1. Enhanced insulin action following subcutaneous co-administration of insulin and C-peptide in rats
M Kubota, Y Sato, O Khookhor, K Ekberg, A V Chibalin, J Wahren Diabetes Metab Res Rev. 2014 Feb;30(2):124-31. doi: 10.1002/dmrr.2471.
Background: This study was undertaken to examine if C-peptide (C) may interact with hexameric insulin and facilitate its disaggregation into the physiologically active monomeric form. Methods: Regular insulin (I) or an insulin analogue (IA) were injected s.c. in rats together with C or its C-terminal pentapeptide (PP). I or IA and C or PP were administered either as a physical mixture or into two separate s.c. depots. Whole body glucose utilization was evaluated using the euglycemic clamp technique. Phosphorylation of Akt/PKB and GSK in liver and skeletal muscles and ⁸⁶Rb⁺ uptake by L6 cells were measured. Results: S.c. injection of a mixture of I and C or I and PP resulted in a 30-55% greater (P < 0.01-0.001) and 15-27% (P < 0.05-0.001) longer stimulation of whole body glucose utilization than after separate injections. Insulin-stimulated phosphorylation of Akt/PKB in liver increased 35% more after injection of I and C in mixture compared with after separate injections. Phosphorylation of GSK3 was augmented by 50% (P < 0.05) following the injection of I and C in mixture compared with separate injections. Stimulation of myotubes with premixed I and C (1 nM) elicited 20% additional increase in ouabain-sensitive ⁸⁶Rb⁺ uptake (P < 0.05) in comparison with the effect when I and C were added separately. Conclusions: Subcutaneous co-administration of insulin and C results in augmented insulin bioactivity at the level of tissue glucose uptake, intracellular signalling, and enzyme activation. These effects may be attributed to augmented C mediated disaggregation of hexameric insulin into its physiologically active monomeric form.
2. An integrated microbiome and metabolomic analysis identifies immunoenhancing features of Ganoderma lucidum spores oil in mice
Xu Wu, Jiliang Cao, Mingxing Li, Peifen Yao, Hongyi Li, Wendong Xu, Cheng Yuan, Juyan Liu, Shengpeng Wang, Peng Li, Yitao Wang Pharmacol Res. 2020 Aug;158:104937. doi: 10.1016/j.phrs.2020.104937. Epub 2020 May 26.
Ganoderma lucidum (Leyss. ex Fr.) Karst. is a valuable dietary supplement used worldwide for promoting health as well as a medicinal fungus for handling fatigue, immunological disorders, and cancer. Previous studies have revealed the immunoenhancing effect of G. lucidum and the polysaccharide extract, with potential involvement of gut microbiome. The oil of G. lucidum spores (GLSO)is one of the well-known G. lucidum-related products. However, there is little evidence supporting the immune promotion activity and the underlying mechanisms. The present study aims to investigate the immunoenhancing effect of GLSO in mice. GLSO enhanced macrophage phagocytosis and NK cell cytotoxicity of mice. Further microbiome and metabolomics studies showed that GLSO induced structural rearrangement of gut microbiota, mediating alterations in a wide range of metabolites. By clustering, multivariate and correlation analysis, the immunoenhancing effect of GLSO was found to be highly correlated with elevated abundance of several bacterial genera (Lactobacillus, Turicibacter and Romboutsia) and species (Lactobacillus_intestinalis and Lactobacillus_reuteri), and decreased level of Staphylococcus and Helicobacter, which resulted in the regulation of a range of key metabolites such as dopamine, prolyl-glutamine, pentahomomethionine, leucyl-glutamine, l-threonine, stearoylcarnitine, dolichyl β-d-glucosyl phosphate, etc. These results provide new insights into the understanding of the modulatory effect of GLSO on immune system.
3. Proteasome active sites allosterically regulate each other, suggesting a cyclical bite-chew mechanism for protein breakdown
A F Kisselev, T N Akopian, V Castillo, A L Goldberg Mol Cell. 1999 Sep;4(3):395-402. doi: 10.1016/s1097-2765(00)80341-x.
In eukaryotes, the 20S proteasome contains two chymotrypsin-like, two trypsin-like, and two active sites shown here to have caspase-like specificity. We report that certain sites allosterically regulate each other's activities. Substrates of a chymotrypsin-like site stimulate dramatically the caspase-like activity and also activate the other chymotrypsin-like site. Moreover, substrates of the caspase-like sites inhibit allosterically the chymotrypsin-like activity (the rate-limiting one in protein breakdown) and thus can reduce the degradation of proteins by 26S proteasomes. These allosteric effects suggest an ordered, cyclical mechanism for protein degradation. We propose that the chymotrypsin-like site initially cleaves ("bites") the polypeptide, thereby stimulating the caspase-like sites. Their activation accelerates further cleavage ("chewing") of the fragments, while the chymotrypsin-like activity is temporarily inhibited. When further caspase-like cleavages are impossible, the chymotryptic site is reactivated and the cycle repeated.
