Sphingosine Kinase 1 Plays an Important Role in Atorvastatin-Mediated Anti-Inflammatory Effect against Acute Lung Injury

Atorvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitor and inhibits cholesterol synthesis. Recently, atorvastatin also showed anti-inflammatory effect in acute lung injury, ameliorating pulmonary gas-blood exchanging function. Sphingosine kinase 1 plays a central role in endothelial (EC) cytoskeleton rearrangement and EC barrier integrity regulation. In this study, the role of sphingosine kinase 1 in atorvastatin anti-inflammatory effect against acute lung injury was investigated. Both wild-type (WT) and SphK1-/- mice were challenged with high tidal volume ventilation (40 ml/kg body weight, 65 breathing/min, 4 hours). The acute lung injury was evaluated and the mechanisms were explored. In WT mice, atorvastatin treatment significantly decreased acute lung injury responding to high tidal volume ventilation (HT), including protein, cellular infiltration, and cytokine releasing; comparing to WT mice, SphK1-/- mice showed significantly worsen pulmonary injuries on HT model. Moreover, the atorvastatin-mediated anti-inflammatory effect was diminished in SphK1-/- mice. To further confirm the role of SphK1 in VILI, we then compared the inflammatory response of endothelial cells that were isolated from WT and SphK1-/- mice to cyclic stretching. Similarly, atorvastatin significantly decreased cytokine generation from WT EC responding to cyclic stretching. Atorvastatin also significantly preserved endothelial junction integrity in WT EC against thrombin challenge. However, the inhibitory effect of atorvastatin on cytokine generation induced by cyclic stretching was abolished on SphK1-/- mice EC. The endothelial junction integrity effects of atorvastatin also diminished on SphK1-/- mouse EC. Signal analysis indicated that atorvastatin inhibited JNK activation induced by cyclic stretch. SphK1 knockout also blocked atorvastatin-mediated VE-cadherin junction enhancement. In summary, by inhibition of MAPK activity and maintenance of EC junction homeostasis, SphK1 plays a critical role in atorvastatin-mediated anti-inflammatory effects in both cellular and in vivo model. This study also offers an insight into mechanical stress-mediated acute lung injury and potential therapy in the future.

Therapeutic Effect of Platinum Nanoparticles on Atherosclerosis Research Model Based on Microfluidics and Determination of Injury

The atherosclerosis (AS) microenvironment plays an important role in pathogenicity, including blood flow and blood pressure, high cholesterol, high blood sugar, angiotensin II, tumor necrosis factor, and the like. The AS microfluidic model was established, and the fluid shear stress and cyclic stretching were set to 5.07 Pa and 1.17 Hz to simulate normal blood flow, respectively. The effects of different biochemical environments on endothelial cells (ECs) and cardiomyocytes were analyzed. The results confirmed that different biochemical environments had significant damage to ECs and cardiomyocytes. Subsequently, the further effect of ECs on cardiomyocytes in AS microenvironment was studied, and the results proved that ECs caused further damage to cardiomyocytes under AS biochemical factors. We used Pt nanoparticles (Pt NPs) to study the anti-AS efficiency. The results showed that the addition of Pt NPs played a particular role in the AS treatment of ECs in the AS microenvironment, and the protection for myocardial cells was achieved.

Softening Effects in Biological Tissues and NiTi Knitwear during Cyclic Loading

Samples of skin, tendons, muscles, and knitwear composed of NiTi wire are studied by uniaxial cyclic tension and stretching to rupture. The metal knitted mesh behaves similar to a superelastic material when stretched, similar to soft biological tissues. The superelasticity effect was found in NiTi wire, but not in the mesh composed of it. A softening effect similar to biological tissues is observed during the cyclic stretching of the mesh. The mechanical behavior of the NiTi mesh is similar to the biomechanical behavior of biological tissues. The discovered superelastic effects allow developing criteria for the selection and evaluation of mesh materials composed of titanium nickelide for soft tissue reconstructive surgery.

Assessment of SMA Electrical Resistance Change during Cyclic Stretching with Small Elongation

In this article, changes in NiTi alloy (Flexinol) electrical resistance during cyclic stretching with small elongation were investigated. A dedicated test stand consisting of motorized vertical test stand, force gauge, and electric resistance measuring device with an accuracy of 0.006 Ω was developed. A dedicated control algorithm was developed using LabVIEW software. Changes in electrical resistance were investigated for the 0.1 mm Flexinol wire with length of 120 mm. Testing was performed in the elongation range between 0.25% and 1.5% in martensite phase. Tested samples were subjected to 30 stretching cycles with a movement speed of 10 mm/min. Obtained results show that the cyclic stretching of Flexinol wire reduces its electrical resistance with each stretching cycle. Moreover, it was noted that changes in Flexinol electrical resistance during cycling stretching depend on the assumed elongation and number of the already performed stretching cycles. The observed electrical resistance change decreases with each stretching cycle. Thus, the observed changes are greater during the first stretching cycles. For elongations exceeding 1%, the Flexinol electrical resistance in the first stretching cycle increases. In each subsequent cycle, electrical resistance decreases, as in the case of the smallest value of assumed elongation. In almost all tested cases (except in the case with 1.5% of assumed elongation), Flexinol electrical resistance after 30 stretching cycles was smaller than before the test.

Constructing a Segregated Magnetic Graphene Network in Rubber Composites for Integrating Electromagnetic Interference Shielding Stability and Multi-Sensing Performance

A flexible, wearable electronic device composed of magnetic iron oxide (Fe3O4)/reduced graphene oxide/natural rubber (MGNR) composites with a segregated network was prepared by electrostatic self-assembly, latex mixing, and in situ reduction. The segregated network offers the composites higher electrical conductivity and more reliable sensing properties. Moreover, the addi-tion of Fe3O4 provides the composites with better electromagnetic interference shielding effectiveness (EMI SE). The EMI shielding property of MGNR composites is more stable under tensile deformation and long-term cycling conditions and has a higher sensitivity to stretch strain compared with the same structure made from reduced graphene oxide/natural rubber (GNR) composites. The EMI SE value of MGNR composites reduces by no more than 2.9% under different tensile permanent deformation, cyclic stretching, and cyclic bending conditions, while that of GNR composites reduces by approximately 16% in the worst case. Additionally, the MGNR composites have a better sensing performance and can maintain stable signals, even in the case of cyclic stretching with a very small strain (0.05%). Furthermore, they can steadily monitor the changes in resistance signals in various human motions such as finger bending, wrist bending, speaking, smiling, and blinking, indicating that the MGNR composites can be used in future wearable electronic flexibility devices.

Cyclic stretching-induced epithelial cell reorientation is driven by microtubule-modulated transverse extension during the relaxation phase

Many types of adherent cells are known to reorient upon uniaxial cyclic stretching perpendicularly to the direction of stretching to facilitate such important events as wound healing, angiogenesis, and morphogenesis. While this phenomenon has been documented for decades, the underlying mechanism remains poorly understood. Using an on-stage stretching device that allowed programmable stretching with synchronized imaging, we found that the reorientation of NRK epithelial cells took place primarily during the relaxation phase when cells underwent rapid global retraction followed by extension transverse to the direction of stretching. Inhibition of myosin II caused cells to orient along the direction of stretching, whereas disassembly of microtubules enhanced transverse reorientation. Our results indicate distinct roles of stretching and relaxation in cell reorientation and implicate a role of myosin II-dependent contraction via a microtubule-modulated mechanism. The importance of relaxation phase also explains the difference between the responses to cyclic and static stretching.

Spatiotemporal model of cellular mechanotransduction via Rho and YAP

How cells sense and respond to mechanical stimuli remains an open question. Recent advances have identified the translocation of Yes-associated protein (YAP) between nucleus and cytoplasm as a central mechanism for sensing mechanical forces and regulating mechanotransduction. We formulate a spatiotemporal model of the mechanotransduction signalling pathway that includes coupling of YAP with the cell force-generation machinery through the Rho family of GTPases. Considering the active and inactive forms of a single Rho protein (GTP/GDP-bound) and of YAP (non-phosphorylated/phosphorylated), we study the cross-talk between cell polarization due to active Rho and YAP activation through its nuclear localization. For fixed mechanical stimuli, our model predicts stationary nuclear-to-cytoplasmic YAP ratios consistent with experimental data at varying adhesive cell area. We further predict damped and even sustained oscillations in the YAP nuclear-to-cytoplasmic ratio by accounting for recently reported positive and negative YAP-Rho feedback. Extending the framework to time-varying mechanical stimuli that simulate cyclic stretching and compression, we show that the YAP nuclear-to-cytoplasmic ratio’s time dependence follows that of the cyclic mechanical stimulus. The model presents one of the first frameworks for understanding spatiotemporal YAP mechanotransduction, providing several predictions of possible YAP localization dynamics, and suggesting new directions for experimental and theoretical studies.

Evolution of a confluent gut epithelium under cyclic stretching

The progress of food in the gastrointestinal (GI) tract is driven by a peristaltic motion generated by the muscle belt surrounding the GI tract. In turn, the response of the intestinal epithelial cells to the peristaltic stresses affects the dynamics of the epithelial structure. In this work, we study the effect of cyclic stretching (0.125 Hz, 10% strain) on the spatial organization of the intestinal epithelium using intestinal cells deposited on a flat elastomeric substrate to mimic the peristaltic motion in vitro. A confluent monolayer of Caco-2 cells is grown on a PDMS chip to probe the morphological and orientational response of the tissue to cyclic stretching. The PDMS chips are either covalently or non-covalently coated with laminin to recapitulate the basement membrane. We observe a significant orientational response where the cells rearrange their long axes perpendicular to the stretching direction for both coating conditions. The experiment is modeled by a vertex model where the cells store elastic energy with varying strain and effectively have a rotational diffusive motion through rearrangements of their shapes. The model also predicts a transition between the perpendicular orientation and orientation at an oblique angle determined by the level of the cell elastic anisotropy. It provides a general framework to study cell response and relaxation dynamics under cyclic stretching across different cell types. We also discuss potential relevance of peristalsis in determining planar cell polarity in 3D architectures.