Argyrin B, a non-competitive inhibitor of the human immunoproteasome exhibiting preference for ß1i.

Inhibitors of the proteasome have found broad therapeutic applications; however, they show severe toxicity due to the abundance of proteasomes in healthy cells. In contrast, inhibitors of the immunoproteasome, which is upregulated during disease states, are less toxic and have increased therapeutic potential including against autoimmune disorders. In this project, we report argyrin B, a natural product cyclic peptide to be a reversible, non-competitive inhibitor of the immunoproteasome. Argyrin B showed selective inhibition of the ß5i and ß1i sites of the immunoproteasome over the ß5c and ß1c sites of the constitutive proteasome with nearly 20-fold selective inhibition of ß1i over the homologous ß1c. Molecular modelling attributes the ß1i over ß1c selectivity to the small hydrophobic S1 pocket of ß1i and ß5i over ß5c to site-specific amino acid variations that enable additional bonding interactions and stabilization of the binding conformation. These findings facilitate the design of immunoproteasome selective and reversible inhibitors that may have a greater therapeutic potential and lower toxicity.

Follicular fluid levels of inhibin A, inhibin B, and activin A levels reflect changes in follicle size but are not independent markers of the oocyte's ability to fertilize.

OBJECTIVE: To investigate the biochemical relationship between follicular/oocyte maturity and follicular inhibins and activin levels. DESIGN: Prospective study. SETTING: Research laboratory in university hospital. PATIENT(S): Thirty-five women undertook IVF/ICSI program. INTERVENTION(S): Individual follicular fluid aspirations, oocyte isolation, follicular fluid storage. MAIN OUTCOME MEASURE(S): Inhibin A, inhibin B, and activin A concentrations, oocyte retrieval, and fertility outcome. RESULT(S): Inhibin A, inhibin B, and activin A concentrations varied from 7.9 to 436 ng/mL, 9.7 to 786 ng/mL, and 1.7 to 267.9 ng/mL, respectively. There was no change of inhibin A concentrations, whereas inhibin B and activin A concentrations dropped dramatically as the follicles enlarged. Total follicular content of inhibin A and activin A increased, and inhibin B remained constant. Both inhibin A and inhibin B levels were significantly higher in those follicles from which an oocyte could be recovered, but they did not differ with respect to subsequent oocyte fertilization. CONCLUSION(S): Inhibin A is actively produced throughout follicular growth to retain a set concentration. In contrast, inhibin B appears not to be actively produced, and the concentration drops as follicles enlarge. Activin A concentrations also decrease, but there is some extra synthesis. Higher levels of inhibin A and B are associated with oocyte presence but not with fertilization rates.

Phytochemical evaluation of selected antioxidant-containing medicinal plants for use in the preparation of a herbal formula--a preliminary study.

Oxidative damage is implicated in the pathogenesis of a number of diseases. Scientific research shows positive links between accumulated free-radical damage and age-related diseases such as atherosclerosis, Alzheimer, and osteoarthritis. There are reports that plant-derived phenolic compounds such as flavonoids have antioxidant properties capable of reducing the risk of developing these diseases. This work aims to evaluate the antioxidant activity of selected medicinal plants traditionally used by herbalists, in particular for the treatment of arthritis, with a view to developing a formula for treating age and age-related diseases. Thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) analyses of each plant confirmed the presence of a number of flavonoids reported in the literature, as well as unidentified compounds. The antioxidant activities of these plants were determined by DPPH (= '1,1-diphenyl-2-picryl-hydrazyl') radical scavenging, and by inhibition of linoleic acid peroxidation. All the crude plant extracts showed marked antioxidant activities in both assays. The extracts' inhibitory effects on linoleic acid peroxidation was concentration-dependent, with the highest activity shown at 0.1% (w/v). These results suggest that the phenolic compounds, particularly the flavonoids, may, in part, be responsible for the antioxidant activity of traditional plant extracts.