Mammalian Diaphanous1 signalling in neurovascular complications of diabetes.

Over the past few decades, diabetes gradually has become one of the top non-communicable disorders, affecting 476.0 million in 2017 and is predicted to reach 570.9 million people in 2025. It is estimated that 70 to 100% of all diabetic patients will develop some if not all, diabetic complications over the course of the disease. Despite different symptoms, mechanisms underlying the development of diabetic complications are similar, likely stemming from deficits in both neuronal and vascular components supplying hyperglycaemia-susceptible tissues and organs. Diaph1, protein diaphanous homolog 1, although mainly known for its regulatory role in structural modification of actin and related cytoskeleton proteins, in recent years attracted research attention as a cytoplasmic partner of the receptor of advanced glycation end-products (RAGE) a signal transduction receptor, whose activation triggers an increase in proinflammatory molecules, oxidative stressors and cytokines in diabetes and its related complications. Both Diaph1 and RAGE are also a part of the RhoA signalling cascade, playing a significant role in the development of neurovascular disturbances underlying diabetes-related complications. In this review, based on the existing knowledge as well as compelling findings from our past and present studies, we address the role of Diaph1 signalling in metabolic stress and neurovascular degeneration in diabetic complications. In light of the most recent developments in biochemical, genomic and transcriptomic research, we describe current theories on the aetiology of diabetes complications, highlighting the function of the Diaph1 signalling system and its role in diabetes pathophysiology.

Novel insights into the nervous system affected by prolonged hyperglycemia.

Multiple molecular pathways including the receptor for advanced glycation end-products-diaphanous related formin 1 (RAGE-Diaph1) signaling are known to play a role in diabetic peripheral neuropathy (DPN). Evidence suggests that neuropathological alterations in type 1 diabetic spinal cord may occur at the same time as or following peripheral nerve abnormalities. We demonstrated that DPN was associated with perturbations of RAGE-Diaph1 signaling pathway in peripheral nerve accompanied by widespread spinal cord molecular changes. More than 500 differentially expressed genes (DEGs) belonging to multiple functional pathways were identified in diabetic spinal cord and of those the most enriched was RAGE-Diaph1 related PI3K-Akt pathway. Only seven of spinal cord DEGs overlapped with DEGs from type 1 diabetic sciatic nerve and only a single gene cathepsin E (CTSE) was common for both type 1 and type 2 diabetic mice. In silico analysis suggests that molecular changes in spinal cord may act synergistically with RAGE-Diaph1 signaling axis in the peripheral nerve. KEY MESSAGES: Molecular perturbations in spinal cord may be involved in the progression of diabetic peripheral neuropathy. Diabetic peripheral neuropathy was associated with perturbations of RAGE-Diaph1 signaling pathway in peripheral nerve accompanied by widespread spinal cord molecular changes. In silico analysis revealed that PI3K-Akt signaling axis related to RAGE-Diaph1 was the most enriched biological pathway in diabetic spinal cord. Cathepsin E may be the target molecular hub for intervention against diabetic peripheral neuropathy.

Role of RAGE in the Pathogenesis of Neurological Disorders.

This review reflects upon our own as well as other investigators' studies on the role of receptor for advanced glycation end-products (RAGE), bringing up the latest information on RAGE in physiology and pathology of the nervous system. Over the last ten years, major progress has been made in uncovering many of RAGE-ligand interactions and signaling pathways in nervous tissue; however, the translation of these discoveries into clinical practice has not come to fruition yet. This is likely, in part to be the result of our incomplete understanding of this crucial signaling pathway. Clinical trials examining the therapeutic efficacy of blocking RAGE-external ligand interactions by genetically engineered soluble RAGE or an endogenous RAGE antagonist, has not stood up to its promise; however, other trials with different blocking agents are being considered with hope for therapeutic success in diseases of the nervous system.

Fallow Deer (Dama dama) as a Reservoir of Shiga Toxin-Producing Escherichia coli (STEC).

Shiga toxin-producing Escherichia (E.) coli (STEC) are responsible for the outbreaks of serious diseases in humans. Only a few reports on fallow deer as a reservoir of foodborne pathogens have been published to date. The purpose of this study was to determine the occurrence of STEC strains in the fallow deer population in Poland. In all, 94 fallow deer swabs were tested. Polymerase chain reaction (PCR) was performed to detect the virulence profile of stx1, stx2 and eae or aggR genes, to identify the subtypes of stx1 and stx2 genes and to perform O and H serotyping. STEC and attaching and effacing (AE)-STEC were identified in 13 isolates (13.83%). The most hazardous virulence profile was detected in three strains, namely stx2d serotype O103:HNM, eae/stx1a serotype O26:HNM and eae/stx1a serotype O157:H7. The predominant stx gene was stx2, which was identified in 76.92% of isolates. E. coli O157 was detected in 4/94 (4.26%). Other E. coli serogroups, O26, O103, O111 and O145, were identified in 14/94 fallow deer (14.89%). The present findings suggest that fallow deer are carriers of STEC/AE-STEC that are potentially pathogenic to humans.