The Impact of the Fluid-Solid Coupling Behavior of Macro and Microstructures in the Spiral Cochlea on Hearing.

The cilia of the outer hair cells (OHCs) are the key microstructures involved in cochlear acoustic function, and their interactions with lymph in the cochlea involve complex, highly nonlinear, coupled motion and energy conversions, including macroscopic fluid-solid coupling. Recent optical measurements have shown that the frequency selectivity of the cochlea at high sound levels is entirely mechanical and is determined by the interactions of the hair bundles with the surrounding fluid. In this paper, an analytical mathematical model of the spiral cochlea containing macro- and micromeasurements was developed to investigate how the phonosensitive function of OHCs' motions is influenced by the macrostructural and microstructural fluid-solid coupling in the spiral cochlea. The results showed that the macrostructural and microstructural fluid-solid coupling exerted the radial forces of OHCs through the flow field, deflecting the cilia and generating frequency-selective properties of the microstructures. This finding showed that microstructural frequency selectivity arises from the radial motions of stereocilia hair bundles and enhances the hearing of sound signals at specific frequencies. It also implied that the macrostructural and microstructural fluid-solid couplings influence the OHCs' radial forces and that this is a key factor in the excitation of ion channels that enables their activity in helping the brain to detect sound.

Temperature Dependence of Interfacial Bonding and Configuration Transition in Graphene/Hexagonal Boron Nitride Containing Grain Boundaries and Functional Groups.

The quasi-three-dimensional effect induced by functional groups (FGo) and the in-plane stress and structural deformation induced by grain boundaries (GBs) may produce more novel physical effects. These physical effects are particularly significant in high-temperature environments and are different from the behavior in bulk materials, so its physical mechanism is worth exploring. Considering the external field (strain and temperature field), the internal field (FGo and GBs) and the effect of distance between FGs and GBs on the bonding energy, configuration transition, and stress distribution of graphene/h-BN with FGo and GBs (GrO-BN-GBs) in the interface region were studied by molecular dynamics (MD). The results show that the regions linked by hydroxyl + epoxy groups gradually change from honeycomb to diamond-like structures as a result of a hybridization transition from sp2 to sp3. The built-in distortion stress field generated by the coupling effect of temperature and tension loading induces the local geometric buckling of two-dimensional materials, according the von Mises stresses and deflection theory. In addition, the internal (FGo and GBs) and external field (strain and temperature field) have a negative chain reaction on the mechanical properties of GrO-BN-GBs, and the negative chain reaction increases gradually with the increase in the distance between FGo and GBs. These physical effects are particularly obvious in high-temperature environments, and the behavior of physical effects in two-dimensional materials is different from that in bulk materials, so its physical mechanism is worth exploring.

Ang II Promotes SUMO2/3 Modification of RhoGDI1 Through Aos1 and Uba2 Subunits, and then Regulates RhoGDI1 Stability and Cell Proliferation.

PURPOSE: Ang II regulates RhoGDI1 stability and cell proliferation via SUMOylation. However, how Ang II regulates RhoGDI1 SUMOylation remains unknown. In this study, we focused on revealing the effects of E1 subunits (Aos1 and Uba2) on RhoGDI1 SUMOylation in HA-VSMC proliferation. METHODS: The expressions of Aos1, Uba2, and SUMO1 were suppressed by siRNA transfection. HA-VSMCs were treated with Ang II (100 nM) for 24 h. RhoGDI1 SUMOylation and ubiquitination were checked by co-immunoprecipitation. Cell proliferation was detected by EdU assay. RESULTS: Uba2 or Aos1 suppression significantly inhibited Ang II-induced SUMO2/3 modification of RhoGDI1 and cell proliferation, while not affecting SUMO1 modification of RhoGDI1. In addition, Uba2 or Aos1 suppression promoted RhoGDI1 ubiquitination and degradation. These indicate that both Uba2 and Aos1 are necessary for SUMO2/3 modification of RhoGDI1 that participates in cell proliferation by regulating RhoGDI1 ubiquitination and stability. Moreover, SUMO1 suppression did not affect RhoGDI1 ubiquitination and degradation and cell proliferation in Ang II-induced VSMCs, suggesting that SUMO1 modification does not participate in RhoGDI1 stability and cell proliferation. CONCLUSION: This study reveals the differences between SUMO2/3 and SUMO1 modification in regulating RhoGDI1 stability and Ang II-mediated cell proliferation. Schematic summary of roles of SUMO1 and SUMO2/3 modification of RhoGDI1 in regulating RhoGDI1 stability and cell proliferation in Ang II-treated HA-VSMCs.

Celastrol exerts anti-inflammatory effect in liver fibrosis via activation of AMPK-SIRT3 signalling.

Celastrol, a pentacyclic tritepene extracted from Tripterygium Wilfordi plant, showing potent liver protection effects on several liver-related diseases. However, the anti-inflammatory potential of celastrol in liver fibrosis and the detailed mechanisms remain uncovered. This study was to investigate the anti-inflammatory effect of celastrol in liver fibrosis and to further reveal mechanisms of celastrol-induced anti-inflammatory effects with a focus on AMPK-SIRT3 signalling. Celastrol showed potent ameliorative effects on liver fibrosis both in activated hepatic stellate cells (HSCs) and in fibrotic liver. Celastrol remarkably suppressed inflammation in vivo and inhibited the secretion of inflammatory factors in vitro. Interestingly, celastrol increased SIRT3 promoter activity and SIRT3 expression both in fibrotic liver and in activated HSCs. Furthermore, SIRT3 silencing evidently ameliorated the anti-inflammatory potential of celastrol. Besides, we found that celastrol could increase the AMPK phosphorylation. Further investigation showed that SIRT3 siRNA decreased SIRT3 expression but had no obvious effect on phosphorylation of AMPK. In addition, inhibition of AMPK by employing compound C (an AMPK inhibitor) or AMPK1α siRNA significantly suppressed SIRT3 expression, suggesting that AMPK was an up-stream protein of SIRT3 in liver fibrosis. We further found that depletion of AMPK significantly attenuated the inhibitory effect of celastrol on inflammation. Collectively, celastrol attenuated liver fibrosis mainly through inhibition of inflammation by activating AMPK-SIRT3 signalling, which makes celastrol be a potential candidate compound in treating or protecting against liver fibrosis.

Research on the correlation of mechanical properties of BN-graphene-BN/BN vertically-stacked nanostructures in the presence of interlayer sp3 bonds and nanopores with temperature.

In this study, we investigate the coupling of an internal field (defect field-sp3 bonds and nanopores) and an external field (strain and temperature). Simultaneously, we provide a design idea of hybrid materials. The mechanical properties of hybrid materials under the condition of internal and external field coupling were studied. When nanopores and sp3 bonds are considered simultaneously, we found that internal (sp3 bonds and defects) and external field (temperature and strain fields) have a negative chain reaction on the mechanical properties of BN-graphene-BN/BN vertically-stacked nanostructures, and the negative chain reaction will gradually increase with the change in parameters (such as the increase in temperature). The sp3 bonds can be regarded as a special defect, which will increase the initial strain of the system. In addition, the mechanical properties of the nanostructure, containing square nanopores in the boron nitride region are most sensitive to temperature change, relative to the nanopore in the other two regions. Atoms (around square nanopores) are more likely to overcome the binding energy and lose stability from the inherent equilibrium position, relative to that of circular nanopores.

Tetrahydroxystilbene glucoside protects against LPS-induced endothelial dysfunction via inhibiting RhoA/ROCK signaling and F-actin remodeling.

We analyzed the role of the RhoA/ROCK pathway in regulating endothelial dysfunction triggered by LPS and the protective effects of TSG (2, 3, 5, 4'-tetrahydroxystilbene-2-O-ß-D-glucoside). Human umbilical vein endothelial cells (HUVECs) were treated with LPS at different concentrations or at different time points. Cells were also pretreated with 30 µM ROCK inhibitor Y27632 for 30 min or different concentrations of TSG for 24 h and then were incubated with 100 µg/ml LPS for another 24 h. The results showed that LPS treatment significantly reduced endothelial cell viability, increased LDH release, and promoted cell necrosis in a dose- and time-dependent manner, which was dramatically inhibited by TSG pretreatment. Furthermore, LPS induction significantly enhanced the expression of RhoA, ROCK1, and ROCK2 and the activation of ROCK; these effects were reduced by TSG pretreatment. The suppression of either RhoA or ROCK significantly improved LPS-induced endothelial cell viability, and reduced cell necrosis and LDH release. In addition, LPS treatment promoted F-actin skeleton rearrangement and contraction ring formation around the plasma membrane, which was greatly inhibited by the suppression of the RhoA/ROCK pathway or TSG pretreatment. In conclusion, TSG may inhibit F-actin cytoskeletal remodeling by blocking RhoA/ROCK signaling and thus reduce LPS-induced endothelial cell toxicity.

RhoA/ROCK Pathway Activation is Regulated by AT1 Receptor and Participates in Smooth Muscle Migration and Dedifferentiation via Promoting Actin Cytoskeleton Polymerization.

BACKGROUND: In this study, we investigated the mechanism of Rho GTPases signaling on Ang II-mediated cell migration and dedifferentiation in human aortic vascular smooth muscle cells (HA-VSMCs) and an Ang II-infusion mouse model. METHODS: Cells were pretreated with different inhibitors or Ang II. Cell migration was detected by Wound healing and Transwell assay. Mice were treated with Ad-RhoA-shRNA virus or Irbesartan or fasudil and then infused with Ang II. RESULTS: Ang II treatment induced HA-VSMCs migration in a dose- and time-dependent manner and reduced the expression of VSMC contractile proteins. These effects were significantly suppressed by the inhibition of Ang II type 1 receptor (AT1 receptor), RhoA, and Rho-associated kinase (ROCK). Furthermore, Ang II treatment promoted the activation of RhoA and ROCK, which was reduced by AT1 receptor inhibition. Meanwhile, Ang II treatment induced F-actin polymerization, which was inhibited after ROCK inhibition. In mice, Ang II infusion increased VSMC migration into the neointima and reduced VSMC differentiation proteins levels, and these effects were shown to be dependent on AT1 receptor and RhoA/ROCK pathway. CONCLUSION: This study reveals a novel mechanism by which Ang II regulates RhoA/ROCK signaling and actin polymerization via AT1 receptor and then affects VSMC dedifferentiation.

A derivative of betulinic acid protects human Retinal Pigment Epithelial (RPE) cells from cobalt chloride-induced acute hypoxic stress.

The Retinal Pigment Epithelium (RPE) is a monolayer of cells located above the choroid. It mediates human visual cycle and nourishes photoreceptors. Hypoxia-induced oxidative stress to RPE is a vital cause of retinal degeneration such as the Age-related Macular Degeneration. Most of these retinal diseases are irreversible with no efficient treatment, therefore protecting RPE cells from hypoxia stress is an important way to prevent or slow down the progression of retinal degeneration. Betulinic acid (BA) and betulin (BE) are pentacyclic triterpenoids with anti-oxidative property, but little is known about their effect on RPE cells. We investigated the protective effect of BA, BE and their derivatives against cobalt chloride-induced hypoxia stress in RPE cells. Human ARPE-19 cells were exposed to BA, BE and their eighteen derivatives (named as H3H20) that we customized through replacing moieties at C3 and C28 positions. We found that cobalt chloride reduced cell viability, increased Reactive Oxygen Species (ROS) production as well as induced apoptosis and necrosis in ARPE-19 cells. Interestingly, the pretreatment of 3-O-acetyl-glycyl- 28-O-glycyl-betulinic acid effectively protected cells from acute hypoxia stress induced by cobalt chloride. Our immunoblotting results suggested that this derivative attenuated the cobalt chloride-induced activation of Akt, Erk and JNK pathways. All findings were further validated in human primary RPE cells. In summary, this BA derivate has protective effect against the acute hypoxic stress in human RPE cells and may be developed into a candidate agent effective in the prevention of prevalent retinal diseases.

ROCK inhibitors alleviate myofibroblast transdifferentiation and vascular remodeling via decreasing TGFß1-mediated RhoGDI expression.

The aim of this study was to investigate the effects of the Rho GDP dissociation inhibitor (RhoGDI) on TGFß1-mediated vascular adventitia myofibroblast transdifferentiation and on the inhibition of ROCK inhibitors. Myofibroblast transdifferentiation and vascular remodeling model were induced by TGFß1 in vitro and by balloon injury in vivo. H&E (Hematoxylin & Eosin) and PSR (Picrosirius Red) staining were used to observe vascular morphology while immunofluorescence, immunohistochemistry, and Western blotting were used to measure protein expression. Fasudil treatment reduced the expression of TGFß1, RhoGDI1, and RhoGDI2 in addition to vascular remodeling in the rat balloon injury model. TGFß1 induced the expression of α-SMA, TGFßRI, phospho-TGFßRI, RhoGDI1, RhoGDI2, and collagen secretion in human aortic adventitial fibroblasts (HAAFs). These effects were diminished after treatment with Y27632. Suppressing both RhoGDI1 and RhoGDI2 expression also blocked TGFß1-induced α-SMA expression and collagen secretion in HAAFs. Moreover, TGFßR inhibition blocked TGFß1-mediated collagen secretion and the expression of α-SMA, RhoGDI1, and RhoGDI2. These data suggested that ROCK inhibitors alleviate myofibroblast transdifferentiation and vascular remodeling by decreasing TGFß1-mediated expression of RhoGDI.

Biomarkers in VSMC phenotypic modulation and vascular remodeling.

Vascular smooth muscle cells (VSMCs) are not terminally differentiated and can change their phenotype in response to environmental cues. Phenotype switching of VSMCs to less differentiated forms has led to an underestimation of their role in the development of vascular remodeling and many vascular diseases in both humans and animal models of this disease. In recent studies, many factors, such as microRNAs, matrix metalloproteinases, integrins, oxidative stress, autophagy, have been shown to play important roles in the mechanisms of VSMC phenotypic switch and vascular remodeling. This review highlights the current knowledge regarding the molecular mechanisms of VSMC phenotypic modulation in vascular remodeling. In this review, we want to provide effective molecular targets and opportunities for the future development of new therapeutics to regulate vascular remodeling diseases.

Distinct Roles For ROCK1 and ROCK2 in the Regulation of Oxldl-Mediated Endothelial Dysfunction.

BACKGROUND/AIMS: This study used Rho-associated protein kinase (ROCK) isoform-selective suppression or a ROCK inhibitor to analyze the roles of ROCK1 and ROCK2 in regulating endothelial dysfunction triggered by oxidized low-density lipoprotein (oxLDL). METHODS: ROCK1 or ROCK2 expression in human umbilical vein endothelial cells (HUVECs) was suppressed by small interfering RNA (siRNA). HUVECs were pretreated with 30 µM Y27632 (pan ROCK inhibitor) for 30 min before exposure to 200 µg/mL oxLDL for an additional 24 h. Cell viability was determined by the MTT assay, and cell apoptosis was evaluated by the TUNEL assay. Protein expression and phosphorylation were assessed by Western blot analysis. The morphology of total and phosphorylated vimentin (p-vimentin) and the co-localization of vimentin with vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) were detected by the immunofluorescence assay. The adhesion of promonocytic U937 cells to HUVECs was observed by light microscopy. RESULTS: ROCK2 suppression or Y27632 treatment, rather than ROCK1 deletion, effectively reduced endothelial cell apoptosis and preserved cell survival. ROCK2 suppression exhibited improved vimentin and p-vimentin cytoskeleton stability and decreased vimentin cleavage by attenuating caspase-3 activity. In addition, increased p-vimentin expression induced by oxLDL was significantly inhibited by ROCK2 deletion or Y27632 treatment. In contrast, ROCK1 suppression showed no obvious effects on the vimentin cytoskeleton, but significantly regulated the expression of adhesion molecules. Endothelial ICAM-1 or VCAM-1 expression induced by oxLDL was obviously inhibited by ROCK1 suppression or Y27632 treatment. Moreover, the expression of ICAM-1 induced by oxLDL could also be reduced by ROCK2 suppression. Furthermore, ROCK2 deficiency or Y27632 treatment inhibited the redistribution of adhesion molecules and their co-localization with vimentin caused by oxLDL. These effects resulted in the significant inhibition of monocyte-endothelial adhesion induced by oxLDL. CONCLUSION: The results of this study support the novel concept that ROCK1 is involved in oxLDL-induced cell adhesion by regulating adhesion molecule expression, whereas ROCK2 is required for both endothelial apoptosis and adhesion by regulating both the vimentin cytoskeleton and adhesion molecules. Consequently, ROCK1 and ROCK2 have distinct roles in the regulation of oxLDL-mediated endothelial dysfunction.

RhoA/ROCK signaling regulates smooth muscle phenotypic modulation and vascular remodeling via the JNK pathway and vimentin cytoskeleton.

The RhoA/ROCK signaling pathway regulates cell morphology, adhesion, proliferation, and migration. In this study, we investigated the regulatory role of RhoA/ROCK signaling on PDGF-BB-mediated smooth muscle phenotypic modulation and vascular remodeling and clarified the molecular mechanisms behind these effects. PDGF-BB treatment induced the activation of RhoA, ROCK, PDGF-Rß, and the expression of PDGF-Rß in HA-VSMCs (human aortic vascular smooth muscle cells). PDGF-Rß inhibition and RhoA suppression blocked PDGF-BB-induced RhoA activation and ROCK induction. In addition, PDGF-BB-mediated cell proliferation and migration were suppressed by PDGF-Rß inhibition, RhoA suppression, and ROCK inhibition, suggesting that PDGF-BB promotes phenotypic modulation of HA-VSMCs by activating the RhoA/ROCK pathway via the PDGF receptor. Moreover, suppressing both ROCK1 and ROCK2 blocked cell cycle progression from G0/G1 to S phase by decreasing the transcription and protein expression of cyclin D1, CDK2, and CDK4 via JNK/c-Jun pathway, thus reducing cell proliferation in PDGF-BB-treated HA-VSMCs. ROCK1 deletion, rather than ROCK2 suppression, significantly inhibited PDGF-BB-induced migration by reducing the expression of vimentin and preventing the remodeling of vimentin and phospho-vimentin. Furthermore, ROCK1 deletion suppressed vimentin by inhibiting the phosphorylation of Smad2/3 and the nuclear translocation of Smad4. These findings suggested that ROCK1 and ROCK2 might play different roles in PDGF-BB-mediated cell proliferation and migration in HA-VSMCs. In addition, PDGF-BB and its receptor participated in neointima formation and vascular remodeling by promoting cell cycle protein expression via the JNK pathway and enhancing vimentin expression in a rat balloon injury model; effects that were inhibited by treatment with fasudil. Together, the results of this study reveal a novel mechanism through which RhoA/ROCK signaling regulates smooth muscle phenotypic modulation and vascular remodeling via the JNK pathway and vimentin cytoskeleton.

RGD and polyhistidine tumor homing peptides potentiates the action of human Maspin as an antineoplastic candidate.

Maspin, a non-inhibitory member of serine protease family, acts as an effective tumor suppressor by inhibiting cell inhesion and mobility. We found that exogenous wild-type rMaspin had a low effect on tumor growth in vivo. However, when the peptide Arg-Gly-Asp-hexahistidine (RGD-6His) was introduced into rMaspin, the modified rMaspin showed significant inhibitory activity in angiogenic assays and tumor-bearing animal models. Overall, our data suggested that both the RGD and hexahistidine fragments contributed to improve the fusion protein activity and polyhistidine peptide could be considered as flexible linker to separate RGD and Maspin moieties to avoid function interference. Besides, it is an efficient tag to achieve purified recombinant proteins. Furthermore, rMaspin fusing with RGD and hexahistidine could be a viable anticancer candidate.

Tetrahydroxystilbene glucoside inhibits TNF-α-induced migration of vascular smooth muscle cells via suppression of vimentin.

Vascular smooth muscle cell (VSMC) migration triggered by TNF-α is an important event that occurs during the development of atherosclerosis. 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-d-glucoside (TSG) has been proven to exhibit significant anti-atherosclerotic activity. Herein we investigate the inhibitory effect of TSG on TNF-α-induced VSMC migration and explore the underlying mechanisms. TSG pretreatment markedly inhibited TNF-α-induced cell migration. The inhibition of vimentin redistribution and expression was involved in the inhibitory effect of TSG on VSMC migration. The suppression of vimentin expression by shRNA in VSMCs significantly inhibited TNF-α-induced cell migration. Furthermore, TSG inhibited the TNF-α-induced expression of TGFß1 and TGFßR1, and phosphorylation of TGFßR1 and Smad2/3. TSG also suppressed the nuclear translocation of Smad4 induced by TNF-α. These results suggest that TSG inhibits VSMC migration induced by TNF-α through inhibiting vimentin rearrangement and expression. The interruption of TGFß/Smad pathway appears to be responsible for the suppression of TSG on vimentin expression.

Methylene Blue Attenuates iNOS Induction Through Suppression of Transcriptional Factor Binding Amid iNOS mRNA Transcription.

Inducible nitric oxide synthase (iNOS) critically contributes to the development of endotoxin-mediated inflammation. It can be induced by cytokines or endotoxins via distinct signaling pathways. Lipopolysaccharide (LPS) triggers iNOS expression through activation of the inhibitor of κB-α (IκB-α)-nuclear factor κB (NF-κB) cascade, whereas interferon-γ (IFN-γ) acts primarily through Janus kinase (JAK)-signal transducer and activator of transcription 1 (STAT1). Methylene blue (MB), an agent used clinically to treat numerous ailments, has been shown to reduce NO accumulation through suppression of iNOS activity. But it remains unclear whether MB affects iNOS induction. This knowledge gap is addressed in the present study using cultured cells and endotoxemic mice. With mouse macrophages, MB treatment prevented the LPS- and/or IFN-γ-stimulated iNOS protein expression. Real-time PCR experiments showed that iNOS mRNA transcription was robustly blocked by MB treatment. The inhibitory effect of MB on iNOS expression was confirmed in vivo in endotoxemic mice. Further analysis showed that MB had no significant effect on IκB-α degradation and NF-κB or STAT1 phosphorylation in LPS/IFN-γ-stimulated cells. The nuclear transport of active NF-κB or STAT1 was also not affected by MB treatment. But MB treatment markedly reduced the binding of NF-κB and STAT1 to their DNA elements. Chromatin immunoprecipitation assays confirmed that MB reduced NF-κB and STAT1 bindings to iNOS promoter inside the cell. These studies show that MB attenuates transcriptional factor binding amid iNOS mRNA transcription, providing further insight into the molecular mechanism of MB in disease therapy.

Attenuating effects of dihydromyricetin on angiotensin II-induced rat cardiomyocyte hypertrophy related to antioxidative activity in a NO-dependent manner.

CONTEXT: Dihydromyricetin (DMY) displays a range of biological properties. However, whether DMY attenuates cardiomyocyte hypertrophy is unknown. OBJECTIVE: To investigate whether DMY had potential therapeutic value to protect against angiotensin II (Ang II)-induced cardiomyocyte hypertrophy. MATERIALS AND METHODS: Neonatal rat cardiomyocytes were pretreated with DMY (0-320 µM) followed with Ang II (100 nM) stimulation for 24 h, and then degree of hypertrophy was evaluated by cell surface analysis. Levels of reactive oxygen species (ROS) were measured with 2',7'-dichlorfluorescein-diacetate (DCFH-DA) fluorescent staining. Antioxidative activity was evaluated by malondialdehyde (MDA) level, superoxide dismutase (SOD) activity, and total antioxidant capacity (T-AOC). Cyclic guanosine monophosphate (cGMP) was determined with a radioimmunoassay. RESULTS: Pre-incubation with DMY (20, 40, 80, and 160 µM) for 8 h, 12 h, 24 h, or 48 h decreased cell surface areas. It down-regulated mRNA expression of atrial natriuretic factor (1.95- to 1.24-fold) and ß-myosin heavy chains (3.51- to 2.32-fold), reduced levels of MDA as well as increased SOD activity and T-AOC. Expression of SOD and thioredoxin were enhanced by DMY, whereas p22(phox) and phosphorylation of mitogen-activated protein kinases were inhibited. Content of cGMP (0.54- to 0.80-fold) and phosphorylation of endothelial nitric oxide synthase at serine 1177 (0.70- to 1.05-fold) were augmented by DMY. Moreover, attenuating effect of DMY on hypertrophy was abolished when NO production was inhibited by l-NAME. CONCLUSION: Attenuating effects of DMY on Ang II-induced cardiomyocyte hypertrophy related to antioxidative activity in a NO-dependent manner.

Tetrahydroxystilbene glucoside protects against oxidized LDL-induced endothelial dysfunction via regulating vimentin cytoskeleton and its colocalization with ICAM-1 and VCAM-1.

BACKGROUND: Endothelial cell dysfunction triggered by oxidized low-density lipoprotein (oxLDL) is the main event occurring during the development of atherosclerosis. 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (TSG), an active component of the rhizome extract from Polygonum multiflorum, exhibits significant anti-atherosclerotic activity. However, the protective effects of TSG against oxLDL-induced endothelial dysfunction have not been clarified. We investigated the cytoprotective effects of TSG in human umbilical vein endothelial cells (HUVECs) and explored underlying mechanisms. METHODS AND RESULTS: TSG pretreatment markedly attenuated oxLDL-mediated loss of cell viability, release of lactate dehydrogenase (LDH), cell apoptosis, and monocyte adhesion. OxLDL increased vimentin mRNA and protein levels, vimentin cleavage, caspase-3 activation, adhesion molecules levels and their colocalization with vimentin in HUVECs. These alterations were attenuated by pretreatment with TSG. Meanwhile, TSG inhibited both the expression of TGFß1 and the phosphorylation of Smad2 and Smad3, and TSG suppressed the nuclear translocation of Smad4 induced by oxLDL. Using shRNA, oxLDL-induced cell apoptosis and monocyte adhesion were significantly inhibited by vimentin suppression in HUVECs. CONCLUSIONS: These results suggest that TSG protects HUVECs against oxLDL-induced endothelial dysfunction through inhibiting vimentin expression and cleavage, and the expression of adhesion molecules and their colocalization with vimentin. The interruption of TGFß/Smad pathway and caspase-3 activation appears to be responsible for the downregulation of TSG on vimentin expression and fragmentation, respectively.

Damage identification of piles based on vibration characteristics.

A method of damage identification of piles was established by using vibration characteristics. The approach focused on the application of the element strain energy and sensitive modals. A damage identification equation of piles was deduced using the structural vibration equation. The equation contained three major factors: change rate of element modal strain energy, damage factor of pile, and sensitivity factor of modal damage. The sensitive modals of damage identification were selected by using sensitivity factor of modal damage firstly. Subsequently, the indexes for early-warning of pile damage were established by applying the change rate of strain energy. Then the technology of computational analysis of wavelet transform was used to damage identification for pile. The identification of small damage of pile was completely achieved, including the location of damage and the extent of damage. In the process of identifying the extent of damage of pile, the equation of damage identification was used in many times. Finally, a stadium project was used as an example to demonstrate the effectiveness of the proposed method of damage identification for piles. The correctness and practicability of the proposed method were verified by comparing the results of damage identification with that of low strain test. The research provided a new way for damage identification of piles.

Genetic variants in human leukocyte antigen-DP influence both hepatitis C virus persistence and hepatitis C virus F protein generation in the Chinese Han population.

Chronic hepatitis C is a serious liver disease that often results in cirrhosis or hepatocellular carcinoma. The aim of this study was to assess the association of human leukocyte antigen-DP (HLA-DP) variants with risk of chronic hepatitis C virus (HCV) or anti-F antibody generation. We selected two single nucleotide polymorphisms (SNPs) in a region including HLA-DPA1 (rs3077) and HLA-DPB1 (rs9277534) and genotyped SNPs in 702 cases and 342 healthy controls from the Chinese population using TaqMan SNP genotyping assay. Moreover, the exon 2 of the HLA-DPA1 and HLA-DPB1 genes were amplified and determined by sequencing-based typing (SBT). The results showed that rs3077 significantly increased the risk of chronic HCV infection in additive models and dominant models (odds ratio (OR) = 1.32 and 1.53). The rs3077 also contributed to decrease the risk of anti-F antibody generation in additive models and dominant models (OR = 0.46 and 0.56). Subsequent analyses revealed the risk haplotypes (DPA1*0103-DPB1*0501 and DPA1*0103-DPB1*0201) and protective haplotypes (DPA1*0202-DPB1*0501 and DPA1*0202-DPB1*0202) to chronic HCV infection. Moreover, we also found that the haplotype of DPA1*0103-DPB1*0201 and DPA1*0202-DPB1*0202 were associated with the anti-F antibody generation. Our findings show that genetic variants in HLA-DP gene are associated with chronic HCV infection and anti-F antibody generation.

Pathogenic mechanism analysis of cochlear key structural lesion and phonosensitive hearing loss.

Due to ethical issues and the very fine and complex structure of the cochlea, it is difficult to directly perform experimental measurement on the human cochlea. Therefore, the finite element method has become an effective and replaceable new research means. Accurate numerical analysis on human ear using finite element method can provide better understanding of sound transmission and can be used to assess the influence of diseases on hearing and to treat hearing loss. In this research, a three-dimensional (3D) finite element model (FEM) of the human ear of cochlea was presented to investigate the destruction of basilar membrane (BM), round window (RW) sclerosis and perilymph fistula, the key structures of the cochlea, and analyze the effects of these abnormal pathological states in the cochlea on cochlear hearing, resulting in the changes in cochlear sense structure biomechanical behavior and quantitative prediction of the degree and harm of the disorder to the decline of human hearing. Therefore, this paper can deepen reader's understanding of the cochlear biomechanical mechanism and provide a theoretical foundation for clinical otology.