Image_2_Potential roles of synaptotagmin family members in cancers: Recent advances and prospects.TIF

With the continuous development of bioinformatics and public database, more and more genes that play a role in cancers have been discovered. Synaptotagmins (SYTs) are abundant, evolutionarily conserved integral membrane proteins composed of a short N-terminus, a variable linker domain, a single transmembrane domain, and two C2 domains, and they constitute a family of 17 isoforms. The synaptotagmin family members are known to regulate calcium-dependent membrane fusion events. Some SYTs play roles in hormone secretion or neurotransmitter release or both, and much evidence supports SYTs as Ca2+ sensors of exocytosis. Since 5 years ago, an increasing number of studies have found that SYTs also played important roles in the occurrence and development of lung cancer, gastric cancer, colon cancer, and other cancers. Down-regulation of SYTs inhibited cell proliferation, migration, and invasion of cancer cells, but promoted cell apoptosis. Growth of peritoneal nodules is inhibited and survival is prolonged in mice administrated with siSYTs intraperitoneally. Therefore, most studies have found SYTs serve as an oncogene after overexpression and may become potential prognostic biomarkers for multiple cancers. This article provides an overview of recent studies that focus on SYT family members’ roles in cancers and highlights the advances that have been achieved.</p

Image_1_Potential roles of synaptotagmin family members in cancers: Recent advances and prospects.TIF

With the continuous development of bioinformatics and public database, more and more genes that play a role in cancers have been discovered. Synaptotagmins (SYTs) are abundant, evolutionarily conserved integral membrane proteins composed of a short N-terminus, a variable linker domain, a single transmembrane domain, and two C2 domains, and they constitute a family of 17 isoforms. The synaptotagmin family members are known to regulate calcium-dependent membrane fusion events. Some SYTs play roles in hormone secretion or neurotransmitter release or both, and much evidence supports SYTs as Ca2+ sensors of exocytosis. Since 5 years ago, an increasing number of studies have found that SYTs also played important roles in the occurrence and development of lung cancer, gastric cancer, colon cancer, and other cancers. Down-regulation of SYTs inhibited cell proliferation, migration, and invasion of cancer cells, but promoted cell apoptosis. Growth of peritoneal nodules is inhibited and survival is prolonged in mice administrated with siSYTs intraperitoneally. Therefore, most studies have found SYTs serve as an oncogene after overexpression and may become potential prognostic biomarkers for multiple cancers. This article provides an overview of recent studies that focus on SYT family members’ roles in cancers and highlights the advances that have been achieved.</p

Dominant Conformation of Valsartan in Sodium Dodecyl Sulfate Micelle Environment

The interaction of valsartan (VST), a novel antihypertensive drug, with sodium dodecyl sulfate (SDS) micelles has been investigated using Nuclear Magnetic Resonance (NMR) spectroscopy and Molecular Dynamics (MD) simulation. VST has two conformations in solution, exchanging slowly on the NMR time scale via the trans/cis (conformer A/B) isomerization of the amide bond. It is suggested that drugs in the sartan class incorporate and diffuse into biological membranes before they interact with AT1 receptors. SDS is used to mimic the membrane environment to characterize two VST conformers. 1H NMR chemical shift analysis, proton relaxation rates, and self-diffusion coefficient measurements suggest that conformer A has a higher binding affinity to SDS and is the dominant conformer distributed in the SDS micelles. The location of VST in the micelles is determined by NOE measurements and by the MD simulation, showing that the butyl chain and biphenyl groups of VST interact with the alkyl group of SDS through hydrophobic interactions. Preferable binding free energy is found for conformer A by the MD simulation, which demonstrates that the relatively concentrated hydrophobic surface of conformer A is responsible for its higher affinity to the micelles. Our results are in good agreement with a recent simulation of VST bound onto the AT1 receptor by Potamitis et. al (J. Chem. Inf. Model. 2009) who demonstrate that conformer A (trans conformation in their definition) is the one binding to the receptor. The results presented in our study suggest that the biological membrane plays an essential role in stabilization of the active state of VST. Thus, understanding the interactions between the sartan drugs and the membrane environment should facilitate the studies of the functional mechanism of these compounds with their receptor and provide insight on the development of new approaches for drug discovery

3D geometrical models for 40, 60, and 75 yo human subjects (<i>left</i>) and associated values of segmental biaxial material stiffness (MPa) in three regions (<i>right</i>): Ascending Thoracic Aorta (ATA), proximal Descending Thoracic Aorta (DTA), and Infrarenal Abdominal Aorta (IAA).

Lengths along the aortic centerline are parameterized by s ∈[0,1], where s = 0 corresponds to the aortic root at the beginning of the ATA and s = 1 to the aorto-iliac bifurcation (left). Listed values of aortic material stiffness (right) were assigned at locations indicated by the black dots within the ATA, DTA and IAA and linearly interpolated to obtain a continuous distribution of stiffness, as illustrated colorimetrically on the aortic geometries for the circumferential values. Stiffness was assigned separately in circumferential (blue) and axial (red) directions at each location and for each age group. The % numbers refer to the percent difference in value relative to the prior age group.</p

Effects of age-associated regional changes in aortic stiffness on human hemodynamics revealed by computational modeling - Table 6

Effects of age-associated regional changes in aortic stiffness on human hemodynamics revealed by computational modeling - Table

Spatial and temporal distribution of external tissue support parameters: Stiffness coefficient <i>k</i>_<i>s</i> and damping coefficient <i>c</i>_<i>s</i>.

<p>Spatial and temporal distribution of external tissue support parameters: Stiffness coefficient <i>k</i>_<i>s</i> and damping coefficient <i>c</i>_<i>s</i>.</p

Computed values of circumferential material stiffness (Pa), local Pulse Pressure (<i>PP</i>, in mmHg), distensibility (Pa^-1), Pulse Wave Velocity (<i>PWV</i>, in m/s), and change in strain energy storage (<i>ΔW</i>, in Pa x 100) as a function of region (aortic segments 1 to 6) for three different ages: 40, 60, and 75 yo.

<p>The 18 different computed values for each of the 5 metrics consistently show strong regional variations at each age.</p

Pressure and flow waveforms for 40 (black), 60 (orange) and 75 (blue) yo subjects at four different locations along the aorta; namely ATA (I), DTA (II), SAA (III) and IAA (IV).

<p>Pressure and flow waveforms for 40 (black), 60 (orange) and 75 (blue) yo subjects at four different locations along the aorta; namely ATA (I), DTA (II), SAA (III) and IAA (IV).</p

Iterative approach for tuning external tissue support parameters: Stiffness coefficient <i>k</i>_<i>s</i> and damping coefficient <i>c</i>_<i>s</i>.

<p>Iterative approach for tuning external tissue support parameters: Stiffness coefficient <i>k</i>_<i>s</i> and damping coefficient <i>c</i>_<i>s</i>.</p

Schematics of the baseline 30 yo subject-specific model and the three numerically aged models corresponding to the 40, 60, and 75 yo groups.

<p>The tables summarize the prescribed values of regional inner diameters and aortic centerline lengths. All dimensions are given in mm.</p