PubMed · 4451866
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C Laroche, J Vigne, J Grégoire. 1974-11-30. [Therapeutic interactions].. https://pubmed.ncbi.nlm.nih.gov/4451866/
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Seals accumulate xenobiotics through dietary biomagnification and exposure to polluted marine environments, with contaminants concentrating in their blubber. Biotransformation mitigates xenobiotic toxicity by converting lipophilic compounds into excretable hydrophilic metabolites, a process coordinated by nuclear receptors including the Pregnane X Receptor (PXR), whose plastic ligand-binding domain enables broad xenobiotic sensing. By examining PXR in pinnipeds, we investigated the evolutionary conservation and functional characterization of PXR using genomic sequence analysis, protein structural prediction, and transactivation assays, revealing broadly conserved structural features alongside species-specific functional divergence in receptor responsiveness to environmental stressors. Specifically, the obtained results highlight divergent gene and functional landscapes with ORF-disrupting mutations identified in Monachus monachus and Neomonachus schauinslandi that abolish receptor activation toward known PXR ligands. In contrast, Leptonychotes weddelli retained an intact PXR ORF but showed reduced receptor activity, revealing functional divergence in PXR among pinnipeds.
Glucoamylase (E.C: 3.2.1.3, alpha-(1-->4)-glucan glucohydrolase) mainly hydrolyzes starch and has been extensively used in the starch, glucose (dextrose), and fermentation industries. Immobilized glucoamylase has an inherent disadvantage of lower conversion rates and low thermostability of less than 55 degrees C when used in continuous operations. We have developed crosslinked enzyme crystals (CLEC) of glucoamylase that overcome the above disadvantages, possess good thermal stability and retain 98.6% of their original activity at 70 degrees C for 1h, 77% activity at 80 degrees C for 1h, and 51.4% activity at 90 degrees C for 0.5h. CLEC glucoamylase has a specific activity of 0.0687 IU/mg and a yield of 50.7% of the original activity of the enzyme under optimum conditions with starch as the substrate. The crystals obtained are rhombohedral in shape having a size approximately 10-100 microm, a density of 1.8926 g/cm(3) and a surface area of 0.7867 m(2)/g. The pH optimum of the glucoamylase crystals was sharp at pH 4.5, unlike the soluble enzyme. The kinetic constants V(max) and K(m) exhibited a 10-fold increase as a consequence of crystallization and crosslinking. The continuous production of glucose from 10% soluble starch and 10% maltodextrin (12.5 DE) by a packed-bed reactor at 60 degrees C had a productivity of 110.58 g/L/h at a residence time of 7.6 min and 714.1g/L/h at a residence time of 3.4 min, respectively. The CLEC glucoamylase had a half-life of 10h with 4% starch substrate at 60 degrees C.
The aim of this study was to investigate the effect of the size of biodegradable microparticles (monolithic dispersions) on the release rate of an incorporated drug in a quantitative way. 5-Fluorouracil-loaded, poly(lactic-co-glycolic acid)-based microparticles were prepared with a solid-in-oil-in-water solvent extraction technique. In vitro drug release from different-sized particle fractions was measured in phosphate buffer pH 7.4. Differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and size exclusion chromatography (SEC) were used to monitor the degradation behavior of the polymer and morphological changes of the microparticles upon exposure to the release medium. Based on these experimental results, an appropriate mathematical theory was identified and used to get further insight into the underlying physical and chemical processes, which are involved in the control of drug release. Interestingly, the relative as well as the absolute release rate of the drug increased with increasing microparticle radius, despite of the increasing diffusion pathways. SEC, DSC and SEM analysis revealed that the degradation behavior of the matrix forming polymer was not significantly affected by the size of the devices and that autocatalytic effects do not seem to play a major role. Importantly, the initial drug loading significantly increased with increasing radius of the drug delivery system. Thus, large microparticles became more porous during drug release than small microparticles, leading to higher apparent diffusivities and drug transport rates. This effect overcompensated the effect of the increasing diffusion pathways with increasing microparticle radius, resulting in increased drug release rates with increasing device dimension. The applied mathematical model, considering drug diffusion with non-constant diffusivities (to account for polymer degradation) was able to quantitatively describe the observed drug release patterns. Importantly, an exponential relationship could be established between the diffusion coefficient and the initial loading of the drug. Based on this dependency, it was possible to predict the resulting drug release kinetics for arbitrary microparticle sizes in a quantitative way.