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Background: High fibre intake is associated with lower blood pressure (BP) in epidemiological and clinical studies. Prebiotic fibre resists digestion in the upper gastrointestinal tract and is fermented by gut microbiota in the intestine. The impact of lack of prebiotic dietary fibre in BP remains unknown. Objectives: To determine the consequences of lack of prebiotic dietary fibre to the development of hypertension through changes in the gut microbiome, associated receptors and immune-based mechanisms using a slow pressor angiotensin II (Ang II) model. Methods: C57BL/6 mice were fed a ‘no fibre’ or ‘high fibre’ diets for 3-weeks prior to sham or Ang II minipump implantation (n=4-21/group), and were followed for 4-weeks post-surgery. Gnotobiotic mice received faecal transplant from ‘no fibre’ sham or Ang II mice (n=5-6/group). Cardiac function, BP and gut microbiome (by 16S sequencing) were determined. Results: Ang II mice that received a ‘no fibre’ diet had significantly higher BP than sham (SBP mean±SEM: 143.7±3.5 vs 91.2±1.8, P Conclusions: Lack of prebiotic dietary fibre leads to the development of a hypertensinogenic gut microbiome, hypertension and its complications. SCFA might represent new therapeutic opportunities through modulation of G-coupled protein receptors and Treg cells.

Type 2 diabetes is characterized by islet amyloid deposition, which is associated with β-cell loss. hIAPP is the unique peptide component of these deposits. We previously found that expression of tPA, the initiator of fibrinolysis, is upregulated in islets by amyloid formation in vitro. As plasmin, the proteolytic product of tPA activity, cleaves Aβ and attenuates amyloid deposition in Alzheimer’s disease, we hypothesized that the increase in islet tPA by amyloid deposition serves a protective function by generating plasmin to limit further accumulation of hIAPP. We therefore sought to determine whether the tPA/plasmin system reduces amyloid formation by hIAPP and, if so, what islet cell type produces tPA. Using a thioflavin T assay, we found 4 µM plasmin abrogated 20 µM hIAPP fibril formation by 91.6±0.9% (n=5; p In summary, plasmin rapidly degrades hIAPP, curbing its aggregation into amyloid. As tPA is expressed in macrophages, enhancing its activity or its production by islet macrophages may represent a novel strategy to generate plasmin, cleave hIAPP and thus reduce islet amyloid formation and β-cell loss. Disclosure N. Esser: None. M.F. Hogan: None. A. Aplin: None. A.T. Templin: None. S. El-Osta: None. D. Raleigh: None. J.S. Edgar: None. S. Zraika: Research Support; Self; Novartis Pharmaceuticals Corporation. R.L. Hull: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Funding U.S. Department of Veterans Affairs (BX001060); National Institutes of Health (GM078114); Belgian American Educational Foundation; Société Francophone du Diabète

StAR is a cholesterol transport protein that transports cholesterol from the cytoplasm into the mitochondrial matrix for further metabolism by CYP enzymes. Depending on the CYP expressed, this results in production of corticosteroids, gonadal steroids, neurosteroids or oxysterols. These products generally exert positive effects on cellular health and function but can also be harmful. We previously showed that StAR is produced in β cells and is increased under conditions of amyloid formation in human islet amyloid polypeptide (hIAPP) transgenic mouse islets, a model of human islet amyloidosis in type 2 diabetes (T2D). Further, CYP11A1, CYP11B1, CYP7A1 and CYP17A1 are not expressed in mouse islets, and CYP27A1 is expressed but decreases with amyloid deposition. Therefore, we hypothesized that increased StAR in islets is deleterious to β-cell health as the downstream CYP enzymes are not present to metabolize mitochondrial cholesterol. We first demonstrated (by immunoblot) that StAR is expressed in human islets, a requirement if it is to play a role in T2D. Also in human islets, only CYP27A1 is detectable, while CYP11A1 and CYP7A1 are not (n=4). We next used a lentivirus to increase StAR expression (or a control lentivirus) in INS-1 cells, which resulted in reduced mitochondrial membrane potential (100±2.0% vs. 78.1±1.2%, n=2, p In summary, StAR is expressed in human islets and increasing its expression is deleterious due to changes in mitochondrial function and β-cell survival. Thus, reducing StAR expression and/or increasing expression of downstream CYP enzymes may be a novel strategy to protect β cells in T2D. Disclosure M.F. Hogan: None. N. Esser: None. A.T. Templin: None. S. Zraika: Research Support; Self; Novartis Pharmaceuticals Corporation. R.L. Hull: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. S. El-Osta: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Funding American Diabetes Association (1-18-PDF-174 to M.F.H.); National Institutes of Health (T32HL007028, F32DK109584); U.S. Department of Veterans Affairs (BX001060); University of Washington

Drug resistance genes, such as MDR1, involved in drug efflux, and their regulation have been the subject of intense research efforts in the past 10 years. Many factors and cellular signalling pathways play a role in the regulation of MDR1 gene expression. Commonly used chemotherapeutic agents activate in vitro and in vivo general stress response pathways, potential targets of which include MDR1 and other drug resistance genes. The contribution of these agents to the emergence of drug-resistant tumour cells is of concern. Recent evidence points to a role for the epigenetic regulation of MDR1 gene expression. The identification of key components in the DNA methylation/chromatin system of gene regulation may in time lead to more informed and targeted approaches to treating drug-resistant tumours. Copyright 2000 Harcourt Publishers Ltd.

B-cell chronic lymphocytic leukaemia (CLL) cells commonly express the multidrug resistance phenotype. The aim of this study was to establish whether the normal homologue in B-cell ontogeny of B-CLL also expressed the multidrug resistance (mdr) phenotype. Human tonsillar lymphocytes were sorted to yield two B-cell subsets based on the expression of CD19, CD5 and CD10. The normal homologue was represented by a population of B cells that was CD19 positive, CD10 negative and weakly expressed CD5. Based upon functional analysis and the detection of mdr1 mRNA by semi-quantitative PCR, these cells expressed the mdr phenotype. In contrast, functional multidrug resistance could not be demonstrated in CD19-positive CD10-positive cells with strong expression of CD5, nor could mdr1 mRNA be found in these cells. MRP was variably expressed in both B-cell subsets with no discernable differences in the pattern of expression. We conclude that normal B cells with a phenotype resembling that of B-CLL cells express the multidrug resistance phenotype.