Mesenchymal stromal cell secretory molecules improve the functional survival of human islets

This is the final version. Available on open access from Wiley via the DOI in this recordData availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.AIMS: Human islet transplantation as a therapy for type 1 diabetes is compromised by the loss of functional beta cells in the immediate post-transplantation period. Mesenchymal stromal cells (MSCs) and MSC-derived secretory peptides improve the outcomes of islet transplantation in rodent models of diabetes. Here, we utilized a mouse model for human islet transplantation and assessed the effects of a cocktail of MSC-secreted peptides (screened by MSC-secretome for human islet GPCRs) on the functional survival of human islets. METHODS: Human islets from nine donors (Age: 36-57; BMI: 20-35) were treated with a cocktail of human recombinant annexin A1 (ANXA1), stromal cell-derived factor-1 (SDF-1/CXCL12) and complement component C3 (C3a). Glucose-stimulated insulin secretion (GSIS) was assessed in static incubation, and cytokine-induced apoptosis was assessed by measuring caspase 3/7 activity. mRNA expression levels were determined by qPCR. Human islet function in vivo was assessed using a novel model for human islet transplantation into a T1D mouse model. Human islet function in vivo was assessed using islet transplantation under the kidney capsule of immunodeficient mice prior to STZ destruction of endogenous mouse beta cells to model T1DM. RESULTS: Pretreatment with a cocktail of MSC-secreted peptides increased GSIS in vitro and protected against cytokine-induced apoptosis in human islets isolated from nine donors. Animals transplanted with either treated or untreated human islets remained normoglycaemic for up to 28 days after STZ-administration to ablate the endogenous mouse beta cells, whereas non-transplanted animals showed significantly increased blood glucose immediately after STZ administration. Removal of the human islet graft by nephrectomy resulted in rapid increases in blood glucose to similar levels as the non-transplanted controls. Pretreating human islets with the MSC-derived cocktail significantly improved glucose tolerance in graft recipients, consistent with enhanced functional survival of the treated islets in vivo. CONCLUSION: Pretreating human islets before transplantation with a defined cocktail of MSC-derived molecules could be employed to improve the quality of human islets for transplantation therapy for type 1 diabetes.Medical Research Council (MRC)Diabetes Research and Wellness FoundationKing’s Health Partners Research & Development Fun

Modulation of innate immune responses at birth by prenatal malaria exposure and association with malaria risk during the first year of life.

BACKGROUND: Factors driving inter-individual differences in immune responses upon different types of prenatal malaria exposure (PME) and subsequent risk of malaria in infancy remain poorly understood. In this study, we examined the impact of four types of PME (i.e., maternal peripheral infection and placental acute, chronic, and past infections) on both spontaneous and toll-like receptors (TLRs)-mediated cytokine production in cord blood and how these innate immune responses modulate the risk of malaria during the first year of life. METHODS: We conducted a birth cohort study of 313 mother-child pairs nested within the COSMIC clinical trial (NCT01941264), which was assessing malaria preventive interventions during pregnancy in Burkina Faso. Malaria infections during pregnancy and infants' clinical malaria episodes detected during the first year of life were recorded. Supernatant concentrations of 30 cytokines, chemokines, and growth factors induced by stimulation of cord blood with agonists of TLRs 3, 7/8, and 9 were measured by quantitative suspension array technology. Crude concentrations and ratios of TLR-mediated cytokine responses relative to background control were analyzed. RESULTS: Spontaneous production of innate immune biomarkers was significantly reduced in cord blood of infants exposed to malaria, with variation among PME groups, as compared to those from the non-exposed control group. However, following TLR7/8 stimulation, which showed higher induction of cytokines/chemokines/growth factors than TLRs 3 and 9, cord blood cells of infants with evidence of past placental malaria were hyper-responsive in comparison to those of infants not-exposed. In addition, certain biomarkers, which levels were significantly modified depending on the PME category, were independent predictors of either malaria risk (GM-CSF TLR7/8 crude) or protection (IL-12 TLR7/8 ratio and IP-10 TLR3 crude, IL-1RA TLR7/8 ratio) during the first year of life. CONCLUSIONS: These findings indicate that past placental malaria has a profound effect on fetal immune system and that the differential alterations of innate immune responses by PME categories might drive heterogeneity between individuals to clinical malaria susceptibility during the first year of life

Establishment of a 3D In Vitro Model to Accelerate the Development of Human Therapies against Corneal Diabetes

The authors thank Dr. John M Asara, Min Yuan, and Susanne Breitkopf for their technical help with metabolomics experiments, Dr. Ben Fowler for his technical help with TEM experiments and also Tina B McKay for many thoughtful discussions and scientific insights during the study.Purpose To establish an in vitro model that would mirror the in vivo corneal stromal environment in diabetes (DM) patients. Methods Human corneal fibroblasts from Healthy (HCFs), Type 1DM (T1DM) and Type 2DM (T2DM) donors were isolated and cultured for 4 weeks with Vitamin C stimulation in order to allow for extracellular matrix (ECM) secretion and assembly. Results Our data indicated altered cellular morphology, increased cellular migration, increased ECM assembly, and severe mitochondrial damage in both T1DM and T2DMs when compared to HCFs. Furthermore, we found significant downregulation of Collagen I and Collagen V expression in both T1DM and T2DMs. Furthermore, a significant up regulation of fibrotic markers was seen, including α-smooth muscle actin in T2DM and Collagen III in both T1DM and T2DMs. Metabolic analysis suggested impaired Glycolysis and Tricarboxylic acid cycle (TCA) pathway. Conclusion DM has significant effects on physiological and clinical aspects of the human cornea. The benefits in developing and fully characterizing our 3D in vitro model are enormous and might provide clues for the development of novel therapeutics.Yeshttp://www.plosone.org/static/editorial#pee

A female-emitted pheromone component is associated with reduced male courtship in the parasitoid wasp Spalangia endius

During courtship interactions, the courted individual may not always be prepared to mate. For example, mating or courtship may be detrimental to its fitness and resistance is expected under these circumstances. As such, various resistance strategies have evolved, from physically fending off courting individuals to producing behavioural signals of unreceptivity. In the parasitoid wasp Spalangia endius, females rarely re-mate and mated females are avoided by males in favour of virgin females. Further, mated females appear to advertise their mating status by the release of a pheromone component (methyl 6-methylsalicylate), but direct evidence of the nature of this release is lacking. Here we used real-time chemical analysis to track the emission of the pheromone component during courtship interactions between virgin males and either virgin or mated females. We found that females actively release methyl 6-methylsalicylate when courted and that significantly greater concentrations are released by previously mated females. Further, high concentrations of this component are associated with both the prevention and termination of courtship

Hypoglycaemic and anti-hyperglycaemic activity of Tabernanthe iboga aqueous extract in fructose-fed Streptozotocin type 2 diabetic rats

Publisher Copyright: © 2020, Institute of Korean Medicine, Kyung Hee University. This is a post-peer-review, pre-copyedit version of Bading-Taïka, B., Souza, A., Bourobou Bourobou, HP. et al. Hypoglycaemic and anti-hyperglycaemic activity of Tabernanthe iboga aqueous extract in fructose-fed streptozotocin type 2 diabetic rats. ADV TRADIT MED (ADTM) (2020). https://doi.org/10.1007/s13596-020-00484-0Root bark preparations of the Gabonese plant Tabernanthe iboga (T. iboga) has long been used in traditional medicine in Central and West African regions for the management of type 2 diabetes (T2D). This study is the first investigation of in vivo hypoglycaemic activity in healthy rats and anti-hyperglycaemic activity of T. iboga in a 10% fructose-fed (40 mg/kg i.p.) streptozotocin (STZ) injected type 2 diabetic rat model. T. iboga at 50 to 200 mg/kg induced hypoglycaemia activity over 3 h fasted glucose tolerance in healthy Wistar rats and anti-hyperglycaemic effects on non-fasted and fasted blood glucose in fructose-fed STZ T2D rats with no toxicity. Fructose-fed STZ T2D rats developed characteristic type 2 diabetic complications over 6 weeks exhibiting significantly elevated fasting and non-fasting blood glucose, polydipsia, reduced body weight gain and glucose and insulin tolerance compared with STZ alone and normal control rats. T. iboga (50 mg/kg and 200 mg/kg bw) administered p.o. once daily for 4 weeks significantly improved diabetic symptoms of polydipsia, reduced body weight, hyperglycaemia, glucose and insulin tolerance (as AUC) compared with fructose-fed STZ T2D rats. T. iboga aqueous extract (50 mg/kg and 200 mg/kg) also significantly reversed altered actions of marker enzymes of liver including alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), creatinine, HbA1c and elevated triglycerides in fructose-fed STZ type 2 diabetic rats. Our outcomes show that daily oral provision of T. iboga improves type 2 diabetes complications, superior to glibenclamide, in rat fructose-fed STZ model and offers the potential for safe clinical management of T2D in Gabon.Peer reviewe