10 research outputs found
Resveratrol regulates insulin resistance to improve the glycolytic pathway by activating SIRT2 in PCOS granulosa cells
ScopeInsulin resistance (IR) has a close relationship with the main clinical manifestations of patients with PCOS; hence, the research and development of new drugs to treat PCOS by improving IR is a desiderate task at present. Resveratrol (RES) possesses a variety of beneficial pharmacological functions, such as antioxidation, anti-inflammatory, regulating glucose, and lipid metabolism. However, whether RES could improve IR and the underlying mechanisms remained unclear in PCOS.Methods and resultsSD rats received a high-fat diet and letrozole for 30 days to establish the PCOS model and then intervened with RES for 30 days. The results demonstrated that RES played a protective role on the IR in PCOS rats, which significantly decreased the levels of blood glucose and serum insulin, up regulated the expression of IGF1R, and down regulated the expression of IGF1. In vitro, KGN cells were treated with insulin, RES, and AGK2, respectively. We found that a high dose of insulin (4Ī¼g/mL) significantly inhibited KGN cell viability, decreased the level of lactic acid, and increased the level of pyruvate, while RES (25Ī¼M) attenuated the growth-inhibitory effect, as well as increased the level of lactic acid and decreased the level of pyruvate after high levels of insulin treatment. Simultaneously, RES up regulated the expression level of the crucial rate-limiting enzymes relating to glycolytic pathways, such as LDHA, HK2, and PKM2. Furthermore, AGK2 remarkably inhibited the expression level of SIRT2, which was similar to the same negative effects processed by insulin. Meanwhile, RES overtly repaired the glycolysis process by reversing the levels of lactic acid and pyruvate, together with up regulating the expression level of LDHA, HK2, and PKM2, after AGK2 treatment.ConclusionRES could effectively improve insulin resistance and restore the glycolysis pathway by regulating SIRT2, which may contribute to attenuating the ovarian damage of PCOS rats and provide a potential treatment for patients with PCOS
Site-Specific Electrodeposition Enables Self-Terminating Growth of Atomically Dispersed Metal Catalysts
The growth of atomically dispersed metal catalysts (ADMCs) remains a great challenge owing to the thermodynamically driven atom aggregation. Here we report a surface-limited electrodeposition technique that uses site-specific substrates for the rapid and room-temperature synthesis of ADMCs. We obtained ADMCs by the underpotential deposition (UPD) of a single-atom nonnoble metal onto the chalcogen atoms of chemically exfoliated transition metal dichalcogenides and subsequent galvanic displacement with a more-noble single-atom metal. The site-specific electrodeposition (SSED) enables the formation of energetically favorable metalāsupport bonds, and then automatically terminates the sequential formation of metallic bonding. The self-terminating effect restricts the metal deposition to the atomic scale. The modulated ADMCs exhibit remarkable activity and stability in the hydrogen evolution reaction compared to state-of-the-art single-atom electrocatalysts. We demonstrate that this SSED methodology could be extended to the synthesis of a variety of ADMCs (for example, Pt, Pd, Rh, Cu, Pb, Bi, and Sn single atoms), showing its general scope for the large-scale production of functional ADMCs in heterogenous catalysis. </p
Dimerization of Cell-Adhesion Molecules Can Increase Their Binding Strength
Cell-adhesion
molecules (CAMs) often exist as homodimers under
physiological conditions. However, owing to steric hindrance, simultaneous
binding of two ligands to the homodimers at the same location can
hardly be satisfied, and the molecular mechanism underlying this natural
design is still unknown. Here, we present a theoretical model to understand
the rupture behavior of cell-adhesion bonds formed by multiple binding
ligands with a single receptor. We found that the dissociation forces
for the cell-adhesion bond could be greatly enhanced in comparison
with the monomer case through a ligand rebinding and exchange mechanism.
We also confirmed this prediction by measuring dimeric cRGD (cyclic
Arg-Gly-Asp) unbinding from integrin (Ī±<sub>v</sub>Ī²<sub>3</sub>) using atomic force microscopy-based single-molecule force
spectroscopy. Our finding addresses the mechanism of increasing the
binding strength of cell-adhesion bonds through dimerization at the
single-molecule level, representing a key step toward the understanding
of complicated cell-adhesion behaviors. Moreover, our results also
highlight a wealth of opportunities to design mechanically stronger
bioconjunctions for drug delivery, biolabeling, and surface modification
Single Molecule Study of Force-Induced Rotation of CarbonāCarbon Double Bonds in Polymers
Carbonācarbon
double bonds (Cī»C) are ubiquitous in
natural and synthetic polymers. In bulk studies, due to limited ways
to control applied force, they are thought to be mechanically inert
and not to contribute to the extensibility of polymers. Here, we report
a single molecule force spectroscopy study on a polymer containing
Cī»C bonds using atomic force microscope. Surprisingly, we found
that it is possible to directly observe the <i>cis</i>-to-<i>trans</i> isomerization of Cī»C bonds at the time scale
of ā¼1 ms at room temperature by applying a tensile force ā¼1.7
nN. The reaction proceeds through a diradical intermediate state,
as confirmed by both a free radical quenching experiment and quantum
chemical modeling. The force-free activation length to convert the <i>cis</i> Cī»C bonds to the transition state is ā¼0.5
Ć
, indicating that the reaction rate is accelerated by ā¼10<sup>9</sup> times at the transition force. On the basis of the density
functional theory optimized structure, we propose that because the
pulling direction is not parallel to Cī»C double bonds in the
polymer, stretching the polymer not only provides tension to lower
the transition barrier but also provides torsion to facilitate the
rotation of <i>cis</i> Cī»C bonds. This explains the
apparently low transition force for such thermally āforbiddenā
reactions and offers an additional explanation of the ālever-arm
effectā of polymer backbones on the activation force for many
mechanophores. This work demonstrates the importance of precisely
controlling the force direction at the nanoscale to the force-activated
reactions and may have many implications on the design of stress-responsive
materials
Association between <i>MGMT</i> Promoter Methylation and Non-Small Cell Lung Cancer: A Meta-Analysis
<div><p>Background</p><p>O<sup>6</sup>-methylguanine-DNA methyltransferase (MGMT) is one of most important DNA repair enzyme against common carcinogens such as alkylate and tobacco. Aberrant promoter methylation of the gene is frequently observed in non-small cell lung cancer (NSCLC). However, the importance of epigenetic inactivation of the gene in NSCLC published in the literature showed inconsistence. We quantified the association between <i>MGMT</i> promoter methylation and NSCLC using a meta-analysis method.</p> <p>Methods</p><p>We systematically reviewed studies of <i>MGMT</i> promoter methylation and NSCLC in PubMed, EMBASE, Ovid, ISI Web of Science, Elsevier and CNKI databases and quantified the association between <i>MGMT</i> promoter methylation and NSCLC using meta-analysis method. Odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated to evaluate the strength of association. Potential sources of heterogeneity were assessed by subgroup analysis and meta-regression.</p> <p>Results</p><p>A total of 18 studies from 2001 to 2011, with 1, 160 tumor tissues and 970 controls, were involved in the meta-analysis. The frequencies of <i>MGMT</i> promote methylation ranged from 1.5% to 70.0% (median, 26.1%) in NSCLC tissue and 0.0% to 55.0% (median, 2.4%) in non-cancerous control, respectively. The summary of OR was 4.43 (95% CI: 2.85, 6.89) in the random-effects model. With stratification by potential source of heterogeneity, the OR was 20.45 (95% CI: 5.83, 71.73) in heterogeneous control subgroup, while it was 4.16 (95% CI: 3.02, 5.72) in the autologous control subgroup. The OR was 5.31 (95% CI: 3.00, 9.41) in MSP subgroup and 3.06 (95% CI: 1.75, 5.33) in Q-MSP subgroup.</p> <p>Conclusion</p><p>This meta-analysis identified a strong association between methylation of <i>MGMT</i> gene and NSCLC. Prospective studies should be required to confirm the results in the future.</p> </div
Funnel plot for assessment of publication bias.
<p><b>Each hollow point represents a separate study for the indicated association</b>. The area of the hollow point reflects the weight (inverse of the variance). Horizontal line stands for the mean magnitude of the effect.</p
Forest plot of MGMT methylation in tumor tissue verse control group between <i>MGMT</i> promoter methylation and NSCLC.
<p>Forest plot of MGMT methylation in tumor tissue verse control group between <i>MGMT</i> promoter methylation and NSCLC.</p
Cingulin and paracingulin tether myosins-2 to junctions to mechanoregulate the plasma membrane
The mechanisms that regulate the spatial sorting of nonmuscle myosins-2 (NM2) isoforms and couple them mechanically to the plasma membrane are unclear. Here we show that the cytoplasmic junctional proteins cingulin (CGN) and paracingulin (CGNL1) interact directly with NM2s through their C-terminal coiled-coil sequences. CGN binds strongly to NM2B, and CGNL1 to NM2A and NM2B. Knockout (KO), exogenous expression, and rescue experiments with WT and mutant proteins show that the NM2-binding region of CGN is required for the junctional accumulation of NM2B, ZO-1, ZO-3, and phalloidin-labeled actin filaments, and for the maintenance of tight junction membrane tortuosity and apical membrane stiffness. CGNL1 expression promotes the junctional accumulation of both NM2A and NM2B and its KO results in myosin-dependent fragmentation of adherens junction complexes. These results reveal a mechanism for the junctional localization of NM2A and NM2B and indicate that, by binding to NM2s, CGN and CGNL1 mechanically couple the actomyosin cytoskeleton to junctional protein complexes to mechanoregulate the plasma membrane.</p