Glycan Antagonists and Inhibitors: A Fount for Drug Discovery

Brown, Jillian R.; Crawford, Brett E.

doi:10.1080/10409230701751611

Cited by 77 publications

(32 citation statements)

References 309 publications

(259 reference statements)

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“…Given that specific glycan chains unique to a host of acute‐phase reactants are captured by GlycA, and presumably the contributing acute‐phase proteins bear glycan sequence that do not contribute GlycA, a better understanding of the holo‐glycan sequence for each contributing protein may shed light on the potential utility of GlycA for developing diagnostics, and perhaps therapy, that address CVD through inflammation. Research endeavors exploiting glycan biology are already making gains in virology and cancer‐preventive research . It is worth noting that heparin, which is broadly indicated in the management of coronary events, is one of the oldest known anticoagulants and was later discovered to be a glycan‐based therapeutic …”

Section: Discussionmentioning

confidence: 99%

Circulating N‐Linked Glycoprotein Side‐Chain Biomarker, Rosuvastatin Therapy, and Incident Cardiovascular Disease: An Analysis From the JUPITER Trial

Akinkuolie

Glynn

Padmanabhan

et al. 2016

JAHA

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BackgroundGlycA, a novel protein glycan biomarker of N‐acetyl side chains of acute‐phase proteins, was recently associated with incident cardiovascular disease (CVD) in healthy women. Whether GlycA predicts CVD events in the setting of statin therapy in men and women without CVD but with evidence of chronic inflammation is unknown.Methods and ResultsIn the Justfication for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial (NCT00239681), participants with low‐density lipoprotein cholesterol <130 mg/dL and high‐sensitivity C‐reactive protein (hsCRP) ≥2 mg/L were randomized to rosuvastatin 20 mg/day or placebo. GlycA was quantified by nuclear magnetic resonance spectroscopy in 12 527 before randomization and 10 039 participants at 1 year. A total of 310 first primary CVD events occurred during maximum follow‐up of 5.0 years (median, 1.9). GlycA changed minimally after 1 year on study treatment: 6.8% and 4.7% decrease in the rosuvastatin and placebo groups, respectively. Overall, baseline GlycA levels were associated with increased risk of CVD: multivariable‐adjusted hazard ratio (HR) per SD increment, 1.20 (95% CI, 1.08–1.34; P=0.0006). After additionally adjusting for hsCRP, this was slightly attenuated (HR, 1.18; 95% CI, 1.04–1.35; P=0.01). On‐treatment GlycA levels were also associated with CVD; corresponding multivariable‐adjusted HRs per SD before and after additionally adjusting for hsCRP: 1.27 (95% CI, 1.13–1.42; P<0.0001) and 1.24 (95% CI, 1.07–1.44; P=0.004), respectively. Tests for heterogeneity by treatment arm were not significant (P for interaction, >0.20).ConclusionIn the JUPITER trial, increased levels of GlycA were associated with an increased risk of CVD events independent of traditional risk factors and hsCRP.Clinical Trials Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

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Section: Discussionmentioning

confidence: 99%

Circulating N‐Linked Glycoprotein Side‐Chain Biomarker, Rosuvastatin Therapy, and Incident Cardiovascular Disease: An Analysis From the JUPITER Trial

Akinkuolie

Glynn

Padmanabhan

et al. 2016

JAHA

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“…Disregulation of glycosylation may change the functions of glycoproteins, and as such is involved in many diseases, including cancer, cardiovascular disease, and certain immunological disorders [5,25,29,33]. Glycotransferases conduct the attachment of carbohydrate sequences to the polypeptide portions of glycoproteins, and they are specifically selected as the therapeutic target for correlated diseases [3,13,19].…”

Section: Introductionmentioning

confidence: 99%

Sialyltransferase7A, a Klf4-responsive gene, promotes cardiomyocyte apoptosis during myocardial infarction

Zhang

Zhu

et al. 2015

Basic Res Cardiol

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Myocardial infarction (MI) is one major cause of heart failure through its induction of cardiomyocyte death. However, the molecular mechanisms associated with MI-induced cardiomyocyte apoptosis in the context of sialylation of heart are not yet understood. In this study, we found that sialyltransferase7A (Siat7A), one of the members of sialyltransferase family, was significantly increased in the ischemic myocardium, as well as in the human cardiomyocyte cell line AC16 under hypoxic condition. The Sialyl-Tn antigen (Neu5Acα2-6GalNAc-O-Ser/Thr) synthesized by Siat7A also increased in the AC16 cardiomyocytes following hypoxic stimulus. Increased Siat7A promoted cardiomyocyte apoptosis. The knockdown of Siat7A expression reduced cardiomyocyte apoptosis in both of vivo and vitro. Furthermore, the decreased extracellular signal-regulated kinase ERK1 and ERK2 (ERK1/2) activity was involved in the Siat7A-induced cardiomyocyte apoptosis. Notably, we showed that Krüppel-like factor 4 (Klf4), one of the transcription factors, specifically bound to the Siat7A promoter by ChIP assays. Deletion and mutagenesis analysis identified that Klf4 could transactivate the Siat7A promoter region (nt -655 to -636 bp). The upregulated Siat7A expression, which was paralleled by the increased Klf4 in the ischemic myocardium, contributed to cardiomyocyte apoptosis. Our study suggests Siat7A could be a valuable target for developing treatments for MI patients.

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“…34 Also recent advancement has led into development of various glycan antagonists and inhibitors of STs and FUTs. 35 In conclusion, increase in ST3GAL1 transcript levels in malignant tissues as compared to adjacent normal tissues and higher expression in advanced stage and metastatic tumors highlights its role in aggressive behavior of the disease. A significant decrease in FUT3 and FUT5 mRNA expressions in oral cancer tissues and significant association of increased FUT3 expression with lower survival of oral cancer patients indicates its potential utility in prognostication and disease monitoring.…”

Section: Discussionmentioning

confidence: 99%

Expression of Glycosyltransferases; ST3GAL1, FUT3, FUT5, and FUT6 Transcripts in Oral Cancer

Vajaria¹,

Patel²,

Begum³

et al. 2014

Glycobiology Insights

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ABSTRACT:Oral carcinogenesis process is frequently accompanied by alterations in glycosylation, regulated by sialyltransferase (ST) and fucosyltransferase (FUT) enzymes. The study aimed to assess ST3GAL1, FUT3, FUT5, and FUT6 mRNA expression by semi-quantitative reverse transcriptase PCR in 50 oral cancer and 50 adjacent normal tissues. The results indicated increased ST3GAL1 mRNA levels in malignant tissues as compared to adjacent normal tissues. A significant decrease in FUT3 and FUT5 transcripts was observed in malignant tissues as compared to adjacent normal tissues. Survival analysis of FUT3 transcript levels depicted significant lower survival with values above cutoff. The levels of ST3GAL1 and FUT6 were found to be higher in metastatic tissues as compared to the non-metastatic tissues and were also higher in advanced disease as compared to the early disease. The results indicated potential clinical utility of ST3GAL1, FUT3, FUT5, and FUT6 transcript levels in oral cancer pathogenesis.

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Glycan Antagonists and Inhibitors: A Fount for Drug Discovery

Cited by 77 publications

References 309 publications

Circulating N‐Linked Glycoprotein Side‐Chain Biomarker, Rosuvastatin Therapy, and Incident Cardiovascular Disease: An Analysis From the JUPITER Trial

Circulating N‐Linked Glycoprotein Side‐Chain Biomarker, Rosuvastatin Therapy, and Incident Cardiovascular Disease: An Analysis From the JUPITER Trial

Sialyltransferase7A, a Klf4-responsive gene, promotes cardiomyocyte apoptosis during myocardial infarction

Expression of Glycosyltransferases; ST3GAL1, FUT3, FUT5, and FUT6 Transcripts in Oral Cancer

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