans

Adaptation of Cryo‐Sectioning for IEM Labeling of Asymmetric Samples: A Study Using Caenorhabditis elegans

Bromodomain and Extra-terminal (BET) Protein Inhibitors Suppress Chondrocyte Differentiation and Restrain Bone Growth

Nanomaterials in the Prevention, Diagnosis, and Treatment of Mycobacterium Tuberculosis Infections

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