Using Caenorhabditis elegans as a Model for Obesity Pharmacology Development.

The Caenorhabditis elegans model is a rapid and inexpensive method to address pharmacologic questions. We describe the use of C. elegans to explore 2 pharmacologic questions concerning candidate antiobesity drugs and illustrate its potential usefulness in pharmacologic research: (1) to determine a ratio of betahistine-olanzapine that blocks the olanzapine-induced intestinal fat deposition (IFD) as detected by Nile red staining and (2) to identify the mechanism of action of a pharmaceutical candidate AB-101 that reduces IFD. Olanzapine (53 µg/mL) increased the IFD (12.1 ± 0.1%, P < 0.02), which was blocked by betahistine (763 µg/mL, 39.3 ± 0.01%, P < 0.05) in wild-type C. elegans (N2). AB-101 (1.0%) reduced the IFD in N2 (P < 0.05), increased the pharyngeal pumping rate (P < 0.05), and reversed the elevated IFD induced by protease inhibitors atazanavir and ritonavir (P < 0.05). AB-101 did not affect IFD in a ACS null mutant strain acs-4(ok2872) III/hT2[bli-4(e937) let-?(q782) qIs48](I;III) suggesting an involvement of the lipid oxidation pathway and an upregulation of CPT-1. Our studies suggest that C. elegans may be used as a resource in pharmacologic research. This article is intended to stimulate a greater appreciation of its value in the development of new pharmaceutical interventions.

How manufacturing won or lost the COVID-19 vaccine race.

The development of vaccines for COVID-19 occurred at an unprecedented pace, and 32 vaccines using a broad range of technologies had received authorization for use on an emergency basis by the end of 2021, from either a national regulatory authority or the World Health Organization. However, 27 of those 32 vaccines had little impact on the global course of the pandemic. Only five vaccines, from AstraZeneca, Pfizer/BioNTech, Sinovac, Moderna, and Sinopharm, were manufactured, authorized, and distributed in time to significantly impact the number of deaths worldwide. Together, these five vaccines averted an estimated 17 million deaths in the first year of the vaccination campaign. The shared characteristic of these five manufacturers was their ability to rapidly develop and scale up vaccine production to deliver the large manufacturing volumes required to immunize large segments of the global population. Because the development and manufacturing of these vaccines was generally on the critical path to authorization and supply, the technical activities involved with development, scale-up, testing, technology transfer, and full-scale manufacturing, as well as aspects of the Chemistry, Manufacturing, and Controls (CMC) regulatory interactions, are examined for each vaccine and technology for which information is available in the public domain to provide lessons learned and recommendations on proactive actions to better prepare us for a future pandemic response. The critical success factors include prior experience with commercialization and approval, robust quality systems, rigorous process development strategies, flexible manufacturing facilities with a skilled workforce, collaboration, access to consumables, reagents, and adjuvants (if relevant), and an equitable distribution of the global vaccine manufacturing network.

Dietary Plant Lectins Appear to Be Transported from the Gut to Gain Access to and Alter Dopaminergic Neurons of Caenorhabditis elegans, a Potential Etiology of Parkinson's Disease.

Lectins from dietary plants have been shown to enhance drug absorption in the gastrointestinal tract of rats, be transported trans-synaptically as shown by tracing of axonal and dendritic paths, and enhance gene delivery. Other carbohydrate-binding protein toxins are known to traverse the gut intact in dogs. Post-feeding rhodamine- or TRITC-tagged dietary lectins, the lectins were tracked from gut to dopaminergic neurons (DAergic-N) in transgenic Caenorhabditis elegans (C. elegans) [egIs1(Pdat-1:GFP)] where the mutant has the green fluorescent protein (GFP) gene fused to a dopamine transport protein gene labeling DAergic-N. The lectins were supplemented along with the food organism Escherichia coli (OP50). Among nine tested rhodamine/TRITC-tagged lectins, four, including Phaseolus vulgaris erythroagglutinin (PHA-E), Bandeiraea simplicifolia (BS-I), Dolichos biflorus agglutinin (DBA), and Arachis hypogaea agglutinin (PNA), appeared to be transported from gut to the GFP-DAergic-N. Griffonia Simplicifolia and PHA-E, reduced the number of GFP-DAergic-N, suggesting a toxic activity. PHA-E, BS-I, Pisum sativum (PSA), and Triticum vulgaris agglutinin (Succinylated) reduced fluorescent intensity of GFP-DAergic-N. PHA-E, PSA, Concanavalin A, and Triticum vulgaris agglutinin decreased the size of GFP-DAergic-N, while BS-I increased neuron size. These observations suggest that dietary plant lectins are transported to and affect DAergic-N in C. elegans, which support Braak and Hawkes' hypothesis, suggesting one alternate potential dietary etiology of Parkinson's disease (PD). A recent Danish study showed that vagotomy resulted in 40% lower incidence of PD over 20 years. Differences in inherited sugar structures of gut and neuronal cell surfaces may make some individuals more susceptible in this conceptual disease etiology model.

Prowashonupana barley dietary fibre reduces body fat and increases insulin sensitivity in Caenorhabditis elegans model.

Prowashonupana barley (PWB) is high in ß-glucan with moderate content of resistant starch. PWB reduced intestinal fat deposition (IFD) in wild type Caenorhabditis elegans (C. elegans, N2), and in sir-2.1 or daf-16 null mutants, and sustained a surrogate marker of lifespan, pharyngeal pumping rate (PPR), in N2, sir-2.1, daf-16, or daf-16/daf-2 mutants. Hyperglycaemia (2% glucose) reversed or reduced the PWB effect on IFD in N2 or daf-16/daf-2 mutants with a sustained PPR. mRNA expression of cpt-1, cpt-2, ckr-1, and gcy-8 were dose-dependently reduced in N2 or daf-16 mutants, elevated in daf-16/daf-2 mutants with reduction in cpt-1, and unchanged in sir-2.1 mutants. mRNA expressions were increased by hyperglycaemia in N2 or daf-16/daf-2 mutants, while reduced in sir-2.1 or daf-16 mutants. The effects of PWB in the C. elegans model appeared to be primarily mediated via sir-2.1, daf-16, and daf-16/daf-2. These data suggest that PWB and ß-glucans may benefit hyperglycaemia-impaired lipid metabolism.