Search

Diabetes is recognised as the world's fastest growing chronic condition globally. Helminth infections have been shown to be associated with a lower prevalence of type 2 diabetes (T2D), in part due to their ability to induce a type 2 immune response. Therefore, to understand the molecular mechanisms that underlie the development of T2D-induced insulin resistance, we treated mice fed on normal or diabetes-promoting diets with excretory/secretory products (ES) from the gastrointestinal helminth Nippostrongylus brasiliensis. We demonstrated that treatment with crude ES products from adult worms (AES) or infective third-stage larvae (L3ES) from N. brasiliensis improved glucose tolerance and attenuated body weight gain in mice fed on a high glycaemic index diet. N. brasiliensis ES administration to mice was associated with a type 2 immune response measured by increased eosinophils and IL-5 in peripheral tissues but not IL-4, and with a decrease in the level of IL-6 in adipose tissue and corresponding increase in IL-6 levels in the liver. Moreover, treatment with AES or L3ES was associated with significant changes in the community composition of the gut microbiota at the phylum and order levels. These data highlight a role for N. brasiliensis ES in modulating the immune response associated with T2D, and suggest that N. brasiliensis ES contain molecules with therapeutic potential for treating metabolic syndrome and T2D. [ABSTRACT FROM AUTHOR]

Toxocariasis is a zoonotic disease affecting humans that is predominantly caused by Toxocara canis and T. cati, primarily parasites of dogs and cats, respectively. Toxocara generally establishes long-term infections by co-opting its host's physiological processes, while at the same time exploiting the nutritional environment. Adult stage T. canis reside in the gut of the definitive canine host where they employ a suite of strategies to combat intestinal immune responses by actively producing and releasing excretory-secretory products (ESPs). The protein component of T. canis ESPs has been widely studied, but characterisation of the non-protein ESP complement remains neglected. To characterize the secreted metabolome of Toxocara ESPs and to shed light on the parasite's metabolic processes, we profiled the ESPs of T. canis using both gas chromatography (GC) and liquid chromatography (LC) mass spectrometry approaches. We successfully identified 61 small molecules, including 41 polar metabolites, 14 medium-long chain fatty acids (MLCFAs) and six short chain fatty acids (SCFAs). We identified talose, stearic acid and isovalerate as the major compounds belonging to the polar, MLCFA and SCFA chemical classes, respectively. Most of the 61 identified metabolites appear to have been produced by T. canis via three distinct metabolic pathways - fatty acid, amino acid and carbohydrate metabolism. The majority of the identified ESPs have known biological properties, especially as immunomodulators. However, there is limited/no information on the biological roles or applications of 31 ESP biomolecules, suggesting that these may have novel activities that merit further investigation. [ABSTRACT FROM AUTHOR]

Granulins are a family of unique protein growth factors which are found in a range of species and have several bioactivities that include cell proliferation and wound healing. They typically contain six disulfide bonds, but the sequences, structures and bioactivities vary significantly. We have previously shown that an N-terminally truncated version of a granulin from the human liver fluke, Opisthorchis viverrini, can fold independently into a "mini-granulin" structure and has potent wound healing properties in vivo. The incorporation of a non-native third disulfide bond, with respect to the full-length granulin module, was critical for the formation of regular secondary structure in the liver fluke derived peptide. By contrast, this third disulfide bond is not required for a carp granulin-1 truncated peptide to fold independently. This distinction led us to explore granulins from the zebrafish model organism. Here we show that the mini-granulin fold occurs in a naturally occurring paragranulin (half-domain) from zebrafish, and is also present in a truncated form of a full-length zebrafish granulin, suggesting this structure might be a common property in either naturally occurring or engineered N-terminally truncated granulins and the carp granulin-1 folding is an anomaly. The in vitro folding yield is significantly higher in the naturally occurring paragranulin, but only the truncated zebrafish granulin peptide promoted the proliferation of fibroblasts consistent with a growth factor function, and therefore the function of the paragranulin remains unknown. These findings provide insight into the folding and evolution of granulin domains and might be useful in the elucidation of the structural features important for bioactivity to aid the design of more potent and stable analogues for the development of novel wound healing agents. [ABSTRACT FROM AUTHOR]