Pathogenesis of paclitaxel-induced peripheral neuropathy: A current review of in vitro and in vivo findings using rodent and human model systems

Ocriplasmin (Jetrea®) is a recombinant protease used to treat vitreomacular traction. To gain insight into vitreoretinal observations reported after ocriplasmin treatment, we have developed anin vivoporcine ocriplasmin-induced posterior vitreous detachment (PVD) model in which we investigated vitreoretinal tissues by optical coherence tomography, histology, and cytokine profiling. Eight weeks postinjection, ocriplasmin yielded PVD in 82% of eyes. Subretinal fluid (85%) and vitreous hyperreflective spots (45%) were resolved by week 3. Histological analysis of extracellular matrix (ECM) proteins such as laminin, fibronectin, and collagen IV indicated no retinal ocriplasmin-induced ECM distribution changes. Retinal morphology was unaffected in all eyes. Cytokine profiles of ocriplasmin-treated eyes were not different from vehicle. In cell-based electrical resistance assays, blood-retinal barrier permeability was altered by ocriplasmin concentrations of 6 μg/mL and higher, with all effects being nontoxic, cell-type specific, and reversible. Ocriplasmin was actively taken up by RPE and Müller cells, and our data suggest both lysosomal and transcellular clearance routes for ocriplasmin. In conclusion, transient hyperreflective spots and fluid in a porcine ocriplasmin-induced PVD model did not correlate with retinal ECM rearrangement nor inflammation. Reversiblein vitroeffects on blood-retinal barrier permeability provide grounds for a hypothesis on the mechanisms behind transient subretinal fluid observed in ocriplasmin-treated patients.

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Effects of early geometric confinement on the transcriptomic profile of human cerebral organoids

10.1101/2021.02.18.431674 ◽

2021 ◽

Author(s):

Dilara Sen ◽

Alexis Voulgaropoulos ◽

Albert J. Keung

Keyword(s):

Stem Cell Differentiation ◽

Cell Types ◽

Brain Regions ◽

Embryoid Bodies ◽

Model Systems ◽

Human Model ◽

Spatial Factors ◽

Neural Lineage

ABSTRACTBackgroundBiophysical factors such as shape and mechanical forces are known to play crucial roles in stem cell differentiation, embryogenesis and neurodevelopment. However, the complexity and experimental challenges capturing such early stages of development, and ethical concerns associated with human embryo and fetal research, limit our understanding of how these factors affect human brain organogenesis. Human cerebral organoids (hCO) are attractive models due to their ability to model important brain regions and transcriptomics of early in vivo brain development. Furthermore, they provide three-dimensional environments that better mimic the in vivo environment. To date, they have been used to understand the effects of genetics and soluble factors on neurodevelopment. Establishing links between spatial factors and hCO development will require the development of new approaches.ResultsHere, we investigated the effects of early geometric confinements on transcriptomic changes during hCO differentiation. Using a custom and tunable agarose microwell platform we generated embryoid bodies (EB) of diverse shapes and then further differentiated those EBs to whole brain hCOs. Our results showed that the microwells did not have negative gross impacts on the ability of the hCOs to differentiate generally towards neural fates, and there were clear shape dependent effects on neural lineage specification. In particular, we observed that non-spherical shapes showed signs of altered neurodevelopmental kinetics and favored the development of medial ganglionic eminence-associated brain regions and cell types over cortical regions.ConclusionsThe findings presented here suggest a role for spatial factors in brain region specification during hCO development. Understanding these spatial patterning factors will not only improve understanding of in vivo development and differentiation, but also provide important handles with which to advance and improve control over human model systems for in vitro applications.

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Lignans from Bursera fagaroides: Chemistry, Pharmacological Effects and Molecular Mechanism. A Current Review

Life ◽

10.3390/life11070685 ◽

2021 ◽

Vol 11 (7) ◽

pp. 685

Author(s):

Mayra Antúnez-Mojica ◽

Antonio Romero-Estrada ◽

Israel Hurtado-Díaz ◽

Alfonso Miranda-Molina ◽

Laura Alvarez

Keyword(s):

Molecular Mechanisms ◽

Medicinal Tree ◽

Chemical Structures ◽

In Vivo Assays ◽

Current Review ◽

Anti Cancer ◽

Future Direction ◽

A Current

Bursera fagaroides is a medicinal tree endemic to México, it belongs to the Burseraceae family and has proven antitumor activity. Modern research, performed principally with the bark extracts, have indicated that lignans are the main active constituents of B. fagaroides, with a high content of aryltetralin, aryldihydronaphtalene, dibenzylbutirolactone, and dibenzylbutane-type lignans as the constituents of the active extracts. In general, lignans from B. fagaroides exhibited potent anti-cancer activity, although antitumor, anti-bacterial, anti-protozoal, anti-inflammatory, and anti-viral properties have also been described. This review covers literature-reported lignans from B. fagaroides, chemical structures, nomenclature, chromatographic techniques of isolation, characterization strategies, and highlights the anti-cancer molecular mechanisms of lignans. Evaluation of the anticancer function of lignans has been extensively investigated since the cytotoxic in vitro results and in vivo assays in mice and zebrafish models to the tubulin molecular recognition by NMR. Also, we discuss the future direction for studying this important plant species and its lignan metabolites.

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Panel Discussion II: Usefulness of in vitro and in vivo Model Systems for Predicting the Adverse Public Health Outcome for Antimicrobial Drug Residues in Food

Microbial Ecology in Health and Disease ◽

10.1080/08910600050216174 ◽

2000 ◽

Vol 12 (3) ◽

pp. 45-53

Author(s):

Andrew Beaulieu ◽

Jacques Boisseau ◽

Carl Cerniglia ◽

Denis Corpet ◽

A. Haydée Fernández ◽

...

Keyword(s):

Public Health ◽

Health Outcome ◽

Panel Discussion ◽

Antimicrobial Drug ◽

Model Systems ◽

In Vivo Model ◽

Drug Residues ◽

Public Health Outcome

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In Vitro and In Vivo Model Systems for the Study of Allergic and Inflammatory Disorders in Man

CHEST Journal ◽

10.1378/chest.87.5_supplement.162s ◽

1985 ◽

Vol 87 (5) ◽

pp. 162S-164S ◽

Cited By ~ 4

Author(s):

Stephen P. Peters ◽

Robert M. Naclerio ◽

Alkis Togias ◽

Robert P. Schleimer ◽

Donald W. MacGlashan ◽

...

Keyword(s):

Model Systems ◽

In Vivo Model ◽

Inflammatory Disorders

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Mechanistic physiology-based pharmacokinetic modeling to elucidate vincristine-induced peripheral neuropathy following treatment with novel kinase inhibitors

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-021-04302-5 ◽

2021 ◽

Author(s):

Venkatesh Pilla Reddy ◽

Adrian J. Fretland ◽

Diansong Zhou ◽

Shringi Sharma ◽

Buyun Chen ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Kinase Inhibitors ◽

Pbpk Model ◽

Model Development ◽

Limited Information ◽

Time Curve ◽

Btk Inhibitor ◽

Chop Therapy

Abstract Purpose Limited information is available regarding the drug–drug interaction (DDI) potential of molecular targeted agents and rituximab plus cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone (R-CHOP) therapy. The addition of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib to R-CHOP therapy results in increased toxicity versus R-CHOP alone, including higher incidence of peripheral neuropathy. Vincristine is a substrate of P-glycoprotein (P-gp, ABCB1); drugs that inhibit P-gp could potentially cause increased toxicity when co-administered with vincristine through DDI. While the combination of the BTK inhibitor acalabrutinib and R-CHOP is being explored clinically, the DDI potential between these therapies is unknown. Methods A human mechanistic physiology-based pharmacokinetic (PBPK) model of vincristine following intravenous dosing was developed to predict potential DDI interactions with combination therapy. In vitro absorption, distribution, metabolism, and excretion and in vivo clinical PK parameters informed PBPK model development, which was verified by comparing simulated vincristine concentrations with observed clinical data. Results While simulations suggested no DDI between vincristine and ibrutinib or acalabrutinib in plasma, simulated vincristine exposure in muscle tissue was increased in the presence of ibrutinib but not acalabrutinib. Extrapolation of the vincristine mechanistic PBPK model to other P-gp substrates further suggested DDI risk when ibrutinib (area under the concentration–time curve [AUC] ratio: 1.8), but not acalabrutinib (AUC ratio: 0.92), was given orally with venetoclax or digoxin. Conclusion Overall, these data suggest low DDI risk between acalabrutinib and P-gp substrates with negligible increase in the potential risk of vincristine-induced peripheral neuropathy when acalabrutinib is added to R-CHOP therapy.

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Antidiabetic Properties of Naringenin: A Citrus Fruit Polyphenol

Biomolecules ◽

10.3390/biom9030099 ◽

2019 ◽

Vol 9 (3) ◽

pp. 99 ◽

Cited By ~ 16

Author(s):

Danja J. Den Hartogh ◽

Evangelia Tsiani

Keyword(s):

Insulin Resistance ◽

Animal Studies ◽

Citrus Fruit ◽

Epidemiological Studies ◽

Personal Health ◽

Current Review ◽

Vegetables And Fruits

Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by insulin resistance and hyperglycemia and is associated with personal health and global economic burdens. Current strategies/approaches of insulin resistance and T2DM prevention and treatment are lacking in efficacy resulting in the need for new preventative and targeted therapies. In recent years, epidemiological studies have suggested that diets rich in vegetables and fruits are associated with health benefits including protection against insulin resistance and T2DM. Naringenin, a citrus flavanone, has been reported to have antioxidant, anti-inflammatory, hepatoprotective, nephroprotective, immunomodulatory and antidiabetic properties. The current review summarizes the existing in vitro and in vivo animal studies examining the anti-diabetic effects of naringenin.

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Role of SHH in Patterning Human Pluripotent Cells towards Ventral Forebrain Fates

Cells ◽

10.3390/cells10040914 ◽

2021 ◽

Vol 10 (4) ◽

pp. 914

Author(s):

Melanie V. Brady ◽

Flora M. Vaccarino

Keyword(s):

Stem Cell ◽

Human Brain ◽

Human Development ◽

Disease Modeling ◽

Model Systems ◽

Advantages And Disadvantages ◽

Technical Ability ◽

Cellular Phenotypes

The complexities of human neurodevelopment have historically been challenging to decipher but continue to be of great interest in the contexts of healthy neurobiology and disease. The classic animal models and monolayer in vitro systems have limited the types of questions scientists can strive to answer in addition to the technical ability to answer them. However, the tridimensional human stem cell-derived organoid system provides the unique opportunity to model human development and mimic the diverse cellular composition of human organs. This strategy is adaptable and malleable, and these neural organoids possess the morphogenic sensitivity to be patterned in various ways to generate the different regions of the human brain. Furthermore, recapitulating human development provides a platform for disease modeling. One master regulator of human neurodevelopment in many regions of the human brain is sonic hedgehog (SHH), whose expression gradient and pathway activation are responsible for conferring ventral identity and shaping cellular phenotypes throughout the neural axis. This review first discusses the benefits, challenges, and limitations of using organoids for studying human neurodevelopment and disease, comparing advantages and disadvantages with other in vivo and in vitro model systems. Next, we explore the range of control that SHH exhibits on human neurodevelopment, and the application of SHH to various stem cell methodologies, including organoids, to expand our understanding of human development and disease. We outline how this strategy will eventually bring us much closer to uncovering the intricacies of human neurodevelopment and biology.

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New Endeavors of (Micro)Tissue Engineering: Cells Tissues Organs on-Chip and Communication Thereof

Cells Tissues Organs ◽

10.1159/000516356 ◽

2021 ◽

pp. 1-15

Author(s):

Haysam M.M.A.M. Ahmed ◽

Liliana S. Moreira Teixeira

Keyword(s):

Tissue Engineering ◽

Food Additives ◽

Market Potential ◽

Model Systems ◽

Human Model ◽

Human Stem Cells ◽

Animal Testing ◽

Preclinical Research ◽

On Chip

The development of new therapies is tremendously hampered by the insufficient availability of human model systems suitable for preclinical research on disease target identification, drug efficacy, and toxicity. Thus, drug failures in clinical trials are too common and too costly. Animal models or standard 2D in vitro tissue cultures, regardless of whether they are human based, are regularly not representative of specific human responses. Approaching near human tissues and organs test systems is the key goal of organs-on-chips (OoC) technology. This technology is currently showing its potential to reduce both drug development costs and time-to-market, while critically lessening animal testing. OoC are based on human (stem) cells, potentially derived from healthy or disease-affected patients, thereby amenable to personalized therapy development. It is noteworthy that the OoC market potential goes beyond pharma, with the possibility to test cosmetics, food additives, or environmental contaminants. This (micro)tissue engineering-based technology is highly multidisciplinary, combining fields such as (developmental) biology, (bio)materials, microfluidics, sensors, and imaging. The enormous potential of OoC is currently facing an exciting new challenge: emulating cross-communication between tissues and organs, to simulate more complex systemic responses, such as in cancer, or restricted to confined environments, as occurs in osteoarthritis. This review describes key examples of multiorgan/tissue-on-chip approaches, or linked organs/tissues-on-chip, focusing on challenges and promising new avenues of this advanced model system. Additionally, major emphasis is given to the translation of established tissue engineering approaches, bottom up and top down, towards the development of more complex, robust, and representative (multi)organ/tissue-on-chip approaches.

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Transcription of Candidate Virulence Genes ofHaemophilus ducreyi during Infection of Human Volunteers

Infection and Immunity ◽

10.1128/iai.69.3.1483-1487.2001 ◽

2001 ◽

Vol 69 (3) ◽

pp. 1483-1487 ◽

Cited By ~ 21

Author(s):

Robert E. Throm ◽

Stanley M. Spinola

Keyword(s):

Experimental Infection ◽

Virulence Genes ◽

Human Model ◽

Specific Gene ◽

Gene Products ◽

Virulence Determinants ◽

Reverse Transcription Pcr ◽

Human Volunteers

ABSTRACT Haemophilus ducreyi expresses several putative virulence factors in vitro. Isogenic mutant-to-parent comparisons have been performed in a human model of experimental infection to examine whether specific gene products are involved in pathogenesis. Several mutants (momp, ftpA, losB, lst, cdtC, and hhdB) were as virulent as the parent in the human model, suggesting that their gene products did not play a major role in pustule formation. However, we could not exclude the possibility that the gene of interest was not expressed during the initial stages of infection. Biopsies of pustules obtained from volunteers infected with H. ducreyiwere subjected to reverse transcription-PCR. Transcripts corresponding to momp, ftpA, losB, lst, cdtB, and hhdA were expressed in vivo. In addition, transcripts for other putative virulence determinants such as ompA2, tdhA, lspA1, andlspA2 were detected in the biopsies. These results indicate that although several candidate virulence determinants are expressed during experimental infection, they do not have a major role in the initial stages of pathogenesis.

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