scholarly journals Quantitative intravital imaging of Plasmodium falciparum sporozoites: A novel platform to test malaria intervention strategies

2019 ◽  
Author(s):  
Christine S. Hopp ◽  
Sachie Kanatani ◽  
Nathan K. Archer ◽  
Robert J. Miller ◽  
Haiyun Liu ◽  
...  
Keyword(s):  
Xenograft Model ◽  
Mouse Skin ◽  
Intervention Strategies ◽  
Rodent Malaria ◽  
Human Malaria ◽  
Drug Candidates ◽  
Detection And Tracking ◽  
Species Specific ◽  
Skin Xenograft

AbstractMalaria infection starts with the injection of motile Plasmodium sporozoites into the host’s skin during a mosquito bite. Previous studies using the rodent malaria model indicate that the dermal inoculation site may be where sporozoites are most vulnerable to antibodies, yet, functional in vivo assays with human malaria parasites are lacking. Here, we present the first characterization of P. falciparum sporozoites in the skin, comparing their motility to two rodent malaria species and investigating whether the environment of its natural host influences P. falciparum sporozoite motility using a human skin xenograft model. The combined data suggest that in contrast to the liver and blood stages, the skin is not a species-specific barrier for Plasmodium. We observe that P. falciparum sporozoites inoculated into mouse skin move with similar speed, displacement and duration, and enter blood vessels in similar numbers as the rodent parasites. Thus, interventions targeting P. falciparum sporozoite migration can be tested in the murine dermis. Importantly, to streamline quantification of sporozoite motility, we developed a toolbox allowing for automated detection and tracking of sporozoites in intravital microscopy videos. This establishes a platform to test vaccine candidates, immunization protocols, monoclonal antibodies and drug candidates for their impact on human malaria sporozoites in vivo. Screening of intervention strategies for in vivo efficacy against Pf sporozoites using this new platform will have the potential to validate targets prior to expensive clinical trials.

scholarly journals hPSC-Derived Enteric Ganglioids Model Human ENS Development and Function

2022 ◽  
Author(s):  
Homa Majd ◽  
Ryan M Samuel ◽  
Jonathan T Ramirez ◽  
Ali Kalantari ◽  
Kevin Barber ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Xenograft Model ◽  
Developmental Relationships ◽  
Drug Candidates ◽  
Effective Strategies ◽  
Wide Range ◽  
Functional Features ◽  
And Function

The enteric nervous system (ENS) plays a central role in gut physiology and mediating the crosstalk between the gastrointestinal (GI) tract and other organs. The human ENS has remained elusive, highlighting the need for an in vitro modeling and mapping blueprint. Here we map out the developmental and functional features of the human ENS, by establishing robust and scalable 2D ENS cultures and 3D enteric ganglioids from human pluripotent stem cells (hPSCs). These models recapitulate the remarkable neuronal and glial diversity found in primary tissue and enable comprehensive molecular analyses that uncover functional and developmental relationships within these lineages. As a salient example of the power of this system, we performed in-depth characterization of enteric nitrergic neurons (NO neurons) which are implicated in a wide range of GI motility disorders. We conducted an unbiased screen and identified drug candidates that modulate the activity of NO neurons and demonstrated their potential in promoting motility in mouse colonic tissue ex vivo. We established a high-throughput strategy to define the developmental programs involved in NO neuron specification and discovered that PDGFR inhibition boosts the induction of NO neurons in enteric ganglioids. Transplantation of these ganglioids in the colon of NO neuron-deficient mice results in extensive tissue engraftment, providing a xenograft model for the study of human ENS in vivo and the development of cell-based therapies for neurodegenerative GI disorders. These studies provide a framework for deciphering fundamental features of the human ENS and designing effective strategies to treat enteric neuropathies.  

scholarly journals Accelerated complete human skin architecture restoration after wounding by nanogenerator-driven electrostimulation

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Aiping Liu ◽  
Yin Long ◽  
Jun Li ◽  
Long Gu ◽  
Aos Karim ◽  
...  
Keyword(s):  
Wound Healing ◽  
Human Skin ◽  
Wound Closure ◽  
Normal Skin ◽  
Xenograft Model ◽  
Clinical Use ◽  
Inflammatory Phase ◽  
Complete Restoration ◽  
Skin Xenograft

Abstract Background Electrostimulation (ES) therapy for wound healing is limited in clinical use due to barriers such as cumbersome equipment and intermittent delivery of therapy. Methods We adapted a human skin xenograft model that can be used to directly examine the nanogenerator-driven ES (NG-ES) effects on human skin in vivo—an essential translational step toward clinical application of the NG-ES technique for wound healing. Results We show that NG-ES leads to rapid wound closure with complete restoration of normal skin architecture within 7 days compared to more than 30 days in the literature. NG-ES accelerates the inflammatory phase of wound healing with more rapid resolution of neutrophils and macrophages and enhances wound bed perfusion with more robust neovascularization. Conclusion Our results support the translational evaluation and optimization of the NG-ES technology to deliver convenient, efficient wound healing therapy for use in human wounds. Graphic abstract

scholarly journals Inhibition by cyclosporin A of rodent malaria in vivo and human malaria in vitro.

1982 ◽  
Vol 37 (3) ◽  
pp. 1093-1100 ◽  
Author(s):  
S P Nickell ◽  
L W Scheibel ◽  
G A Cole
Keyword(s):  
Cyclosporin A ◽  
Rodent Malaria ◽  
Human Malaria

scholarly journals Rodent Malaria Erythrocyte Preference Assessment by an Ex Vivo Tropism Assay

2021 ◽  
Vol 11 ◽  
Author(s):  
Yew Wai Leong ◽  
Erica Qian Hui Lee ◽  
Laurent Rénia ◽  
Benoit Malleret
Keyword(s):  
Ex Vivo ◽  
Preference Assessment ◽  
Cell Tropism ◽  
Malaria Parasites ◽  
Rodent Malaria ◽  
Human Malaria ◽  
Ligand Interactions ◽  
Blood Stage Infection ◽  
Stage Infection

Circulating red blood cells consist of young erythrocytes (early and late reticulocytes) and mature erythrocytes (normocytes). The human malaria parasites, Plasmodium falciparum and P. vivax, have a preference to invade reticulocytes during blood-stage infection. Rodent malaria parasites that also prefer reticulocytes could be useful tools to study human malaria reticulocyte invasion. However, previous tropism studies of rodent malaria are inconsistent from one another, making it difficult to compare cell preference of different parasite species and strains. In vivo measurements of cell tropism are also subjected to many confounding factors. Here we developed an ex vivo tropism assay for rodent malaria with highly purified fractions of murine reticulocytes and normocytes. We measured invasion into the different erythrocyte populations using flow cytometry and evaluated the tropism index of the parasite strains. We found that P. berghei ANKA displayed the strongest reticulocyte preference, followed by P. yoelii 17X1.1, whereas P. chabaudi AS and P. vinckei S67 showed mixed tropism. These preferences are intrinsic and were maintained at different reticulocyte and normocyte availabilities. Our study shed light on the true erythrocyte preference of the parasites and paves the way for future investigations on the receptor-ligand interactions mediating erythrocyte tropism.

Highly Potent rhenium(I) Tricarbonyl Complexes with Dual Anticancer and Anti-Angiogenic Activity Against Colorectal Carcinoma

2020 ◽  
Author(s):  
Joachim Delasoie ◽  
Aleksandar Pavic ◽  
Noémie Voutier ◽  
Sandra Vojnovic ◽  
Aurélien Crochet ◽  
...  
Keyword(s):  
Colorectal Carcinoma ◽  
Anticancer Drugs ◽  
Xenograft Model ◽  
Therapeutic Window ◽  
Low Doses ◽  
Sunitinib Malate ◽  
Angiogenic Activity ◽  
Antimetastatic Activity ◽  
Clinical Drugs

Synthesized and characterized a series of rhenium(I) trycarbonyl-based complexes with increased lipophilicity. Two of these novel compounds were discovered to possess remarkable anticancer, anti-angiogenic and antimetastatic activity <i>in vivo</i> (zebrafish-human CRC xenograft model), being effective at very low doses (1-3 µM). At doses as high as 250 µM the complexes did not provoke toxicity issues encountered in clinical anticancer drugs (cardio-, hepato-, and myelotoxicity). The two compounds exceed the antiproliferative and anti-angiogenic potency of clinical drugs cisplatin and sunitinib-malate, and display a large therapeutic window.

Aflatoxins biosynthesis, toxicity and intervention strategies: A review

2019 ◽  
Author(s):  
Chem Int
Keyword(s):  
Developing Countries ◽  
Molecular Basis ◽  
Genetic Regulation ◽  
Intervention Strategies ◽  
Historical Background ◽  
Economic Losses ◽  
Factors Affecting ◽  
Biomarkers Of Exposure ◽  
Food Commodities

Aflatoxins (AFTs) are toxic products of fungal metabolism, associated with serious health consequences and substantial economic losses to agriculture, livestock and poultry sectors, particularly in the developing countries. This review outlines the current information on AFTs in terms of historical background, classification, relative occurrence and co-existence with other mycotoxins in various food commodities. The phenomenon of aflatoxin (AFT) biosynthesis has been elucidated with reference to molecular basis, genetic regulation and factors affecting the AFT production. Moreover, the in vivo disposition kinetics, toxicological action and toxico-pathological consequences of AFTs have also been highlighted. Currently employed strategies for the detection and detoxification of AFTs, biomarkers of exposure assessment, potential economic impact and regulatory considerations regarding the AFTs have been emphasized.

Recent Advances in the Development of Antimicrobial Peptides (AMPs): Attempts for Sustainable Medicine?

2018 ◽  
Vol 25 (21) ◽  
pp. 2503-2519 ◽  
Author(s):  
Anne Kokel ◽  
Marianna Torok
Keyword(s):  
Side Effects ◽  
Antimicrobial Peptides ◽  
Potential Drug ◽  
Green Technologies ◽  
Specific Antibodies ◽  
Structural Modifications ◽  
Drug Candidates ◽  
Induce Resistance ◽  
Conventional Antibiotics

Background: Since the first isolation of antimicrobial peptides (AMPs) they have attracted extensive interest in medicinal chemistry. However, only a few AMP-based drugs are currently available on the market. Despite their effectiveness, biodegradability, and versatile mode of action that is less likely to induce resistance compared to conventional antibiotics, AMPs suffer from major issues that need to be addressed to broaden their use. Notably, AMPs can lack selectivity leading to side effects and cytotoxicity, and also exhibit in vivo instability. Several strategies are being actively considered to overcome the limitations that restrain the success of AMPs. Methods: In the current work, recent strategies reported for improving AMPs in the context of drug design and delivery were surveyed, and also their possible impact on patients and the environment was assessed. Results: As a major advantage AMPs possess an easily tunable skeleton offering opportunities to improve their properties. Strategic structural modifications and the beneficial properties of cyclic or branched AMPs in term of stability have been reported. The conjugation of AMPs with nanoparticles has also been explored to increase their in vivo stability. Other techniques such as the coupling of AMPs with specific antibodies aim to increase the selectivity of the potential drug towards the target. These strategies were evaluated for their effect on the environment highlighting green technologies. Conclusion: Although further research is needed taking into account both environmental and human health consequences of novel AMPs, several of these compounds are promising drug candidates for use in sustainable medicine.

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