Pterostilbene upregulates MICA/B via the PI3K/AKT signaling pathway to enhance the capability of natural killer cells to kill cervical cancer cells.

Natural killer (NK) cells are triggered by the innate immune response in the tumor microenvironment. The extensive set of stimulating and inhibiting receptors mediates the target recognition of NK cells, and controls the strength of the effector reaction countering specific targeted cells. Yet, lacking major MHC (histocompatibility complex) MICA/B class I chain-related proteins on the membrane of tumor cells results in the failure of NK cell recognition and ability to resist NK cell destruction. Searching databases and molecular docking suggested that in cervical cancer, pterostilbene (3,5-dimethoxy-40-hydroxystilbene; PTS) in Vaccinium corymbosum extract could constrain PI3K/AKT signaling and improving the MICA/B expression. In flow cytometry, MTT assay, viability/cytotoxicity assay, and colony development assays, PTS reduced the development of cervical cancer cells and increased apoptosis. The quantitative real-time PCR (qRT-PCR) and a Western blot indicate that PTS controlled the cytolytic action of NK cells in tumor cells via increasing the MICA/B expression, thus modifying the anti-tumor immune response in cervical cancer.

The hysteresis damage of cold exposure on tissue and transcript levels in mice.

OBJECTIVES: Although cold stress-induced damage to the heart and thyroid has been reported, specific organ associations between the heart and thyroid with delayed injury mechanisms have not been investigated. In this study, we determined the damage time and transcript levels of a large number of genes in the heart and thyroid after cold exposure. Meanwhile, we analysed the relationship between heart and thyroid injury in human medical records to determine the association of delayed injury from cold exposure. METHODS: Mice were exposed to cold stress and hysteresis injury. Gene changes at the transcriptional level were detected using high throughput sequencing technology. The most variable genes were verified at the protein level using Western Blotting and medical records were collected and analysed. RESULTS: The damage was the most severe when the animals were allowed to recover to room temperature for 4 h after exposure to cold stress. During this process, STAT1 and ATF3 genes were acutely up-regulated. Analysis of human medical records showed the highest correlation between AST and T4 under cold stress (p = 0.0011). CONCLUSIONS: Exposure to cold increases blood level of free thyroid hormone and biomarkers of myocardial injury, as well as related mRNA levels. These changes were more pronounced after return to room temperature.

Construction of SLC16A1/3 Targeted Gallic Acid-Iron-Embelin Nanoparticles for Regulating Glycolysis and Redox Pathways in Cervical Cancer.

SLC16A1 and SLC16A3 (SLC16A1/3) are highly expressed in cervical cancers and associated with the malignant biological behavior of cancer. SLC16A1/3 is the critical hub for regulating the internal and external environment, glycolysis, and redox homeostasis in cervical cancer cells. Inhibiting SLC16A1/3 provides a new thought to eliminate cervical cancer effectively. There are few reports on effective treatment strategies to eliminate cervical cancer by simultaneously targeting SLC16A1/3. GEO database analysis and quantitative reverse transcription polymerase chain reaction experiment were used to confirm the high expression of SLC16A1/3. The potential inhibitor of SLC16A1/3 was screened from Siwu Decoction by using network pharmacology and molecular docking technology. The mRNA levels and protein levels of SLC16A1/3 in SiHa and HeLa cells treated by Embelin (EMB) were clarified, respectively. Furthermore, the Gallic acid-iron (GA-Fe) drug delivery system was used to improve its anti-cancer performance. Compared with normal cervical cells, SLC16A1/3 mRNA was over-expressed in SiHa and HeLa cells. Through the analysis of Siwu Decoction, a simultaneously targeted SLC16A1/3 inhibitor EMB was discovered. It was found for the first time that EMB promoted lactic acid accumulation and further induced redox dyshomeostasis and glycolysis disorder by simultaneously inhibiting SLC16A1/3. The gallic acid-iron-Embelin (GA-Fe@EMB) drug delivery system delivered EMB, which had a synergistic anti-cervical cancer effect. Under the irradiation of a near-infrared laser, the GA-Fe@EMB could elevate the temperature of the tumor area effectively. Subsequently, EMB was released and mediated the lactic acid accumulation and the GA-Fe nanoparticle synergistic Fenton reaction to promote ROS accumulation, thereby increasing the lethality of the nanoparticles on cervical cancer cells. GA-Fe@EMB can target cervical cancer marker SLC16A1/3 to regulate glycolysis and redox pathways, synergistically with photothermal therapy, which provides a new avenue for the synergistic treatment of malignant cervical cancer.

Biomechanical response of the pubic symphysis in lateral pelvic impacts: a finite element study.

Automotive side impacts are a leading cause of injuries to the pubic symphysis, yet the mechanisms of those injuries have not been clearly established. Previous mechanical testing of isolated symphyses revealed increased joint laxity following drop tower lateral impacts to isolated pelvic bone structures, which suggested that the joints were damaged by excessive stresses and/or deformations during the impact tests. In the present study, a finite element (FE) model of a female pelvis including a previously validated symphysis sub-model was developed from computed tomography data. The full pelvis model was validated against measured force-time impact responses from drop tower experiments and then used to study the biomechanical response of the symphysis during the experimental impacts. The FE models predicted that the joint underwent a combination of lateral compression, posterior bending, anterior/posterior and superior/inferior shear that exceeded normal physiological levels prior to the onset of bony fractures. Large strains occurred concurrently within the pubic ligaments. Removal of the contralateral constraints to better approximate the boundary conditions of a seated motor vehicle occupant reduced cortical stresses and deformations of the pubic symphysis; however, ligament strains, compressive and shear stresses in the interpubic disc, as well as posterior bending of the joint structure remained as potential sources of joint damage during automotive side impacts.

[Effects of the maca extract on the ultrastructures of mitochondria in the spinal nerve cell and exercise endurance].

OBJECTIVE: To investigate the effects of maca extract on the ultrastructures of mitochondria in the spinal nerve cell and exercise endurance. METHODS: The Wistar rats were randomly divided into 5 groups, including the control group (no swimming), the swimming group (free swimming), and 3 treatment groups treated with the maca extract at the doses of 4.0, 5.3 and 8.0 g/kg body weight. The animals in swimming and treatment groups were then for free swimming in the circulating water flow daily for 15 days. On the 16th day after swimming endurance, the spinal and muscular tissues were collected from all groups. The mitochondrial ultrastructures of the neurons of the spinal cells were observed with the projection electron microscope, and the levels of the glycogen, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and Ca2+ in muscle tissues were determined by the RIA method. RESULTS: When rats were treated with maca extract (at 4.0, 5.3, 8.0 g/kg body weight), the total swimming time and the swimming duration before sinking were increased by 19.83%, 60.28%, 77.55%, and 55.34%, 73.91%, 94.47%, respectively, compared with the simple swimming group(P<0.01), while the sinking times were decreased by 34.35%, 51.18% and 57.96%, compared with those of the swimming group. Also, the levels of SOD, GSH-Px, and muscle glycogen in three treatment groups were enhanced by 5.12%, 22.74%, 52.53%, 44.22%, 77.79%, 98.45%(P<0.01), and 35.08%, 47.83%,81.88% (P<0.01)respectively over the swimming rats without treatment, but the MDA content and the Ca2+ levels were reduced by 20.10%, 31.49% 38.72%, and 6.42%, 17.58%, 26.35%,compared with the simple swimming group(P<0.01). In addition, compared to the swimming group, the mitochondrial densities of volume (VD), surface (SD) and numbers (ND) of spinal nerve cells in rats treated with maca extract (4.0, 5.3, 8.0 g/kg body weight) were reduced by 7.79%, 18.18%, 31.17%, 16.95%, 27.34%, 43.31% and 13.51%, 23.19%, 43.15%, respectively. CONCLUSIONS: Our results demonstrated the protective effects of maca extract on the mitochondria of spinal cell and suggested that maca extract could improve the muscle antioxidant activity by increasing the levels of SOD, GSH-Px, and muscle glycogen.

Isolation and structure revision of 10-deacetyltaxinine from the seeds of the Chinese yew, Taxus mairei.

A new taxoid was isolated from the methanol extract of the seeds of Taxus mairei. Its structures were established as 2alpha,9alpha-diacetoxy-10beta-hydroxy-5alpha-cinnamoyloxytaxa-4(20), 11-dien-13-one (l0-deacetyltaxinine) on the basis of spectral analysis including (1)H-NMR, (13)C-NMR, HMQC, HMBC, NOESY, and HR-FABMS. The structure of previously reported 10-deacetyltaxinine is 9-deacetyltaxinine.

[Studies on chemical constituents in heartwood of Taxus cuspidata].

OBJECTIVE: To study the chemical constituents in the heartwood of Taxus cuspidata. METHOD: Silica gel column chromatography, preparative HPLC and preparative TLC were used to isolate and purify the chemical constituents; 1H- and 13C-NMR spectroscopic methods were used for structural identification. RESULT: Ten compounds, taxinine (1), taxusin (2), beta-sitosterol (3), 1 beta-hydroxybaccatin I (4), 2alpha, 5alpha, 10beta-triacetoxy-14beta-(2'-methyl) butanoyloxy-4 (20), 11-taxadiene (5), 2alpha, 5alpha, 10beta-triacetoxy-14beta-(2'-methyl-3'-hydroxy-butanoyloxyl-4 (20), 11-taxadiene (yunnanxane) (6), 9alpha, 10beta, 13alpha-triacetoxy-5alpha-cinnamoyltaxa-4 (20), 11-diene (7), 2-deacetoxytaxinine J (8), taxezopidine G (9), 2alpha, 7beta, 9alpha, 10beta, 13alpha-pentaacetoxyl-taxa-4 (20), 11-dien-5-ol (5-decinnamoyltaxinine J) (10), were isolated and identified from the heartwood of T. cuspidata. CONCLUSION: Three taxanes, 1 beta-hydroxybaccatin I (4), 2alpha, 5alpha, 10beta-triacetoxy-14beta-(2'-methyl-3'-hydroxy-butanoyloxy)-4 (20), 11-taxadiene (yunnanxane) (6), and 2alpha, 7beta, 9alpha, 10beta, 13alpha-pentaacetoxyltaxa-4 (20) , 11-dien-5-ol (10), were obtained from this plant for the first time.

[Studies on chemical constituents in seeds of Taxus mairei II].

OBJECTIVE: To study the chemical constituents in seeds of Taxus mairei. METHOD: Preparative HPLC, TLC and spectroscopic analyses were used to isolate and elucidate the chemical constituets in the plant. RESULT: Seven taxane diterpenoids were isolated from the seeds of T. mairei and identified as taxinine A(1), 9-deacetyltaxinine(2), 9-deacetyltaxinine E(3), 2-deacetyltaxinine(4), taxezopidine G(5), 2-deacetoxytaxinine J(6), 2-deacetoxytaxuspine C(7). CONCLUSION: Except compounds 5,6, all the compounds were obtained from seeds of this plant for the first time.

Effect of intercostal muscle and costovertebral joint material properties on human ribcage stiffness and kinematics.

Current finite element (FE) models of the human thorax are limited by the lack of local-level validation, especially in the ribcage. This study exercised an existing FE ribcage model for a 50th percentile male under quasi-static point loading and dynamic sternal loading. Both force-displacement and kinematic responses of the ribcage were compared against experimental data. The sensitivity of the model response to changes in the material properties of the costovertebral (CV) joints and intercostal muscles was assessed. The simulations found that adjustments to the CV joints tended to change the amount of rib rotation in the sagittal plane, while changes to the elastic modulus and thickness of the intercostal muscles tended to alter both the stiffness and the direction and magnitude of rib motions. This study can lend insight into the role that the material properties of these two thoracic structures play in the dynamics of the ribcage during a frontal loading condition.

Thoracic response targets for a computational model: a hierarchical approach to assess the biofidelity of a 50th-percentile occupant male finite element model.

Current finite element human thoracic models are typically evaluated against a limited set of loading conditions; this is believed to limit their capability to predict accurate responses. In this study, a 50th-percentile male finite element model (GHBMC v4.1) was assessed under various loading environments (antero-posterior rib bending, point loading of the denuded ribcage, omnidirectional pendulum impact and table top) through a correlation metric tool (CORA) based on linearly independent signals. The load cases were simulated with the GHBMC model and response corridors were developed from published experimental data. The model was found to be in close agreement with the experimental data both qualitatively and quantitatively (CORA ratings above 0.75) and the response of the thorax was overall deemed biofidelic. This study also provides relevant corridors and an objective rating framework that can be used for future evaluation of thoracic models.

Development of structural and material clavicle response corridors under axial compression and three point bending loading for clavicle finite element model validation.

Clavicle injuries were frequently observed in automotive side and frontal crashes. Finite element (FE) models have been developed to understand the injury mechanism, although no clavicle loading response corridors yet exist in the literature to ensure the model response biofidelity. Moreover, the typically developed structural level (e.g., force-deflection) response corridors were shown to be insufficient for verifying the injury prediction capacity of FE model, which usually is based on strain related injury criteria. Therefore, the purpose of this study is to develop both the structural (force vs deflection) and material level (strain vs force) clavicle response corridors for validating FE models for injury risk modeling. 20 Clavicles were loaded to failure under loading conditions representative of side and frontal crashes respectively, half of which in axial compression, and the other half in three point bending. Both structural and material response corridors were developed for each loading condition. FE model that can accurately predict structural response and strain level provides a more useful tool in injury risk modeling and prediction. The corridor development method in this study could also be extended to develop corridors for other components of the human body.

Development and validation of a subject-specific finite element model of a human clavicle.

This study aimed to develop and validate a finite element (FE) model of a human clavicle which can predict the structural response and bone fractures under both axial compression and anterior-posterior three-point bending loads. Quasi-static non-injurious axial compression and three-point bending tests were first conducted on a male clavicle followed by a dynamic three-point bending test to fracture. Then, two types of FE models of the clavicle were developed using bone material properties which were set to vary with the computed tomography image density of the bone. A volumetric solid FE model comprised solely of hexahedral elements was first developed. A solid-shell FE model was then created which modelled the trabecular bone as hexahedral elements and the cortical bone as quadrilateral shell elements. Finally, simulations were carried out using these models to evaluate the influence of variations in cortical thickness, mesh density, bone material properties and modelling approach on the biomechanical responses of the clavicle, compared with experimental data. The FE results indicate that the inclusion of density-based bone material properties can provide a more accurate reproduction of the force-displacement response and bone fracture timing than a model with uniform bone material properties. Inclusion of a variable cortical thickness distribution also slightly improves the ability of the model to predict the experimental response. The methods developed in this study will be useful for creating subject-specific FE models to better understand the biomechanics and injury mechanism of the clavicle.

Influence of mesh density, cortical thickness and material properties on human rib fracture prediction.

The purpose of this paper was to investigate the sensitivity of the structural responses and bone fractures of the ribs to mesh density, cortical thickness, and material properties so as to provide guidelines for the development of finite element (FE) thorax models used in impact biomechanics. Subject-specific FE models of the second, fourth, sixth and tenth ribs were developed to reproduce dynamic failure experiments. Sensitivity studies were then conducted to quantify the effects of variations in mesh density, cortical thickness, and material parameters on the model-predicted reaction force-displacement relationship, cortical strains, and bone fracture locations for all four ribs. Overall, it was demonstrated that rib FE models consisting of 2000-3000 trabecular hexahedral elements (weighted element length 2-3mm) and associated quadrilateral cortical shell elements with variable thickness more closely predicted the rib structural responses and bone fracture force-failure displacement relationships observed in the experiments (except the fracture locations), compared to models with constant cortical thickness. Further increases in mesh density increased computational cost but did not markedly improve model predictions. A ±30% change in the major material parameters of cortical bone lead to a -16.7 to 33.3% change in fracture displacement and -22.5 to +19.1% change in the fracture force. The results in this study suggest that human rib structural responses can be modeled in an accurate and computationally efficient way using (a) a coarse mesh of 2000-3000 solid elements, (b) cortical shells elements with variable thickness distribution and (c) a rate-dependent elastic-plastic material model.

Rib fractures under anterior-posterior dynamic loads: experimental and finite-element study.

The purpose of this study was to investigate whether using a finite-element (FE) mesh composed entirely of hexahedral elements to model cortical and trabecular bone (all-hex model) would provide more accurate simulations than those with variable thickness shell elements for cortical bone and hexahedral elements for trabecular bone (hex-shell model) in the modeling human ribs. First, quasi-static non-injurious and dynamic injurious experiments were performed using the second, fourth, and tenth human thoracic ribs to record the structural behavior and fracture tolerance of individual ribs under anterior-posterior bending loads. Then, all-hex and hex-shell FE models for the three ribs were developed using an octree-based and multi-block hex meshing approach, respectively. Material properties of cortical bone were optimized using dynamic experimental data and the hex-shell model of the fourth rib and trabecular bone properties were taken from the literature. Overall, the reaction force-displacement relationship predicted by both all-hex and hex-shell models with nodes in the offset middle-cortical surfaces compared well with those measured experimentally for all the three ribs. With the exception of fracture locations, the predictions from all-hex and offset hex-shell models of the second and fourth ribs agreed better with experimental data than those from the tenth rib models in terms of reaction force at fracture (difference <15.4%), ultimate failure displacement and time (difference <7.3%), and cortical bone strains. The hex-shell models with shell nodes in outer cortical surfaces increased static reaction forces up to 16.6%, compared to offset hex-shell models. These results indicated that both all-hex and hex-shell modeling strategies were applicable for simulating rib responses and bone fractures for the loading conditions considered, but coarse hex-shell models with constant or variable shell thickness were more computationally efficient and therefore preferred.

Response of the sternum under dynamic 3-point bending - biomed 2010.

The goal of this study was to investigate the response and failure properties of the human sternum under bending loading. Nine sternum specimens from post mortem human surrogates (n=7 male, n=2 female, age: 62.7 +/- 10.9 years) were extracted and potted in a three point bending test setup. Specimens were loaded to failure at their center points in bending at 1100 mm/s, with some specimens previously loaded in a non-failure quasi-static loading test. In two cases, the non-failure test was repeated to show that specimens were not damaged during non-failure testing. The sternum specimens were found generally to be unable to support shear forces in the anterior-posterior direction and as a result had relatively low failure moments (24.1 Nm +/- 20.1 Nm). While two of the specimens did fail in bending, the remaining specimens failed as a result of the high tensile forces introduced by the bending loads. These specimens first experienced compressive loads, and then, as the potted ends continued to rotate, tensile loads, which resulted in failure of the specimens (400-800 N).

A novel capacitance sensor for fireside corrosion measurement.

Fireside corrosion in coal-fired power plants is a leading mechanism for boiler tube failures. Online monitoring of fireside corrosion can provide timely data to plant operators for mitigation implementation. This paper presents a novel sensor concept for measuring metal loss based on electrical capacitance. Laboratory-scale experiments demonstrated the feasibility of design, fabrication, and operation of the sensor. The fabrication of the prototype sensor involved sputtering deposition of a thin metal coating with varying thickness on a ceramic substrate. Corrosion metal loss resulted in a proportional decrease in electrical capacitance of the sensor. Laboratory experiments using a muffle furnace with an oxidation environment demonstrated that low carbon steel coatings on ceramic substrate survived cyclic temperatures over 500 degrees C. Measured corrosion rates of sputtered coating in air had an Arrhenius exponential dependence on temperature, with metal thickness loss ranging from 2.0 nm/h at 200 degrees C to 2.0 microm/h at 400 degrees C. Uncertainty analysis indicated that the overall measurement uncertainty was within 4%. The experimental system showed high signal-to-noise ratio, and the sensor could measure submicrometer metal thickness changes. The laboratory experiments demonstrated that the sensor concept and measurement system are capable of short term, online monitoring of metal loss, indicating the potential for the sensor to be used for fireside corrosion monitoring and other metal loss measurement.

Experimental and computational investigation of human clavicle response in anterior-posterior bending loading - biomed 2009.

Clavicle fractures are common injuries in three-point belt restrained occupants involved in frontal and lateral car collisions. Therefore, better understanding of clavicle loading which occurs during an impact and clavicle structural/material properties could help in the optimization of seatbelt restraint systems. Six clavicles from three post mortem human subjects were tested in a three point -bending test setup with pinned-pinned boundary conditions. The clavicle extremities were fixed into potting cups which were able to rotate freely about a single rotational axis (inferior-superior axis) and then, were loaded in the anterior-posterior direction by an impactor at the middle shaft level. Two tests were performed on each clavicle: a) A noninjurious quasi-static test (1mm/s impactor rate) up to approximately 400 N b) A dynamic test (1m/s impactor rate) to failure. Reaction forces and moments were measured at both clavicle supports. The results showed an averaged clavicle stiffness of 211+/-30 N/mm in the quasi-static tests. Concerning the dynamic tests to failure, the average maximum force was 1159+/-133 N, the average maximum deflection was 4.9+/-0.7 mm, the average clavicle stiffness was 237+/-64 N/mm, and the average maximum strain was 1+/-0.2%. The most common failure location was the middle third of the bone, which is consistent with literature data. A finite element model of a human clavicle was developed and used to simulate the tests. The optimization of the elastic parameters of clavicle finite element model during the simulations of quasi-static tests provided an 8.1 GPa Young modulus for cortical bone. In addition to providing validation data for computational human models and dummies, the results of this study may lend insight into the development of advanced belt restraint systems.

Finite element model development of a child pelvis with optimization-based material identification.

A finite element (FE) model of a 10-years-old child pelvis was developed and validated against experimental data from lateral impacts of pediatric pelves. The pelvic bone geometry was reconstructed from a set of computed tomography images, and a hexahedral mesh was generated using a new octree-based hexahedral meshing technique. Lateral impacts to the greater trochanter and iliac wing of the seated pelvis were simulated. Sensitivity analysis was conducted to identify material parameters that substantially affected the model response. An optimization-based material identification method was developed to obtain the most favorable material property set by minimizing differences in biomechanical responses between experimental and simulation results. This study represents a pilot effort in the development and validation of age-dependent musculoskeletal FE models for children, which may ultimately serve to evaluate injury mechanisms and means of protection for the pediatric population.

A biomechanical study of periacetabular defects and cement filling.

Periacetabular bone metastases cause severe pain and functional disability in cancer patients. Percutaneous acetabuloplasty (PCA) is a minimally invasive, image-guided procedure whereby cement is injected into lesion sites. Pain relief and functional restoration have been observed clinically; however, neither the biomechanical consequences of the lesions nor the effectiveness of the PCA technique are well understood. The objective of this study was to investigate how periacetabular lesion size, cortex involvement, and cement modulus affect pelvic bone stresses and strains under single-legged stance loading. Experiments were performed on a male cadaver pelvis under conditions of intact, periacetabular defect, and cement-filling with surface strains recorded at three strain gage locations. The experimental data were then employed to validate three-dimensional finite element models of the same pelvis, developed using computed tomography data. The models demonstrated that increases in cortical stresses were highest along the posterior column of the acetabulum, adjacent to the defect. Cortical stresses were more profoundly affected in the presence of transcortical defects, as compared to those involving only trabecular bone. Cement filling with a modulus of 2.2 GPa was shown to restore cortical stresses to near intact values, while a decrease in cement modulus due to inclusion of BaSO(4) reduced the restorative effect. Peak acetabular contact pressures increased less than 15% for all simulated defect conditions; however, the contact stresses were reduced to levels below intact in the presence of either cement filling. These results suggest that periacetabular defects may increase the vulnerability of the pelvis to fracture depending on size and cortical involvement and that PCA filling may lower the risk of periacetabular fractures.

1-deoxypaclitaxel and abeo-taxoids from the seeds of Taxus mairei.

A new paclitaxel derivative and two new 2(3-->20)-abeo-taxoids were isolated from a methanol extract of the seeds of Taxus mairei, and their structures were established as 1-deoxypaclitaxel (1), 7beta,10beta-diacetoxy-2alpha,5alpha,13alpha-trihydroxy-2(3-->20)-abeo-taxa-4(20),11-dien-9-one (2), and 2alpha,13alpha-diacetoxy-10beta-hydroxy-2(3-->20)-abeo-taxa-4(20),6,11-triene-5,9-dione (3) on the basis of spectroscopic data analysis. Taxane 1 is the first example of a paclitaxel analogue with a C-1beta hydrogen substituent. Taxane 3 is an 2(3-->20)-abeo-taxane with a rare C-5 ketone and C-6 double bond.