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109 results on '"Ashford, Michael L.J."'

4. Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction

Author

Meakin, Paul J., Coull, Bethany M., Tuharska, Zofia, McCaffery, Christopher, Akoumianakis, Ioannis, Antoniades, Charalambos, Brown, Jane, Griffin, Kathryn J., Platt, Fiona, Ozber, Claire H., Yuldasheva, Nadira Y., Makava, Natallia, Skromna, Anna, Prescott, Alan, McNeilly, Alison D., Siddiqui, Moneeza, Palmer, Colin N.A., Khan, Faisel, and Ashford, Michael L.J.

Subjects
Thermo Fisher Scientific Inc., Obesity -- Development and progression, Endothelin, Type 2 diabetes -- Development and progression, Endothelium, Nitric oxide, Enzymes, Vascular diseases -- Development and progression, Advertising executives, Alzheimer's disease -- Development and progression, Amyloid beta-protein, Health care industry, Wellcome Trust
Abstract

Diabetes, obesity, and Alzheimer's disease (AD) are associated with vascular complications and impaired nitric oxide (NO) production. Furthermore, increased p-site amyloid precursor protein-cleaving (APP-cleaving) enzyme 1 (BACE1), APP, and [beta]-amyloid (A[beta]) are linked with vascular disease development and increased BACE1 and A[beta] accompany hyperglycemia and hyperlipidemia. However, the causal relationship between obesity and diabetes, increased A[beta], and vascular dysfunction is unclear. We report that diet-induced obesity (DIO) in mice increased plasma and vascular A[beta]42 that correlated with decreased NO bioavailability, endothelial dysfunction, and increased blood pressure. Genetic or pharmacological reduction of BACE1 activity and A[beta]42 prevented and reversed, respectively, these outcomes. In contrast, expression of human mutant APP in mice or A[beta]42 infusion into control diet-fed mice to mimic obese levels impaired NO production, vascular relaxation, and raised blood pressure. In humans, increased plasma A[beta]42 correlated with diabetes and endothelial dysfunction. Mechanistically, higher A[beta]42 reduced endothelial NO synthase (eNOS), cyclic GMP (cGMP), and protein kinase G (PKG) activity independently of diet, whereas endothelin-1 was increased by diet and A[beta]42. Lowering A[beta]42 reversed the DIO deficit in the eNOS/cGMP/PKG pathway and decreased endothelin-1. Our findings suggest that BACE1 inhibitors may have therapeutic value in the treatment of vascular disease associated with diabetes., Introduction There is increasing evidence that links vascular disease and endothelial dysfunction (as found in obesity, diabetes, and hypercholesterolemia; i.e., metabolic syndrome) with Alzheimer's disease (AD) and cognitive impairment, through [...]

Published
2020
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14. Dominant Role of the p110β Isoform of PI3K over p110α in Energy Homeostasis Regulation by POMC and AgRP Neurons

Author

Al-Qassab, Hind, Smith, Mark A., Irvine, Elaine E., Guillermet-Guibert, Julie, Claret, Marc, Choudhury, Agharul I., Selman, Colin, Piipari, Kaisa, Clements, Melanie, Lingard, Steven, Chandarana, Keval, Bell, Jimmy D., Barsh, Gregory S., Smith, Andrew J.H., Batterham, Rachel L., Ashford, Michael L.J., Vanhaesebroeck, Bart, and Withers, Dominic J.

Published
2009
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15. The unfolded protein response is activated in skeletal muscle by high-fat feeding: potential role in the downregulation of protein synthesis

Author

Deldicque, Louise, Cani, Patrice D., Philp, Andrew, Raymackers, Jean-Marc, Meakin, Paul J., Ashford, Michael L.J., Delzenne, Nathalie M., Francaux, Marc, and Baar, Keith

Subjects
Protein biosynthesis -- Physiological aspects, Protein biosynthesis -- Research, Ketogenic diet -- Physiological aspects, Ketogenic diet -- Research, Protein folding -- Physiological aspects, Protein folding -- Research, Muscles -- Physiological aspects, Muscles -- Genetic aspects, Muscles -- Research, Biological sciences
Abstract

High-fat diets are known to decrease muscle protein synthesis, the adaptation to overload, and insulin sensitivity. Conditions that disrupt endoplasmic reticulum (ER) homeostasis lead to the activation of the unfolded protein response (UPR) that is associated with decreases in protein synthesis, chronic inflammation, and insulin resistance. The purpose of the present study was to establish whether ER stress is induced by a high-fat diet in skeletal muscle and whether ER stress can decrease mTORC1 activity and protein synthesis in muscle cells. Two independent protocols of high-fat feeding activated the UPR in mice. In the first study, mice consuming a high-fat diet containing 70% fat and < 1% carbohydrates for 6 wk showed higher markers of the UPR (BiP, IRE1[alpha], and MBTPS2) in the soleus and in the tibialis anterior muscles and ATF4 in the tibialis anterior (P < 0.05). In the second study, a 20-wk high-fat diet containing 46% fat and 36% carbohydrates also increased BiP, IRE1[alpha], and phospho-PERK protein and the expression of ATF4, CHOP, and both the spliced and unspliced forms of XBP1 in the plantar flexors (P < 0.05). In [C.sub.2][C.sub.12] muscle cells, tunicamycin, thapsigargin, and palmitic acid all increased UPR markers and decreased phosphorylation of S6K1 (P < 0.05). Collectively, these data show that a high-fat diet activates the UPR in mouse skeletal muscle in vivo. In addition, in vitro studies indicate that palmitic acid, and other well-known ER stress inducers, triggered the UPR in myogenic cells and led to a decrease in protein synthesis and mTORC1 activity. endoplasmic reticulum stress; binding protein; X box binding protein-1; ribosomal protein S6 kinase; protein synthesis doi: 10.1152/ajpendo.00038.2010.

Published
2010

16. AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons

Author

Claret, Marc, Smith, Mark A., Batterham, Rachel L., Selman, Colin, Choudhury, Agharul I., Fryer, Lee G.D., Clements, Melanie, Qassab, Hind Al, Heffron, Helen, Xu, Allison W., Speakman, John R., Barsh, Gregory S., Viollet, Benoit, Vaulont, Sophie, Ashford, Michael L.J., David Carling, and Withers, Dominic J.

Subjects
Cyclic adenylic acid -- Research, Protein kinases -- Research, Homeostasis -- Research, Cellular control mechanisms -- Research
Abstract

Hypothalamic AMP-activated protein kinase (AMPK) has been suggested to act as a key sensing mechanism, responding to hormones and nutrients in the regulation of energy homeostasis. However, the precise neuronal [...]

Published
2007

18. Ca2+ dependence and pharmacology of large-conductance K+ channels in nonlabor and labor human uterine myocytes

Author

Khan, Raheela N., Smith, Stephen K., Morrison, J.J., and Ashford, Michael L.J.

Subjects
Potassium channels -- Research, Myometrium -- Physiological aspects, Muscle cells -- Physiological aspects, Biological sciences
Abstract

Calcium ion dependent and calcium independent potassium channels in human myometrium exhibited differences in sensitivity relative to specific and nonspecific potassium channel blockers. It was further revealed that based on cell-attached recordings for inside-out patches of nonlabor and labor freshly dispersed human pregnant myometrial cells, the properties of large-conductance potassium channels in myocytes isolated from laboring patients are also significantly different from those isolated from nonlaboring patients.

Published
1997

19. The role of insulin receptor substrate 2 in hypothalamic and β cell function

Author

Choudhury, Agharul I., Heffron, Helen, Smith, Mark A., Al-Qassab, Hind, Xu, Allison W., Selman, Colin, Simmgen, Marcus, Clements, Melanie, Claret, Marc, MacColl, Gavin, Bedford, David C., Hisadome, Kazunari, Diakonov, Ivan, Moosajee, Vazira, Bell, Jimmy D., Speakman, John R., Batterham, Rachel L., Barsh, Gregory S., Ashford, Michael L.J., and Withers, Dominic J.

Published
2005

22. Corrigendum to “The BACE1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling” [Metab Clin Exp 85 (2018) 59–75]

Author

Botteri, Gaia, primary, Salvadó, Laia, additional, Gumà, Anna, additional, Hamilton, D. Lee, additional, Meakin, Paul J., additional, Montagut, Gemma, additional, Ashford, Michael L.J., additional, Ceperuelo-Mallafré, Victoria, additional, Fernández-Veledo, Sonia, additional, Vendrell, Joan, additional, Calderón-Dominguez, María, additional, Serra, Dolors, additional, Herrero, Laura, additional, Pizarro, Javier, additional, Barroso, Emma, additional, Palomer, Xavier, additional, and Vázquez-Carrera, Manuel, additional

Published
2019
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23. Activation of large-conductance potassium channels in pregnant human myometrium by pinacidil

Author

Khan, Raheela N., Morrison, John J., Smith, Stephen K., and Ashford, Michael L.J.

Subjects
Potassium channels, Myometrium -- Physiological aspects, Tocolytic agents -- Research, Health
Abstract

Drugs that open the large-conductance calcium-dependent potassium channel in uterine muscle might be useful in preventing premature labor. These channels reduce the generation of nerve impulses, which prevents muscle contraction. Researchers exposed biopsy samples of uterine muscle to a chemical called pinacidil. Pinacidil is a chemical that opens large-conductance calcium-dependent potassium channels. The chemical relaxed the tissue samples and this relaxation was blocked by charybdotoxin, which is a chemical from scorpion venom that blocks large-conductance calcium-dependent potassium channels.

Published
1998

24. The effects of potassium channel openers on isolated pregnant human myometrium before and after the onset of labor: potential for tocolysis

Author

Morrison, John J., Ashford, Michael L.J., Khan, Raheela N., and Smith, Stephen K.

Subjects
Potassium channels, Myometrium -- Physiological aspects, Tocolytic agents -- Research, Health
Abstract

Levcromakalim and pinacidil appear to inhibit spontaneous contractions in human myometrium. Levcromakalim and pinacidil are drugs known as potassium channel openers. The myometrium is the muscular layer of the uterus. Myometrial tissue was obtained from 67 pregnant women before they had cesarean sections. Thirty-one of the women were in labor at the time the tissue was obtained. The tissue was prepared and contractile activity was measured. Levcromakalim and pinacidil inhibited both spontaneous and induced contractions in the samples. Glibenclamide, used to treat diabetes, reduced the relaxant response caused by the potassium channel openers. Tolbutamide, also used to treat diabetes, did not affect the tissue's response to the potassium channel openers. Pinacidil and levcromakalim may be useful in suppressing premature labor.

Published
1993

25. Experimental nonalcoholic steatohepatitis and liver fibrosis are ameliorated by pharmacological activation of Nrf2 (NF-E2-related factor 2)

Author

Sharma, Ritu S., Harrison, David J., Kisielewski, Dorothy, Cassidy, Diane M., McNeilly, Alison D., Gallagher, Jennifer R., Walsh, Shaun V., Honda, Tadashi, McCrimmon, Rory J., Dinkova-Kostova, Albena T., Ashford, Michael L.J., Dillon, John F., Hayes, John D., Medical Research Council, University of St Andrews. School of Medicine, and University of St Andrews. Cellular Medicine Division

Subjects
RM, QH301, QH301 Biology, NASH, NDAS, TBE-31, Nrf2, RM Therapeutics. Pharmacology
Abstract

Funding: Supported by grants MR/J001465/1 (JDH, MLJA, JFD and RJMcC) and MR/N009851/1 (JDH, MLJA, ATD-K and DJH) from the Medical Research Council of the UK and grants from Stony Brook Foundation and Reata Pharmaceuticals, Inc. (TH) Background & Aims: Nonalcoholic steatohepatitis (NASH) is associated with oxidative stress. We surmised that pharmacological activation of NF-E2 p45-related factor 2 (Nrf2) using the acetylenic tricyclic bis(cyano-enone) TBE-31 would suppress NASH because Nrf2 is a transcriptional master regulator of intracellular redox homeostasis. Methods: Nrf2+/+ and Nrf2-/- C57BL/6 mice were fed a high-fat plus fructose (HFFr) or regular chow (RC) diet for 16 weeks or 30 weeks, and then treated for the final 6 weeks, whilst still being fed the same HFFr or RC diets, with either TBE-31 or DMSO vehicle control. Measures of whole body glucose homeostasis, histological assessment of liver, and biochemical and molecular measurements of steatosis, endoplasmic reticulum (ER) stress, inflammation, apoptosis, fibrosis and oxidative stress were performed in livers from these animals. Results: TBE-31−treatment reversed insulin resistance in HFFr-fed wild-type mice, but not in HFFr-fed Nrf2-null mice. TBE-31−treatment of HFFr-fed wild-type mice substantially decreased liver steatosis and expression of lipid synthesis genes, whilst increasing hepatic expression of fatty acid oxidation and lipoprotein assembly genes. Also, TBE-31−treatment decreased ER stress, expression of inflammation genes, and markers of apoptosis, fibrosis and oxidative stress in the livers of HFFr-fed wild-type mice. By comparison, TBE-31 did not decrease steatosis, ER stress, lipogenesis, inflammation, fibrosis or oxidative stress in livers of HFFr-fed Nrf2-null mice. Conclusions: Pharmacological activation of Nrf2 in mice that had already been rendered obese and insulin resistant reversed insulin resistance, suppressed hepatic steatosis, and mitigated against NASH and liver fibrosis, effects that we principally attribute to inhibition of ER, inflammatory and oxidative stress. Publisher PDF

Published
2017

34. Neuronal development is promoted by weakened intrinsic antioxidant defences due to epigenetic repression of Nrf2

Author

Bell, Karen F.S., primary, Al-Mubarak, Bashayer, additional, Martel, Marc-André, additional, McKay, Sean, additional, Wheelan, Nicola, additional, Hasel, Philip, additional, Márkus, Nóra M., additional, Baxter, Paul, additional, Deighton, Ruth F., additional, Serio, Andrea, additional, Bilican, Bilada, additional, Chowdhry, Sudhir, additional, Meakin, Paul J., additional, Ashford, Michael L.J., additional, Wyllie, David J.A., additional, Scannevin, Robert H., additional, Chandran, Siddharthan, additional, Hayes, John D., additional, and Hardingham, Giles E., additional

Published
2015
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37. Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice

Author

Meakin, Paul J., primary, Harper, Alex J., additional, Hamilton, D. Lee, additional, Gallagher, Jennifer, additional, McNeilly, Alison D., additional, Burgess, Laura A., additional, Vaanholt, Lobke M., additional, Bannon, Kirsten A., additional, Latcham, Judy, additional, Hussain, Ishrut, additional, Speakman, John R., additional, Howlett, David R., additional, and Ashford, Michael L.J., additional

Published
2011
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48. Essential Role of Phosphoinositide 3-Kinase in Leptin-inducedKATPChannel Activation in the Rat CRI-G1 Insulinoma Cell Line*

Author

Harvey, Jennie, McKay, Neil G., Walker, Kay S., Van der Kaay, Jeroen, Downes, C.Peter, and Ashford, Michael L.J.

Abstract

The mechanism by which leptin increases ATP-sensitive K+(KATP) channel activity was investigated using the insulin-secreting cell line, CRI-G1. Wortmannin and LY 294002, inhibitors of phosphoinositide 3-kinase (PI3-kinase), prevented activation ofKATPchannels by leptin. The inositol phospholipids phosphatidylinositol bisphosphate and phosphatidylinositol trisphosphate (PtdIns(3,4,5)P3) mimicked the effect of leptin by increasingKATPchannel activity in whole-cell and inside-out current recordings. LY 294002 prevented phosphatidylinositol bisphosphate, but not PtdIns(3,4,5)P3, from increasingKATPchannel activity, consistent with the latter lipid acting as a membrane-associated messenger linking leptin receptor activation and KATPchannels. Signaling cascades, activated downstream from PI 3-kinase, utilizing PtdIns(3,4,5)P3as a second messenger and commonly associated with insulin and cytokine action (MAPK, p70 ribosomal protein-S6 kinase, stress-activated protein kinase 2, p38 MAPK, and protein kinase B), do not appear to be involved in leptin-mediated activation of KATPchannels in this cell line. Although PtdIns(3,4,5)P3appears a plausible and attractive candidate for the messenger that couples KATPchannels to leptin receptor activation, direct measurement of PtdIns(3,4,5)P3demonstrated that insulin, but not leptin, increased global cellular levels of PtdIns(3,4,5)P3. Possible mechanisms to explain the involvement of PI 3-kinases inKATPchannel regulation are discussed.

Published
2000
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49. Inhibition of a calcium-activated, non-selective cation channel, in a rat insulinoma cell line, by adenine derivatives

Author

Sturgess, Nicholas C., Nicholas Hales, C., and Ashford, Michael L.J.

Abstract

The effects of adenosine and adenine nucleotides on a calcium-activated non-selective cation channel, present in the plasma membrane of an insulin-secreting cell line CRI-G1 were investigated. Single-channel currents were recorded from inside-out membrane patches and the adenine derivatives applied to the solution bathing the cytoplasmic aspect of the membrane surface. The activity of this channel is shown to be inhibited by all the derivatives tested. The potency sequence for inhibition was found to be AMP > ADP > ATP > adenosine.

Published
1986
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50. Direct demonstration of sulphonylurea‐sensitive KATPchannels on nerve terminals of the rat motor cortex

Author

Lee, Kevin, Dixon, Alistair K., Rowe, Iain C.M., Ashford, Michael L.J., and Richardson, Peter J.

Abstract

We examined whether ATP‐sensitive potassium (KATP) channels are present on presynaptic terminals of the rat motor cortex, an area of the CNS exhibiting a high density of sulphonylurea binding. A novel fused nerve terminal preparation was developed which produced structures amenable to patch clamp methods. In inside‐out recordings a K+channel was observed which possessed all the major features of the Type 1 KATPchannel, including sensitivity to ATP and the antidiabetic sulphonylureas.

Published
1995
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