Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Owing to its distinct chemico-biological properties, chitosan, a cationic biopolymer, offers a great potential in multifarious bioapplications. One such application is as a dietary antilipidemic supplement to be used to reduce obesity/overweight and to lower cholesterol. The lipid-binding efficiency of chitosan, however, remains debatable. Accordingly, in this study we investigated the interactions of chitosan with selected lipids, cholesterol and fatty acids, the latter including saturated (stearic acid) and unsaturated (oleic, linoleic, alpha-linolenic) acids. The experiments were performed with the Langmuir monolayer technique, in which surface pressure-area isotherms were recorded for the lipid monolayers spread on the acetate buffer pH 4.0 subphase in the absence and presence of chitosan. We found that the presence of chitosan in the subphase strongly influenced the shape and location of the isotherms, proving that there existed attractions between chitosan and lipid molecules. The attractions were revealed by changes of the molecular organization of the monolayers. The common feature of these changes was that all the monolayers studied underwent expansion, in each case reaching saturation with increasing chitosan concentration. In agreement with the lipid molecular structures, the highest expansions were observed for the most unsaturated fatty acids, linoleic and alpha-linolenic, the lowest for stearic acid, with oleic acid and cholesterol being the intermediate cases. By contrast, the main distinguishing feature of these changes was that, although none of the monolayers studied changed its state when completely saturated with chitosan, compared to the parent ones the compactness of the monolayers was modified. The solid monolayers of stearic acid and cholesterol were loosened, whereas those of all the unsaturated acids, liquid in nature, were tightened. On the basis of these results we tentatively propose a mechanism of the chitosan action that includes both electrostatic and hydrophobic lipid-chitosan interactions as well as hydrogen bonding between them.
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PMID:Chitosan as a lipid binder: a langmuir monolayer study of chitosan-lipid interactions. 1763 Jul 96

Understanding the mechanism of saturated fatty acid-induced hepatocyte toxicity may provide insight into cures for diseases such as obesity-associated cirrhosis. Trehalose, a nonreducing disaccharide shown to protect proteins and cellular membranes from inactivation or denaturation caused by different stress conditions, also protects hepatocytes from palmitate-induced toxicity. Our results suggest that trehalose serves as a free radical scavenger and alleviates damage from hydrogen peroxide secreted by the compromised cells. We also observe that trehalose protects HepG2 cells by interacting with the plasma membrane to counteract the changes in membrane fluidity induced by palmitate. The experimental results are supported by molecular dynamics simulations of model cell membranes that closely reflect the experimental conditions. Simulations were performed to understand the specific interactions between lipid bilayers, palmitate, and trehalose. The simulations results reveal the early stages of how palmitate induces biophysical changes to the cellular membrane and the role of trehalose in protecting the membrane structure.
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PMID:Experimental and computational studies investigating trehalose protection of HepG2 cells from palmitate-induced toxicity. 1809 30

CCR2 is the major family of chemokine receptors which involve in the pathophysiology of the acute or chronic inflammatory conditions such as rheumatoid arthritis, atherosclerosis, asthma, obesity, and type-2 diabetes. Herein, we report the results of HQSAR model, developed for CCR2 antagonistic activity of indolopiperidine derivatives. The best HQSAR model with r(2)=0.916, q(2)=0.562 with atom count=4-7 was used to predict the activity of the test set molecules. The predicted values are in good agreement with experimental results and show the potential of the model for untested compounds. Analysis of molecular fragments throws light on essential structural and topological features of indolopiperidine derivatives for antagonist activity. The analysis shows that the presence of tertiary hydrogen bond acceptor groups is important for CCR2 antagonism. Fragments containing benzene ring substituted with one or more chlorine atoms show the positive effect of electron withdrawing group for favorable activity.
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PMID:Probing the structural and topological requirements for CCR2 antagonism: holographic QSAR for indolopiperidine derivatives. 1822 95

Membranes constitute a meeting point for lipids and proteins. Not only do they define the entity of cells and cytosolic organelles but they also display a wide variety of important functions previously ascribed to the activity of proteins alone. Indeed, lipids have commonly been considered a mere support for the transient or permanent association of membrane proteins, while acting as a selective cell/organelle barrier. However, mounting evidence demonstrates that lipids themselves regulate the location and activity of many membrane proteins, as well as defining membrane microdomains that serve as spatio-temporal platforms for interacting signalling proteins. Membrane lipids are crucial in the fission and fusion of lipid bilayers and they also act as sensors to control environmental or physiological conditions. Lipids and lipid structures participate directly as messengers or regulators of signal transduction. Moreover, their alteration has been associated with the development of numerous diseases. Proteins can interact with membranes through lipid co-/post-translational modifications, and electrostatic and hydrophobic interactions, van der Waals forces and hydrogen bonding are all involved in the associations among membrane proteins and lipids. The present study reviews these interactions from the molecular and biomedical point of view, and the effects of their modulation on the physiological activity of cells, the aetiology of human diseases and the design of clinical drugs. In fact, the influence of lipids on protein function is reflected in the possibility to use these molecular species as targets for therapies against cancer, obesity, neurodegenerative disorders, cardiovascular pathologies and other diseases, using a new approach called membrane-lipid therapy.
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PMID:Membranes: a meeting point for lipids, proteins and therapies. 1826 54

Obesity results from alterations in the body's regulation of energy intake, expenditure, and storage. Recent evidence, primarily from investigations in animal models, suggests that the gut microbiota affects nutrient acquisition and energy regulation. Its composition has also been shown to differ in lean vs obese animals and humans. In this article, we review the published evidence supporting the potential role of the gut microbiota in the development of obesity and explore the role that modifying the gut microbiota may play in its future treatment. Evidence suggests that the metabolic activities of the gut microbiota facilitate the extraction of calories from ingested dietary substances and help to store these calories in host adipose tissue for later use. Furthermore, the gut bacterial flora of obese mice and humans include fewer Bacteroidetes and correspondingly more Firmicutes than that of their lean counterparts, suggesting that differences in caloric extraction of ingested food substances may be due to the composition of the gut microbiota. Bacterial lipopolysaccharide derived from the intestinal microbiota may act as a triggering factor linking inflammation to high-fat diet-induced metabolic syndrome. Interactions among microorganisms in the gut appear to have an important role in host energy homeostasis, with hydrogen-oxidizing methanogens enhancing the metabolism of fermentative bacteria. Existing evidence warrants further investigation of the microbial ecology of the human gut and points to modification of the gut microbiota as one means to treat people who are over-weight or obese.
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PMID:Gut microbiota and its possible relationship with obesity. 1838 Sep 92

To understand whether oxidants contribute to the initiation and/or promulgation toward aging, the present study has been undertaken on 220 healthy male volunteers aged 20-80 years selected from the defined electoral area (suburbs of Tirupati, Andhra Pradesh, India) to evaluate the concentrations of free radicals (superoxide anion, hydrogen peroxide), lymphocyte antioxidant enzymes (glutathione S-transferase, superoxide dismutase, catalase), and DNA damage in relation to obesity and smoking (lifestyles). A two fold increase of lymphocyte free radical generation (DNA damage) was observed in older age groups with a reduced antioxidant potential, forming a link between cigarette smoking and oxidative stress represented by an antioxidant imbalance. Body mass index had a positive relationship with oxidative stress, but antioxidant levels did not vary with body mass index. The findings conclude that free radical-mediated oxidative stress and DNA damage accelerate with lifestyle variations under reduced antioxidant potential.
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PMID:Age-related correlation between antioxidant enzymes and DNA damage with smoking and body mass index. 1842 59

11beta-Hydroxysteroid dehydrogenase1(11beta-HSD1) can serve either as an oxo-reductase or dehydrogenase determined by the redox state in the endoplasmic reticulum (ER). This bidirectional enzyme governs paracrine glucocorticoid production. Recent in vitro studies have underscored the key role of cytoplasmic glucose-6-phosphate (G6P) in controlling the flux direction of 11betaHSD-1 by altering the intraluminal ER NADPH/NADP ratio. The hypothesis that other hexose phosphoesters or the plentiful cellular oxidative protector glutathione could also regulate microsomal 11betaHSD-1 activity was tested. Fructose-6-phosphate increased the activity of 11beta-HSD1 reductase in isolated rat and porcine liver microsomes but not porcine fat microsomes. Moreover, oxidized glutathione (GSSG) attenuated 11beta-HSD1 reductase activity by 40% while reduced glutathione (GSH) activated the reductase in liver. Fat microsomes were unaffected because they lack glutathione reductase. Nonetheless, another oxidizing agent, hydrogen peroxide (0.5mM), inhibited both fat and liver 11beta-HSD1 reductase. Consistent with the major role of the redox state, 2.5mM GSSG and hydrogen peroxide augmented the 11beta-HSD1 dehydrogenase, antithetical to the reductase, by 20-30% in liver microsomes. Given the key role of reactive oxygen species and hexose phosphate accumulation in the pathoetiology of obesity and diabetes, these compounds might also modify 11beta-HSD1 in these conditions.
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PMID:Modification of microsomal 11beta-HSD1 activity by cytosolic compounds: glutathione and hexose phosphoesters. 1855 Mar 63

Insulin resistance and hyperinsulinemia are commonly present in obesity and pre-diabetes, and hyperinsulinemia is both a marker and a cause for insulin resistance. However, the molecular link between hyperinsulinemia and insulin resistance remains elusive. The present study examined the effect of chronic insulin treatment on the reactive oxygen species (ROS) production, insulin signalling and insulin-stimulated glucose uptake in 3T3-L1 adipocytes. The results showed that chronic insulin treatment significantly increased the intracellular generation of superoxide anion, hydrogen peroxide and hydroxyl radical. ROS induced by chronic insulin treatment inhibited insulin signalling and glucose uptake, induced endoplasmic reticulum (ER) stress and JNK activation. Furthermore, these effects were reversed by antioxidants N-acetylcysteine, superoxide dismutase or catalase. These results suggested that ROS, ER stress and JNK pathway are involved in insulin resistance induced by chronic insulin treatment. Therefore, oxidative stress could be a potential interventional target for hyperinsulinemia-induced insulin resistance and related diseases.
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PMID:Chronic insulin treatment causes insulin resistance in 3T3-L1 adipocytes through oxidative stress. 1856 16

The zeta chain-associated 70-kDa protein (ZAP-70) of tyrosine kinase plays a critical role in T cell receptor-mediated signal transduction and the immune response. A high level of ZAP-70 expression is observed in leukemia, which suggests ZAP-70 as a logical target for immunomodulatory therapies. (-)-Epigallocatechin gallate (EGCG) is one of the major green tea catechins that is suggested to have a role as a preventive agent in cancer, obesity, diabetes, and cardiovascular disease. Here we identified ZAP-70 as an important and novel molecular target of EGCG in leukemia cells. ZAP-70 and EGCG displayed high binding affinity (Kd = 0.6207 micromol/liter), and additional results revealed that EGCG effectively suppressed ZAP-70, linker for the activation of T cells, phospholipase Cgamma1, extracellular signaling-regulated kinase, and MAPK kinase activities in CD3-activated T cell leukemia. Furthermore, the activation of activator protein-1 and interleukin-2 induced by CD3 was dose-dependently inhibited by EGCG treatment. Notably, EGCG dose-dependently induced caspase-mediated apoptosis in P116.cl39 ZAP-70-expressing leukemia cells, whereas P116 ZAP-70-deficient cells were resistant to EGCG treatment. Molecular docking studies, supported by site-directed mutagenesis experiments, showed that EGCG could form a series of intermolecular hydrogen bonds and hydrophobic interactions within the ATP binding domain, which may contribute to the stability of the ZAP-70-EGCG complex. Overall, these results strongly indicated that ZAP-70 activity was inhibited specifically by EGCG, which contributed to suppressing the CD3-mediated T cell-induced pathways in leukemia cells.
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PMID:(-)-Epigallocatechin gallate regulates CD3-mediated T cell receptor signaling in leukemia through the inhibition of ZAP-70 kinase. 1868 87

Chemokine receptors have evolved as attractive targets for disease conditions which arise due to immunomodulation involving host-defense mechanisms. CCR2, a chemokine receptor, is targeted for diseases like arthritis, multiple sclerosis, vascular disease, obesity, and type 2 diabetes. This study provides a new strategy of a ligand based technique which exploits fingerprint led fragment features in conjunction with structure-guided design for identifying new scaffolds for CCR2. A fragment based mining (FBM) technique was employed on a chemical database to identify novel scaffold hops. The hits were subjected to 3-point pharmacophore fingerprint procedures with Tanimoto similarity metric to compare pharmacophoric fingerprints. The final 66 hits generated by these exercises were predicted by the validated HQSAR model, and the top predicted were suggested as probable scaffolds for CCR2 antagonism. The identified scaffolds were validated through molecular docking studies. The ligands were docked by providing receptor flexibility in the extra cellular domain (1 and 3), N terminal domain, and in the transmembrane (TM1 & TM7) helix region with IFD approach. Some of the scaffolds showed H-bonding potential which was not explored by the data set molecules. All identified scaffolds highlighted a key hydrogen bonding interaction with Thr292 as supported by mutational studies. The observed pi stacking interaction with Tyr188 in data set molecules was also produced by the new scaffolds. Taking the advantage of receptor flexibility the scaffolds explored the hydrophobic binding cleft between helix 1 and 7 occupied by residues Leu44, Leu45, Leu48 and Ile300, Ile303, Ile304, respectively. Two of the identified molecules have promising outcomes and can be considered as novel scaffolds for CCR2 binding.
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PMID:Fingerprint directed scaffold hopping for identification of CCR2 antagonists. 1876 38


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