Metabolite mapping by consecutive nanostructure and silver‐assisted mass spectrometry imaging on tissue sections

Gustafsson, Ove J. R.; Guinan, Taryn; Rudd, David; Kobus, Hilton; Benkendorff, Kirsten; Voelcker, Nicolas H.

doi:10.1002/rcm.7869

Cited by 15 publications

(21 citation statements)

References 42 publications

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“…The advantages of DIOS for imaging complex tissue include improved signal intensity 5 , reduced background spectral noise 8,9 , high efficiency desorption of ions and sensitivity down to yoctomole quantities 10 . The key advantage of DIOS, as compared to other drug metabolite discovery methods, is the capacity to detect and map metabolites that are not amenable to other pharmacokinetic approaches 11 . DIOS-MSI can map spatially-preserved tissue distributions for metabolites which only solubilise in solvents that are unsuitable for traditional pharmacology.…”

Section: Introductionmentioning

confidence: 99%

Mapping insoluble indole metabolites in the gastrointestinal environment of a murine colorectal cancer model using desorption/ionisation on porous silicon imaging

Rudd

Benkendorff

Chahal

et al. 2019

Sci Rep

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Indole derivatives are a structurally diverse group of compounds found in food, toxins, medicines, and produced by commensal microbiota. On contact with acidic stomach conditions, indoles undergo condensation to generate metabolites that vary in solubility, activity and toxicity as they move through the gut. Here, using halogenated ions, we map promising chemo-preventative indoles, i) 6-bromoisatin (6Br), ii) the mixed indole natural extract (NE) 6Br is found in, and iii) the highly insoluble metabolites formed in vivo using desorption/ionisation on porous silicon-mass spectrometry imaging (DIOS-MSI). The functionalised porous silicon architecture allowed insoluble metabolites to be detected that would otherwise evade most analytical platforms, providing direct evidence for identifying the therapeutic component, 6Br, from the mixed indole NE. As a therapeutic lead, 0.025 mg/g 6Br acts as a chemo-preventative compound in a 12 week genotoxic mouse model; at this dose 6Br significantly reduces epithelial cell proliferation, tumour precursors (aberrant crypt foci; ACF); and tumour numbers while having minimal effects on liver, blood biochemistry and weight parameters compared to controls. The same could not be said for the NE where 6Br originates, which significantly increased liver damage markers. DIOS-MSI revealed a large range of previously unknown insoluble metabolites that could contribute to reduced efficacy and increased toxicity.

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Section: Introductionmentioning

confidence: 99%

Mapping insoluble indole metabolites in the gastrointestinal environment of a murine colorectal cancer model using desorption/ionisation on porous silicon imaging

Rudd

Benkendorff

Chahal

et al. 2019

Sci Rep

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“…It is uncertain why this occurs, but it is most likely the result of in vivo metabolism and degradative reactions that occur at high versus low doses. 6-Bromoisatin can form dimers in vivo [ 40 ] and higher concentrations would increase the opportunity for dimers to form. As reported in our previous in vitro studies, brominated indole dimers have lower anti-inflammatory activity than the monomers [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

“…orbita HBG chloroform extract and 6-bromoisatin as anti-inflammatory agents also relies on low in vivo toxicity. In previous rodent models, there was no morbidity, ill health or gastro-intestinal damage apparent after 2–14 weeks of daily oral gavage with the muricid extract or pure 6-bromoisatin [ 20 , 21 , 25 , 26 , 40 ]. As gastro-intestinal damage is the most significant side effect of currently used treatments (NSAIDs) [ 44 ], 6-bromoisatin provides a lead for the development of safer anti-inflammatory drugs.…”

Section: Discussionmentioning

confidence: 99%

Brominated indoles from a marine mollusc inhibit inflammation in a murine model of acute lung injury

Ahmad¹,

Rudd²,

Benkendorff³

et al. 2017

PLoS ONE

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New drug leads for the treatment of inflammation are urgently needed. Marine molluscs are widely used as traditional medicines for the treatment of inflammation. Here we report the positive effects of a hypobranchial gland (HBG) extract and the dominant bioactive compound 6-bromoisatin from the Muricidae mollusc Dicathais orbita, for reducing lipopolysaccharide (LPS) induced acute lung inflammation in a mouse model. Both 6-bromoisatin and the HBG extract suppressed the inflammatory response in mice that were pre-treated by oral gavage at 48, 24 and 1 h prior to LPS infusion. The inflammatory antagonists were tested at concentrations of 0.5 mg/g and 0.1 mg/g HBG extract and 0.1 mg/g and 0.05 mg/g 6-bromoisatin in carrier oil and all treatments reduced inflammation as indicated by a significant suppression of inflammatory markers present in bronchoalveolar lavage fluid (BALF), in comparison to LPS induced positive control mice administered the carrier oil alone (p < 0.0001). Tumour necrosis factor-alpha (TNFα) and interleukin-1 beta (IL-1β) levels, in addition to total protein concentration were all significantly reduced in BALF from mice treated with the extract or 6-bromoisatin. Furthermore, all treatment groups showed significant reductions in neutrophil sequestration and preservation of the lung tissue architecture compared to the positive control (p < 0.0001). The combined results from this study and our previous in vitro studies indicate that 6-bromoisatin in the HGB extracts inhibit the activation of inflammatory signalling pathway. The results from this study further confirm that the HBG extract from Muricidae molluscs and 6-bromoisatin are bioavailable and effective in vivo, thus have potential for development as natural therapeutic agents for inflammation.

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“…IMS facilitated detection of the metabolites at different stages of the reproductive cycle of mature female D. orbita, one of molluscs, and proposed the biological roles of the metabolites based on temporal changes in their distribution. The DIOS substrates were further employed for the detection of drugs, lipids and metabolites (18,19).…”

Section: Nanostructured Surface-assisted Ldi Ims Noncarbon-based Surfmentioning

confidence: 99%

Organic matrix-free imaging mass spectrometry

Kim

Choi

et al. 2020

BMB Rep.

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Mass spectrometry (MS) is an ideal tool for analyzing multiple types of (bio)molecular information simultaneously in complex biological systems. In addition, MS provides structural information on targets, and can easily discriminate between true analytes and background. Therefore, imaging mass spectrometry (IMS) enables not only visualization of tissues to give positional information on targets but also allows for molecular analysis of targets by affording the molecular weights. Matrixassisted laser desorption/ionization-time of flight (MALDI-TOF) MS is particularly effective and is generally used for IMS. However, the requirement for an organic matrix raises several limitations that get in the way of accurate and reliable images and hampers imaging of small molecules such as drugs and their metabolites. To overcome these problems, various organic matrix-free LDI IMS systems have been developed, mostly utilizing nanostructured surfaces and inorganic nanoparticles as an alternative to the organic matrix. This minireview highlights and focuses on the progress in organic matrix-free LDI IMS and briefly discusses the use of other IMS techniques such as desorption electrospray ionization, laser ablation electrospray ionization, and secondary ion mass spectrometry. [BMB Reports 2020; 53(7): 349-356]

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Metabolite mapping by consecutive nanostructure and silver‐assisted mass spectrometry imaging on tissue sections

Cited by 15 publications

References 42 publications

Mapping insoluble indole metabolites in the gastrointestinal environment of a murine colorectal cancer model using desorption/ionisation on porous silicon imaging

Mapping insoluble indole metabolites in the gastrointestinal environment of a murine colorectal cancer model using desorption/ionisation on porous silicon imaging

Brominated indoles from a marine mollusc inhibit inflammation in a murine model of acute lung injury

Organic matrix-free imaging mass spectrometry

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