Ex Vivo Imaging of Ultrasound-Stimulated Metabolic Activity in Rat Pancreatic Slices

Objectives. Recent evidence suggests that gut bacteria-derived metabolites interact with the cardiovascular system and alter blood pressure (BP) in mammals. Here, we evaluated the effect of indole-3-propionic acid (IPA), a gut bacteria-derived metabolite of tryptophan, on the circulatory system. Methods. Arterial BP, electrocardiographic and echocardiographic (ECHO) parameters were recorded in male, anesthetized, 12-week-old Wistar-Kyoto rats at baseline and after intravenous administration of either IPA or vehicle. In additional experiments, rats were pretreated with prazosin or pentolinium to evaluate the involvement of the autonomic nervous system in cardiovascular responses to IPA. IPA's concentrations were measured using UHPLC-MS. The reactivity of endothelium-intact and -denuded mesenteric resistance arteries was tested. Cells' viability and LDH cytotoxicity assays were performed on cultured cardiomyocytes. Results. IPA increased BP with a concomitant bradycardic response but no significant change in QTc interval. The pretreatment with prazosin and pentolinium reduced the hypertensive response. ECHO showed increased contractility of the heart after the administration of IPA. Ex vivo, IPA constricted pre-dilated and endothelium-denuded mesenteric resistance arteries and increased metabolic activity of cardiomyocytes. Conclusions. IPA increases BP via cardiac and vascular mechanisms in rats. Furthermore, IPA increases cardiac contractility and metabolic activity of cardiomyocytes. Our study suggests that IPA may act as a mediator between gut microbiota and the circulatory system.

Download Full-text

Unfolding the Medial Temporal Lobe Cortex to Characterize Neurodegeneration Due to Alzheimer’s Disease Pathology Using Ex vivo Imaging

10.1007/978-3-030-87586-2_1 ◽

2021 ◽

pp. 3-12

Author(s):

Sadhana Ravikumar ◽

Laura Wisse ◽

Sydney Lim ◽

David Irwin ◽

Ranjit Ittyerah ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Temporal Lobe ◽

Medial Temporal Lobe ◽

Ex Vivo ◽

Ex Vivo Imaging

Download Full-text

Tumor Targeted Nanoparticles Improve Therapeutic Index of BCL2 and MCL1 dual inhibition

Blood ◽

10.1182/blood.2020008017 ◽

2020 ◽

Author(s):

Neeta Bala Tannan ◽

Mandana T Manzari ◽

Laurie Herviou ◽

Mariana da Silva Ferreira ◽

Connor J Hagen ◽

...

Keyword(s):

Ex Vivo ◽

Therapeutic Index ◽

Drug Dose ◽

Hematological Toxicity ◽

Bcl2 Family ◽

Fold Reduction ◽

Tumor Killing ◽

Toxic Drugs ◽

Ex Vivo Imaging

Cancer and normal cells utilize multiple anti-apoptotic BCL2 proteins to prevent cell death. Therapeutic targeting of multiple BCL2 family proteins enhances tumor killing, but is also associated with increased systemic toxicity. Here, we demonstrate that the dual targeting of MCL1 and BCL2 proteins, using the small molecules S63845 and venetoclax, induces durable remissions in mice harboring human DLBCL tumors but is accompanied by hematological toxicity and weight loss. To mitigate these toxicities, we encapsulated S63845 or venetoclax into nanoparticles targeting P-selectin that is enriched in tumor endothelial cells. In vivo and ex vivo imaging demonstrated preferential targeting of the nanoparticles to lymphoma tumors over vital organs. Mass-spectrometry analyses after nanoparticle drug administration confirmed tumor enrichment of the drug while reducing plasma levels. Furthermore, nanoparticle encapsulation allowed 3.5 to 6.5-fold reduction in drug dose, induced sustained remissions and minimized toxicity. Our results support the development of nanoparticles to deliver BH3 mimetic combinations in lymphoma and in general for toxic drugs in cancer therapy.

Download Full-text

In-vivo near-infrared optical imaging of growing osteosarcoma cell lesions xenografted in mice: dual-channel quantitative evaluation of volume and mineralization

Acta Radiologica ◽

10.1258/ar.2011.110131 ◽

2011 ◽

Vol 52 (9) ◽

pp. 978-988 ◽

Cited By ~ 8

Author(s):

Hitoshi Nakayama ◽

Tomoyuki Kawase ◽

Kazuhiro Okuda ◽

Larry F Wolff ◽

Hiromasa Yoshie

Keyword(s):

Optical Imaging ◽

Near Infrared ◽

Imaging Technique ◽

Ex Vivo ◽

Acquisition Time ◽

Osteosarcoma Cell ◽

Dual Channel ◽

Nir Imaging ◽

Ex Vivo Imaging

Background In a previous study using a rodent osteosarcoma-grafted rat model, in which cell-dependent mineralization was previously demonstrated to proportionally increase with growth, we performed a quantitative analysis of mineral deposit formation using 99mTc-HMDP and found some weaknesses, such as longer acquisition time and narrower dynamic ranges (i.e. images easily saturated). The recently developed near-infrared (NIR) optical imaging technique is expected to non-invasively evaluate changes in living small animals in a quantitative manner. Purpose To test the feasibility of NIR imaging with a dual-channel system as a better alternative for bone scintigraphy by quantitatively evaluating mineralization along with the growth of osteosarcoma lesions in a mouse-xenograft model. Material and Methods The gross volume and mineralization of osteosarcoma lesions were evaluated in living mice simultaneously with dual-channels by NIR dye-labeled probes, 2-deoxyglucose (DG) and pamidronate (OS), respectively. To verify these quantitative data, retrieved osteosarcoma lesions were then subjected to ex-vivo imaging, weighing under wet conditions, microfocus-computed tomography (μCT) analysis, and histopathological examination. Results Because of less scattering and no anatomical overlapping, as generally shown, specific fluorescence signals targeted to the osteosarcoma lesions could be determined clearly by ex-vivo imaging. These data were well positively correlated with the in-vivo imaging data ( r > 0.8, P < 0.02). Other good to excellent correlations ( r > 0.8, P < 0.02) were observed between DG accumulation and tumor gross volume and between OS accumulation and mineralization volume. Conclusion This in-vivo NIR imaging technique using DG and OS is sensitive to the level to simultaneously detect and quantitatively evaluate the growth and mineralization occuring in this type of osteosarcoma lesions of living mice without either invasion or sacrifice. By possible mutual complementation, this dual imaging system might be useful for accurate diagnosis even in the presence of overlapping tissues.

Download Full-text

Evaluation of the reliability of a new low dose CBCT acquisition protocol in diagnosing impacted canines: an ex-vivo imaging study

Medical Imaging 2019: Physics of Medical Imaging ◽

10.1117/12.2512521 ◽

2019 ◽

Author(s):

Ayesha Ejaz ◽

Callan Donovan ◽

Vaibhav Gandhi ◽

Sumit Yadav ◽

Aditya Tadinada

Keyword(s):

Low Dose ◽

Ex Vivo ◽

Imaging Study ◽

Acquisition Protocol ◽

Impacted Canines ◽

Ex Vivo Imaging

Download Full-text

The Opportunities and Use of Imaging to Measure Target Engagement

SLAS DISCOVERY Advancing Life Sciences ◽

10.1177/2472555219897270 ◽

2019 ◽

Vol 25 (2) ◽

pp. 127-136

Author(s):

Juliana Maynard ◽

Philippa Hart

Keyword(s):

Ex Vivo ◽

Clinical Success ◽

Receptor Occupancy ◽

Accurate Information ◽

Target Engagement ◽

Drug Molecule ◽

Drug Discovery And Development ◽

Ex Vivo Imaging

Lack of efficacy and poor safety outcomes are deemed to be the greatest causes of clinical failure of novel therapeutics. The use of biomarkers that give accurate information on target engagement, providing confidence that pharmacological activity in the target organ is being achieved, is key in optimizing clinical success. Without a measurement of target engagement, it can be very difficult to discern the basis for any lack of efficacy of a drug molecule within the pharmaceutical industry. Target engagement can be measured in both an in vitro and in vivo setting, and in recent years imaging measurements have been used frequently in drug discovery and development to assess target engagement and receptor occupancy in both human and animal models. From this perspective, we assess and look at the advancements in both in vivo and ex vivo imaging to demonstrate the enormous potential that imaging has as an application to provide a greater understanding of target engagement with a correlative therapeutic impact.

Download Full-text