Tumour Enzyme Affinity Mediated Peptide Molecular Crowding for Targeted Disruption of Hyperactivated Glucose Uptake

2022 ◽  
Author(s):  
Bengang Xing ◽  
Germain Kwek ◽  
Shonya Lingesh ◽  
Sayba Zafrin Chowdhury
Keyword(s):  
Glucose Uptake ◽  
Small Molecule ◽  
Specific Binding ◽  
Peptide Inhibitor ◽  
Short Peptides ◽  
Molecular Crowding ◽  
Targeted Disruption

An unconventional environment-responsive molecular crowding via specific binding between small molecule peptide inhibitor derivatives and overexpressed tumour enzyme has been developed. Assemblies of such short peptides selectively localize on tumour...

scholarly journals P0511ENHANCER AND SUPER-ENHANCER DYNAMICS IN REPAIR AFTER ISCHEMIC ACUTE KIDNEY INJURY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Julia Wilflingseder ◽  
Michaela Willi ◽  
Hye Kyung Lee ◽  
Hannes Olauson ◽  
Jakub Jankowsky ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Transcription Factors ◽  
Small Molecule ◽  
Ischemia Reperfusion Injury ◽  
Specific Binding ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Kidney Cortex ◽  
Super Enhancer

Abstract Background and Aims The endogenous repair process of the mammalian kidney allows rapid recovery after acute kidney injury (AKI) through robust proliferation of tubular epithelial cells. There is currently limited understanding of which transcriptional regulators activate these repair programs and how transcriptional dysregulation leads to maladaptive repair. Here we investigate the existence of enhancer dynamics in the regenerating mouse kidney. Method RNA-seq and ChIP-seq (H3K27ac, H3K4m3, BRD4, POL2 and selected transcription factors) were performed on samples from repairing kidney cortex 2 days after ischemia/reperfusion injury (IRI) to identify activated genes, transcription factors, enhancer and super-enhancers associated with kidney repair. Further we investigated the role of super-enhancer activation in kidney repair through pharmacological BET inhibition using the small molecule JQ1 in vitro and in acute kidney injury models in vivo. Results Response to kidney injury leads to genome-wide alteration in enhancer repertoire in-vivo. We identified 16,781 enhancer sites (H3K27ac and BRD4 positive, H3K4me3 negative binding) active in SHAM and IRI samples; 6,512 lost and 9,774 gained after IRI. The lost and gained enhancer sites can be annotated to 62% and 63% of down- and up-regulated transcripts at day 2 after kidney injury, respectively. Super-enhancer analysis revealed 164 lost and 216 gained super-enhancer sites at IRI day 2. 385 super-enhancers maintain activity before and after injury. ChIP-seq profiles of selected transcription factors based on motif analysis show specific binding at corresponding enhancer sites. We observed lost enhancer binding of HNF4A and GR mainly at kidney related enhancer elements. In contrast, STAT3 showed increased binding at injury induces enhancer elements. No dynamic was observed for STAT5. Both transcription factor groups show corresponding mRNA changes after injury. Pharmacological inhibition of enhancer and super-enhancer activity by BRD4 inhibition (JQ1: 50mg/kg/day) before IRI leads to suppression of 40% of injury-induced transcripts associated with cell cycle regulation and significantly increased mortality between days 2 and 3 after AKI. Conclusion This is the first demonstration of enhancer and super-enhancer function in the repairing kidney. In addition, our data call attention to potential caveats for use of small molecule inhibitors of BET proteins that are currently being tested in clinical trials in cancer patients who are at risk for AKI. Our analyses of enhancer dynamics after kidney injury in vivo have the potential to identify new targets for therapeutic intervention.

Blockade of Late-phase Airway Responses and Airway Hyperresponsiveness in Allergic Sheep with a Small-molecule Peptide Inhibitor of VLA-4

1997 ◽  
Vol 156 (3) ◽  
pp. 696-703 ◽  
Author(s):  
WILLIAM M. ABRAHAM ◽  
ASHFAQ AHMED ◽  
MAREK W. SIELCZAK ◽  
MASAHIRO NARITA ◽  
THOMAS ARRHENIUS ◽  
...  
Keyword(s):  
Small Molecule ◽  
Airway Hyperresponsiveness ◽  
Late Phase ◽  
Peptide Inhibitor ◽  
Airway Responses

Developmental changes in glucose transport, lipid composition, and fluidity of jejunal BBM

1997 ◽  
Vol 273 (3) ◽  
pp. R1086-R1093 ◽  
Author(s):  
C. M. Vazquez ◽  
N. Rovira ◽  
V. Ruiz-Gutierrez ◽  
J. M. Planas
Keyword(s):  
Glucose Uptake ◽  
Glucose Transport ◽  
Lipid Composition ◽  
Brush Border Membrane ◽  
Glucose Transporter ◽  
Specific Binding ◽  
Molar Ratio ◽  
Site Density ◽  
Age Related ◽  
Age Dependent

Na(+)-dependent D-glucose uptake was studied in jejunal brush-border membrane (BBM) vesicles of chickens at 2 days and 1, 2, 5-6, and 12-14 wk of age. Both initial rates and accumulation ratios of the Na(+)-dependent D-glucose transport were significantly higher during the 1st wk than at other ages. To explain the age-related changes observed in the transport of D-glucose, the phlorizin-specific binding, Na+ permeability, lipid composition, and fluidity were studied. Transporter site density was quantified using 50 mumol/l phlorizin and found to be higher during the 1st wk. During the 2nd wk it decreased and then remained constant. Permeability of Na+, studied using 22Na+, showed that fluxes were similar during the first 6 wk, and a significant decrease was observed in the oldest group. Furthermore, membrane fluidity results showed a significant age-dependent decrease that correlated well with both the increased molar ratio of cholesterol to phospholipid and the decreased ratio of lipid to protein found during development. In conclusion, changes in the density of Na(+)-dependent D-glucose transporter as well as in lipid content and fluidity might be involved in the changes observed in D-glucose uptake during the posthatching development.

Effect of insulin on glucose uptake by the maternal hindlimb and uterus, and by the fetus in conscious pregnant sheep

1984 ◽  
Vol 100 (1) ◽  
pp. 119-124 ◽  
Author(s):  
W. W. Hay ◽  
J. W. Sparks ◽  
M. Gilbert ◽  
F. C. Battaglia ◽  
G. Meschia
Keyword(s):  
Glucose Uptake ◽  
Specific Binding ◽  
Insulin Receptors ◽  
Fold Increase ◽  
Late Gestation ◽  
Insulin Concentration ◽  
In Vivo Studies ◽  
Pregnant Sheep

ABSTRACT Previous studies have demonstrated the presence of insulin receptors on the maternal surface of the placenta in several species and the specific binding of insulin to the placenta in sheep. However, both in-vitro and in-vivo studies have produced conflicting evidence concerning the effect of insulin on placental glucose uptake. To clarify this problem, we measured maternal hindlimb, uterine and fetal glucose and oxygen extractions and glucose/oxygen quotients in chronically catheterized, non-stressed, late-gestation pregnant sheep over 1 h at a constant concentration of arterial plasma glucose, and again during the next 2 h at the same glucose level but at a higher insulin concentration using glucose 'clamp' methodology. Insulin produced a 4·9-fold increase in glucose extraction and a 3·5-fold increase in glucose/oxygen quotient across the hindlimb; in contrast, insulin did not significantly affect uterine or fetal glucose extraction or glucose/oxygen quotient. We conclude that in contrast to other tissues of the pregnant ewe, placental glucose uptake and transfer are insensitive to variations in maternal insulin concentration. J. Endocr. (1984) 100, 119–124

A small-molecule benzimidazole derivative that potently activates AMPK to increase glucose transport in skeletal muscle: comparison with effects of contraction and other AMPK activators

2014 ◽  
Vol 460 (3) ◽  
pp. 363-375 ◽  
Author(s):  
Yu-Chiang Lai ◽  
Samanta Kviklyte ◽  
Didier Vertommen ◽  
Louise Lantier ◽  
Marc Foretz ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Fatty Acid Oxidation ◽  
Small Molecule ◽  
Benzimidazole Derivative ◽  
Acid Oxidation

Study of a small-molecule AMPK activator that efficiently activates AMPK and stimulates glucose uptake and fatty acid oxidation in skeletal muscle.

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