Structural characteristics of small-molecule inhibitors targeting FTO demethylase

2021 ◽  
Author(s):  
Shuting Gao ◽  
Xitong Li ◽  
Miao Zhang ◽  
Ning Zhang ◽  
Ruiyong Wang ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Structural Characteristics ◽  
Cervical Squamous Cell Carcinoma ◽  
Fto Gene ◽  
Design And Synthesis ◽  
Increased Risk ◽  
Obesity And Cancer

Studies have shown that the FTO gene is closely related to obesity and weight gain in humans. FTO is an N6-methyladenosine demethylase and is linked to an increased risk of obesity and a variety of diseases, such as acute myeloid leukemia, type 2 diabetes, breast cancer, glioblastoma and cervical squamous cell carcinoma. In light of the significant role of FTO, the development of small-molecule inhibitors targeting the FTO protein provides not only a powerful tool for grasping the active site of FTO but also a theoretical basis for the design and synthesis of drugs targeting the FTO protein. This review focuses on the structural characteristics of FTO inhibitors and discusses the occurrence of obesity and cancer caused by FTO gene overexpression.

The GSTM1 and GSTT1 Null Genotypes Increase the Risk for Type 2 Diabetes Mellitus and the Subsequent Development of Diabetic Complications: A Meta-analysis

2018 ◽  
Vol 15 (1) ◽  
pp. 31-43 ◽  
Author(s):  
Sayantan Nath ◽  
Sambuddha Das ◽  
Aditi Bhowmik ◽  
Sankar Kumar Ghosh ◽  
Yashmin Choudhury
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Meta Analysis ◽  
Subsequent Development ◽  
Asian Population ◽  
Gstm1 Null Genotype ◽  
Increased Risk

Background:Studies pertaining to association of GSTM1 and GSTT1 null genotypes with risk of T2DM and its complications were often inconclusive, thus spurring the present study.Methods:Meta-analysis of 25 studies for evaluating the role of GSTM1/GSTT1 null polymorphisms in determining the risk for T2DM and 17 studies for evaluating the role of GSTM1/GSTT1 null polymorphisms in development of T2DM related complications were conducted.Results:Our study revealed an association between GSTM1 and GSTT1 null polymorphism with T2DM (GSTM1; OR=1.37;95% CI =1.10-1.70 and GSTT1; OR=1.29;95% CI =1.04-1.61) with an amplified risk of 2.02 fold for combined GSTM1-GSTT1 null genotypes. Furthermore, the GSTT1 null (OR=1.56;95%CI=1.38-1.77) and combined GSTM1-GSTT1 null genotypes (OR=1.91;95%CI=1.25- 2.94) increased the risk for development of T2DM related complications, but not the GSTM1 null genotype. Stratified analyses based on ethnicity revealed GSTM1 and GSTT1 null genotypes increase the risk for T2DM in both Caucasians and Asians, with Asians showing much higher risk of T2DM complications than Caucasians for the same. </P><P> Discussion: GSTM1, GSTT1 and combined GSTM1-GSTT1 null polymorphism may be associated with increased risk for T2DM; while GSTT1 and combined GSTM1-GSTT1 null polymorphism may increase the risk of subsequent development of T2DM complications with Asian population carrying an amplified risk for the polymorphism.Conclusion:Thus GSTM1 and GSTT1 null genotypes increases the risk for Type 2 diabetes mellitus alone, in combination or with regards to ethnicity.

Small-molecule degraders of cyclin-dependent kinase protein: a review

2021 ◽  
Author(s):  
Bin Yu ◽  
Zekun Du ◽  
Yuming Zhang ◽  
Zhiyu Li ◽  
Jinlei Bian
Keyword(s):  
Cell Cycle ◽  
Drug Resistance ◽  
Protein Degradation ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Structural Characteristics ◽  
Protein A ◽  
Cyclin Dependent Kinase ◽  
Chemical Tools ◽  
Potential Therapeutics

Proteolysis-targeting chimeras are a new modality of chemical tools and potential therapeutics involving the induction of protein degradation. Cyclin-dependent kinase (CDK) protein, which is involved in cycles and transcription cycles, participates in regulation of the cell cycle, transcription and splicing. Proteolysis-targeting chimeras targeting CDKs show several advantages over traditional CDK small-molecule inhibitors in potency, selectivity and drug resistance. In addition, the discovery of molecule glues promotes the development of CDK degraders. Herein, the authors describe the existing CDK degraders and focus on the discussion of the structural characteristics and design of these degraders.

Role of Circulating Microparticles in Type 2 Diabetes Mellitus: Implications for Pathological Clotting

2021 ◽  
Author(s):  
Siphosethu Cassandra Maphumulo ◽  
Etheresia Pretorius
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Systemic Inflammation ◽  
Blood Cells ◽  
Low Grade ◽  
Chronic Hyperglycemia ◽  
Increased Risk

AbstractType 2 diabetes mellitus (T2DM) is a multifactorial chronic metabolic disease characterized by chronic hyperglycemia due to insulin resistance and a deficiency in insulin secretion. The global diabetes pandemic relates primarily to T2DM, which is the most prevalent form of diabetes, accounting for over 90% of all cases. Chronic low-grade inflammation, triggered by numerous risk factors, and the chronic activation of the immune system are prominent features of T2DM. Here we highlight the role of blood cells (platelets, and red and white blood cells) and vascular endothelial cells as drivers of systemic inflammation in T2DM. In addition, we discuss the role of microparticles (MPs) in systemic inflammation and hypercoagulation. Although once seen as inert by-products of cell activation or destruction, MPs are now considered to be a disseminated storage pool of bioactive effectors of thrombosis, inflammation, and vascular function. They have been identified to circulate at elevated levels in the bloodstream of individuals with increased risk of atherothrombosis or cardiovascular disease, two significant hallmark conditions of T2DM. There is also general evidence that MPs activate blood cells, express proinflammatory and coagulant effects, interact directly with cell receptors, and transfer biological material. MPs are considered major players in the pathogenesis of many systemic inflammatory diseases and may be potentially useful biomarkers of disease activity and may not only be of prognostic value but may act as novel therapeutic targets.

scholarly journals Triglyceride-containing lipoprotein sub-fractions and risk of coronary heart disease and stroke: A prospective analysis in 11,560 adults

2020 ◽  
Vol 27 (15) ◽  
pp. 1617-1626 ◽  
Author(s):  
Roshni Joshi ◽  
S Goya Wannamethee ◽  
Jorgen Engmann ◽  
Tom Gaunt ◽  
Deborah A Lawlor ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Odds Ratio ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Increased Risk ◽  
The Individual

Aims Elevated low-density lipoprotein cholesterol (LDL-C) is a risk factor for cardiovascular disease; however, there is uncertainty about the role of total triglycerides and the individual triglyceride-containing lipoprotein sub-fractions. We measured 14 triglyceride-containing lipoprotein sub-fractions using nuclear magnetic resonance and examined associations with coronary heart disease and stroke. Methods Triglyceride-containing sub-fraction measures were available in 11,560 participants from the three UK cohorts free of coronary heart disease and stroke at baseline. Multivariable logistic regression was used to estimate the association of each sub-fraction with coronary heart disease and stroke expressed as the odds ratio per standard deviation increment in the corresponding measure. Results The 14 triglyceride-containing sub-fractions were positively correlated with one another and with total triglycerides, and inversely correlated with high-density lipoprotein cholesterol (HDL-C). Thirteen sub-fractions were positively associated with coronary heart disease (odds ratio in the range 1.12 to 1.22), with the effect estimates for coronary heart disease being comparable in subgroup analysis of participants with and without type 2 diabetes, and were attenuated after adjustment for HDL-C and LDL-C. There was no evidence for a clear association of any triglyceride lipoprotein sub-fraction with stroke. Conclusions Triglyceride sub-fractions are associated with increased risk of coronary heart disease but not stroke, with attenuation of effects on adjustment for HDL-C and LDL-C.

scholarly journals Nutrients and Immunometabolism: Role of Macrophage NLRP3

2020 ◽  
Vol 150 (7) ◽  
pp. 1693-1704
Author(s):  
Kate J Claycombe-Larson ◽  
Travis Alvine ◽  
Dayong Wu ◽  
Nishan S Kalupahana ◽  
Naima Moustaid-Moussa ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Tissue Cell ◽  
Cell Functions ◽  
Pyrin Domain ◽  
Increased Risk ◽  
Vital Cell ◽  
Cell Type Specific ◽  
Specific Regulation

ABSTRACT Inflammation is largely mediated by immune cells responding to invading pathogens, whereas metabolism is oriented toward producing usable energy for vital cell functions. Immunometabolic alterations are considered key determinants of chronic inflammation, which leads to the development of chronic diseases. Studies have demonstrated that macrophages and the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome are activated in key metabolic tissues to contribute to increased risk for type 2 diabetes mellitus, Alzheimer disease, and liver diseases. Thus, understanding the tissue-/cell-type–specific regulation of the NLRP3 inflammasome is crucial for developing intervention strategies. Currently, most of the nutrients and bioactive compounds tested to determine their inflammation-reducing effects are limited to animal models. Future studies need to address how dietary compounds regulate immune and metabolic cell reprograming in humans.

scholarly journals The Long and Short of It: The Role of Telomeres in Fetal Origins of Adult Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Stephanie E. Hallows ◽  
Timothy R. H. Regnault ◽  
Dean H. Betts
Keyword(s):  
Intrauterine Growth Restriction ◽  
The Body ◽  
Premature Aging ◽  
Fetal Origins ◽  
Maternal Malnutrition ◽  
Adult Disease ◽  
Increased Risk

Placental insufficiency, maternal malnutrition, and other causes of intrauterine growth restriction (IUGR) can significantly affect short-term growth and long-term health. Following IUGR, there is an increased risk for cardiovascular disease and Type 2 Diabetes. The etiology of these diseases is beginning to be elucidated, and premature aging or cellular senescence through increased oxidative stress and DNA damage to telomeric ends may be initiators of these disease processes. This paper will explore the areas where telomere and telomerase biology can have significant effects on various tissues in the body in IUGR outcomes.

The Challenge of Lipid Management in Patients with Diabetes or Other Endocrine Disorders

2010 ◽  
Vol 7 (2) ◽  
pp. 92
Author(s):  
Alberico L Catapano ◽  
Liliana Grigore ◽  
Angela Pirillo ◽  
◽  
◽  
...  
Keyword(s):  
Statin Therapy ◽  
Meta Analysis ◽  
Diabetic Patients ◽  
Endocrine Disorders ◽  
Lipid Management ◽  
Increased Risk ◽  
Patients With Diabetes ◽  
Associated Risk Factors

Diabetes increases the risk of developing cardiovascular disease (CVD), and several guidelines suggest that subjects with diabetes are at high risk of developing CVD. The increased risk can be attributed, at least in part, to associated risk factors, including hypertension and dyslipidaemia. The role of statins in primary and secondary prevention of CVD is well established, and the positive effect has been clearly demonstrated also in patients with type 2 diabetes. A number of studies have evaluated the effect of statin therapy on incident CVD and shown that statin therapy produces a great reduction in cardiovascular risk, but a recent meta-analysis revealed a slight increase in the risk of developing diabetes. Such risk is, however, low, especially when compared with the reduction in cardiovascular events and should not interfere with the choice of treating diabetic patients with a cholesterol-lowering therapy.

Design and synthesis of tailored human caseinolytic protease P inhibitors

2018 ◽  
Vol 54 (70) ◽  
pp. 9833-9836 ◽  
Author(s):  
Thomas F. Gronauer ◽  
Melanie M. Mandl ◽  
Markus Lakemeyer ◽  
Mathias W. Hackl ◽  
Martina Meßner ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Target Identification ◽  
Functional Studies ◽  
Design And Synthesis ◽  
Caseinolytic Protease ◽  
Complex Target

To expedite functional studies of human ClpP we introduce tailored small molecule inhibitors. These compounds are active against the proteolytic ClpXP complex. Target identification elucidates anti-proliferative effects against cancer cells.

scholarly journals Perspectives, past, present and future: the proline cycle/proline-collagen regulatory axis

Amino Acids ◽  
2021 ◽  
Author(s):  
James M. Phang
Keyword(s):  
Extracellular Matrix ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Human Tumors ◽  
Regulatory Link

AbstractIn the 35 years since the introduction of the “proline cycle”, its relevance to human tumors has been widely established. These connections are based on a variety of mechanisms discovered by many laboratories and have stimulated the search for small molecule inhibitors to treat cancer or metastases. In addition, the multi-layered connections of the proline cycle and the role of proline and hydroxyproline in collagen provide an important regulatory link between the extracellular matrix and metabolism.

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