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Xin-Ji-Er-Kang (XJEK) is traditional Chinese formula presented excellent protective effects on several heart diseases, but the potential components and targets are still unclear. The aim of this study is to elucidate the effective components of XJEK and reveal its potential mechanism of cardioprotective effect in myocardial ischemia-reperfusion (MIR) injury.Firstly, the key compounds in XJEK, plasma and heart tissue were analyzed by high resolution mass spectrometry. Bioinformatics studies were also involved to disclose the potential targets and the binding sites for the key compounds. Secondly, to study the protective effect of XJEK on MIR injury and related mechanism, mice subjected to MIR surgery and gavage administered with XJEK for 6 weeks. Cardiac function parameters and apoptosis level of cardiac tissue were assessed. The potential mechanism was further verified by knock down of target protein in vitro.Pharmacokinetics studies showed that Sophora flavescens alkaloids, primarily composed with matrine, are the key component of XJEK. And, through bioinformatic analysis, we speculated JAK2 could be the potential target for XJEK, and could form stable hydrogen bonds with matrine. Administration of XJEK and matrine significantly improved heart function and reduced apoptosis of cardiomyocytes by increasing the phosphorylation of JAK2 and STAT3. The anti-apoptosis effect of XJEK and matrine was also observed on AC16 cells, and could be reversed by co-treatment with JAK2 inhibitor AG490 or knock-down of JAK2.XJEK exerts cardioprotective effect on MIR injury, which may be associated with the activation of JAK2/STAT3 signaling pathway.

Surface-enhanced Raman spectroscopy (SERS) has been widely applied in many fields as a sensitive vibrational fingerprint technique. However, SERS faces challenges in quantitative analysis due to the heterogeneity of hot spots. An internal standard (IS) strategy has been employed for correcting the variation of hot spots. However, the method suffers from limitations due to the competitive adsorption between the IS and the target analyte. In this work, we combined the IS strategy with the 3D hybrid nanostructures to develop a bifunctional SERS substrate. The substrate had two functional units. The bottom self-assembly layer consisted of Au@IS@SiO

Cholesterol gallstone (CG) is a common, frequent biliary system disease in China, with a complex and multifactorial etiology. Declined gallbladder motility reportedly contributes to CG pathogenesis. Furthermore, interstitial Cajal-like cells (ICLCs) are reportedly present in human and guinea pig gallbladder tissue. ICLCs potentially contribute to the regulation of gallbladder motility, and aberrant conditions involving the loss of ICLCs and/or a reduction in its pacing potential and reactivity to cholecystokinin may promote CG pathogenesis. This review discusses the association between ICLCs and CG pathogenesis and provides a basis for further studies on the functions of ICLCs and the etiologies of CG.

Gold-palladium two-component nanostructures have attracted extensive attentions due to their synergetic coupling between optical and catalytic properties, and have shown important application potential in solar energy conversion and storage, photoelectric catalysis, photoelectric devices, biological imaging, medical diagnosis and treatment and other fields. However, the synthesis of gold-palladium nanomaterials with synergistic properties still face great challenges. The reason is that the palladium can epitaxially overgrow on the Au seed surface due to the lattice match. It means that the growth of palladium on Au seeds often leads to symmetric core-shell gold-palladium structures (Au@Pd). The Pd shell can greatly prevent the plasmonics of Au core by blocking light and deteriorating the surface plasmon resonance performance through the interface damping. One strategy is to grow ultrathin Pd shell (with thickness smaller than 5 nm) to realize the synergistic coupling between plasmonics and catalysis. The other more challenging way is to break the structural symmetry to prepare Janus-type gold-palladium asymmetric nanostructures. The asymmetric spatial arrangement of the two components within one nanoparticle will significantly improve the synergistic coupling effect. In this study, two methods for preparation of gold-palladium nanostructures in solution and on solid surface respectively were developed. The concave cuboid and dumbbell-shaped nanostructures with asymmetric palladium distribution on Au nanorods were prepared by adjusting the concentration of copper ions in the Au-nanorod seed solution for the first time. It was demonstrated that copper ions can compete with CTAB to adsorb on the surface of Au nanorods, which can regulate the interfacial energy of palladium deposition on the surface of Au nanorods. Therefore, the changing of gold-palladium interfacial energy caused the growth mode to be gradually transformed from the epitaxial growth to discontinuous patch on the seed surface, leading to the generation of an array of gold-palladium asymmetric nanostructures, including gold-palladium concave cuboidal nanoparticles and dumbbell-shaped nanoparticles, where palladium was mainly grown on the two ends of Au nanorods. Besides the solution-mediated synthesis, we also developed substrate-based techniques combined colloidal chemistry to prepare gold-palladium nanostructures. This method combined the merits of substrate-based self-assembly techniques and powerful colloidal chemistry to prepare a rich class of nanostructure architectures with unique properties. The monolayer of Au-octahedron was prepared at an air-solid interface and then transfer to a silicon surface. The substrate-immobilized self-assembly monolayer was used as seeds to induce the growth of palladium by dipping into the growth solution. A series of gold-palladium nanostructures with different palladium loadings were prepared on the solid surface with a monolayer of Au-octahedron as seeds by controlling the palladium content in the growing solution. Because of the steric hindrance effect of solid surface, palladium is preferred to nucleate on the surface of Au octahedron away from solid base. Therefore, the fabricated gold-palladium nanostructures have asymmetric spatial distribution of the gold and palladium components as was demonstrated by SEM and XRD analysis. Through the study of the SERS performance of the gold-palladium nanostructures under different palladium loadings, the surface-supported gold-palladium nanostructures with optimal SERS performance was obtained. The catalytic hydrogenation of p-nitrothiophenol into p-aminothiophenol through the optimal gold-palladium asymmetric nanostructure was monitored by in - situ SERS. The experimental results showed that the asymmetric palladium nanostructures prepared in this study realized the synergistic coupling between catalytic and SERS properties. It is expected that the method to synthesize asymmetric nanostructure developed here will play an important role in the field of heterogeneous catalysis.

BACKGROUND Loss and/or dysfunction of interstitial Cajal-like cells (ICLCs) in the gallbladder may promote cholesterol gallstone formation by decreasing gallbladder motility. AIM To study the effect of cholesterol on the proliferation and apoptosis of ICLCs from guinea pig gallbladders. METHODS Guinea pig gallbladder ICLCs were isolated and cultured in vitro. The cells were exposed to cholesterol solutions at different concentrations (0, 25, 50, and 100 mg/L) for 24 h. Then, cell proliferation was detected by the CCK-8 method and the apoptosis rate was detected by flow cytometry. Further, the expression of the c-Kit protein was detected by Western blot and the expression level of c-Kit mRNA in the cells was detected by real-time quantitative PCR. RESULTS After ICLCs were cultured with cholesterol at concentrations of 25, 50, and 100 mg/L, the proliferation rates decreased significantly (P < 0.05), whereas the apoptosis rates increased significantly (P < 0.05). Moreover, the expression of c-Kit protein and mRNA decreased significantly (P < 0.05). CONCLUSION High cholesterol concentrations can inhibit the proliferation of ICLCs and promote apoptosis. This decrease in the ICLC proliferation rate might be caused by the inhibition of the stem cell factor/c-Kit signaling pathway.

Copper is a trace element necessary for the normal functioning of organisms, but excessive copper contents may be toxic to the heart. The goal of this study was to investigate the role of excessive copper accumulation in mitochondrial damage and cell apoptosis inhibition. In vivo, the heart copper concentration and cardiac troponin I (c-TnI) and N-terminal forebrain natriuretic peptide (NT-pro-BNP) levels increased in the copper-laden model group compared to those of the control group. Histopathological and ultrastructural observations revealed that the myocardial collagen volume fraction (CVF), perivascular collagen area (PVCA) and cardiomyocyte cross-sectional area (CSA) were markedly elevated in the copper-laden model group compared with the control group. Furthermore, transmission electron microscopy (TEM) showed that the mitochondrial double-layer membrane was incomplete in the copper-laden model groups. Furthermore, cytochrome C (Cyt-C) expression was downregulated in mitochondria but upregulated in the cytoplasm in response to copper accumulation. In addition, Bcl-2 expression decreased, while Bax and cleaved caspase-3 levels increased. These results indicate that copper accumulation in cardiomyocyte mitochondria induces mitochondrial injury, and Cyt-C exposure and induces apoptosis, further resulting in heart damage.

Background Xin-Ji-Er-Kang (XJEK) as a herbal formula of traditional Chinese medicine (TCM) has shown the protective effects on myocardial function as well as renal function in mouse models of myocardial infarction. Hypothesis/Purpose We investigated the effects of XJEK on cardiovascular- and renal-function in a heart failure mouse model induced by high salt (HS) and the associated mechanisms. Study design For the purpose of assessing the effects of XJEK on a hypertensive heart failure model, mice were fed with 8% high salt diet. XJEK was administered by oral gavage for 8 weeks. Cardiovascular function parameters, renal function associated biomarkers and XJEK's impact on renin-angiotensin–aldosterone system (RAAS) activation were assessed. To determine the underlying mechanism, the calpain1/junctophilin-2 (JP2)/sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) pathway was further studied in AC16 cells after angiotensin II-challenge or after calpastatin small interfering RNA (siRNA) transfection. Results Mice on HS-diet exhibited hypertensive heart failure along with progressive kidney injury. Similar to fosinopril, XJEK ameliorated hypertension, cardiovascular-and renal- dysfunction in mice of HS-diet group. XJEK inhibited HS-induced activation of RAAS and reversed the abnormal expression pattern of calpain1and JP2 protein in heart tissues. XJEK significantly improved cell viability of angiotensin II-challenged AC16 cells. Moreover, XJEK's impact on calpain1/JP2 pathway was partly diminished in AC16 cells transfected with calpastatin siRNA. Conclusion XJEK was found to exert cardiovascular- and renal protection in HS-diet induced heart failure mouse model. XJEK inhibited HS-diet induced RAAS activation by inhibiting the activity and expression of calpain1 and protected the junctional membrane complex (JMC) in cardiomyocytes.

To investigate the effect of interstitial Cajal-like cells (ICLCs) on contraction of gallbladder muscle strips; and to analyze the changes of ICLCs during cholesterol gallstone formation in guinea pig.The cholesterol gallstone animal model was made by feeding guinea pig with high cholesterol diet (HCD). In vitro isolated gallbladder muscle strips were prepared. Gallbladder motility was assessed by the contraction frequency and amplitude of slow wave in response to CCK-8. The alteration in ICLC density was estimated by using immunohistochemistry. The expression of c-kit and stem cell factor (SCF) were determined.The amplitude and frequency of slow wave was significantly lower in gallbladder muscle strips with the impaired ICLCs. And it is correlated with the decreased contractile response to CCK-8. In HCD guinea pig, the ICLC density and bile flow in response to CCK-8 were remarkably decreased. The results indicated that gallbladder ICLCs can create slow wave potential, and also get involved in the regulation of CCK-8 induced gallbladder smooth muscle motility. In the process of cholesterol gallstone formation, ICLC density clearly decreased. This further impaired gallbladder motility. The decrease in ICLC density may result from decreased expression of c-kit and SCF during cholesterol gallstone formation.

The aim of this study was to investigate the cellular and molecular mechanisms of declined intestinal transit (IT) function in the cholesterol gallstone (CG) formation process. Forty guinea pigs were divided into an experimental group (EG) and a control group (CoG), and the reverse transcription-polymerase chain reaction (RT-PCR) was performed for the analysis of c-kit and stem cell factor (scf) mRNA expression in the small bowel. In addition, immunofluorescence staining and confocal laser microscopy were performed for the observation of the changes in the number of interstitial cells of Cajal (ICCs) in the terminal ileum of each group. RT-PCR showed that, compared with the CoG, the intestinal c-kit and scf mRNA expression levels in the EG were significantly decreased; the average positive area of ICCs in the ileum in the EG was also significantly reduced. During the diet-induced CG formation procedure, the c-kit and scf mRNA expression levels in the small intestine decreased and the number of ICCs decreased. Inhibition of the c-kit/scf pathway may be involved in the declined IT function during the CG formation process.

In this paper, one Automatic Tensioning Device which can realize multi-time tensioning is designed. Through structural designing and motion designing to get the main structure, through initially calculating to get its each part parameters, through ANSYS optimization designing to get its minimum size parameters of each device under the strength conditions, to achieve its goal to optimize the quality of the lightest. Main components of Automatic Tensioning Device are selected as the research object, establishing the optimal equation, using the optimization module of Goal Driven Optimization of ANSYS to optimize its size. The results show that with the strength requirement contented, Automatic Tensioning Device can be optimized by optimizing the Wall Panel.

To observe the reversion of multi-drug resistance by proteasome inhibitor bortezomib in K562/DNR cell line and to analyze the possible mechanism of reversion of multidrug-resistance.MTT method was used to determine the drug resistance of K562/DNR cells and the cellular toxicity of bortezomib. K562/DNR cells were cultured for 12 hours, 24 hours and 36 hours with 100 μg/ml DNR only or plus 4 μg/L bortezomib. The expressions of NF-κB, IκB and P-gp of K562/DNR were detected with Western blot method, the activity of NF-κB was tested by ELISA method and the apoptosis rate was observed in each group respectively.The IC50 of DNR on cells of K562/S and K562/DNR groups were 1.16 μg/ml and 50.43 μg/mL, respectively. The drug-resistant fold was 43.47. The IC10 of PS-341 on Cell strain K562/DNR was 4 μg/L. Therefore, 4 μg/L was selected as the concentration for PS-341 to reverse drug-resistance in this study. DNR induced down-regulation of IκB expression, up-regulation of NF-κB and P-gp expression. After treatment with PS-341, a proteasome inhibitor, the IκB degradation was inhibited, IκB expression increased, NF-κB and P-gp expression decreased in a time dependent manner. Compared to DNR group, the NF-κB p65 activity of DNR+PS-341 group was decreased. Compared to corresponding DNR group, DNR induced apoptosis rate increases after addition of PS-341 in a time dependent manner.Proteasome inhibitor bortezomib can convert the leukemia cell drug resistance. The mechanism may be that bortezomib decreases the degradation of IκB and the expression of NF-κB and P-gp, therefore induces the apoptosis of multi-drug resistant cells.

C/EBP beta (CCAAT/enhancer-binding protein beta) is an important transcription factor involved in cellular proliferation and differentiation. Overexpression of the full-length C/EBP beta protein results in cellular growth arrest and apoptosis. Using a nonviral liposome as carrier, we delivered the full-length C/EBP beta expression plasmid, pCN, into nude mice bearing CW-2 human colon cancer tumors via tail vein. Southern blots revealed that the major organs and tumors were transfected. Experimental gene therapy showed that a strong suppression of tumor growth was observed in the pCN-treated mice, and such suppression was due to the overexpression of C/EBP beta, leading to the increased apoptosis in tumors of pCN-treated mice. No apparent toxic effects of pCN/liposome complex were observed in the animals. Thus, C/EBP beta has tumor suppression effect in vivo and may be used in gene therapy for cancers.

Transfection of cDNA in 3'untranslated region of human nuclear factor for interleukin-6 (NF-IL6 3'UTR) induced tumor suppression in a human hepatoma cell line. cDNA array analysis was used to reveal changes in gene expression profile leading to tumor suppression The results indicate that this suppression was not due to activation of dsRNA-dependent protein kinase, nor to inactivation of oncogenes; rather, all the changes in expression of known genes, induced by NF-IL6 3'UTR cDNA may be ascribed to the suppression of cellular malignancy. Therefore, our results imply that this 3'untranslated region may have played role of a regulator of gene expression profile.

To study the changes of interstitial cells of Cajal (ICCs) and expression of c-kt and scf mRNA in terminal ileum tissue during cholesterol gallstone formation in guinea pigs fed on high cholesterol diet, forty guinea pigs were divided into the gallstone group and the control group. The animals in the gallstone group were fed on a high cholesterol diet (HCD), while those in the control group fed on a standard diet (StD). The guinea pigs were sacrificed at the 8th week. The expression of c-kit and scf in terminal ileum were determined by RT-PCR and the morphological characteristics and number of ICCs were observed and calculated by using immunohistochemistry. RT-PCR showed that, compared with the control group, the c-kit and scf mRNA expression levels in the gallstone group were significantly declined. In the animal assay, the decreased number of ICCs was present obviously in the gallstone group. We concluded from the study that decreased number of ICCs, decreased expression of c-kit and scf in terminal ileum are present in guinea pigs fed on high cholesterol diet. The c-kit/scf pathway inhibition might be involved in the decline of intestinal transit function during cholesterol gallstone formation.

The aim of this study was to investigate the effect of proteasome inhibitor bortezomib on the expression of ERK, JNK, and P38 in daunorubicin (DNR)-resistant K562 cells and its mechanism. MTT method was used to determine the drug-resistant K562 cells and the cellular toxicity of bortezomib; Western blot was used to detect the expression of protein ERK, JNK and P38 in K562 cells after treatment with 100 nmol/L DNR alone or combined with 1 nmol/L and 10 nmol/L bortezomib for 36 hours. Flow cytometry assay was used to detect the apoptosis rate in each group cells. The results indicated that the expression of ERK and P38 were significantly suppressed (p0.05) and the expression of JNK was significantly enhanced (p0.05) in the cells treated by DNR combined with bortezomib. It is concluded that bortezomib can decrease the expressions of protein ERK and P38 and enhance the expression of JNK, the bortezomib reverses the cellular drug-resistance and promote cell apoptosis through MAPK pathway.

The study was aimed to investigate the effects of bortezomib (BTZ) on the expression of ERK, JNK and P38 in daunorubicin (DNR)-resistant K562 cells (K562/DNR) and to clarify the molecular mechanism of BTZ in reversing the drug-resistance in leukemic cells. The K562/DNR cells and the cellular toxicity of BTZ was determined by MTT, then 4 µg/L of BTZ was chosen to do the experiment. The expression of ERK, JNK, p38 and P-gp of K562/DNR cells treated with DNR only or DNR combined with BTZ for 12, 24 and 36 hours was detected by Western blot. The apoptosis rate in each group was assayed by flow cytometry. The results showed that as compared with DNR group, the expression of P-ERK, P-P38 and P-gp was significantly suppressed (p0.05) and the expression of P-JNK was significantly enhanced (p0.05) in the cells treated with DNR combined with BTZ. There was no change in the expression of total ERK, P38 and JNK. The effect increased with the prolonging of time. Meanwhile, the apoptosis rate in cells treated with DNR combined with BTZ increased compared with DNR only. It is concluded that the BTZ can reverse the drug resistance in K562/DNR cells by MAPK signaling pathway and increase the apoptosis of leukemic cells. The effect shows the characteristics of time-dependent manner.

The presence of bacteria in bile is an important factor in the formation of pigment gallstones. The bile of healthy people is sterile and bacteria in the biliary system come from endogenous infection from the gut. Yet, the route of bacterial translocation into the bile duct is still unclear. Theoretically, two routes exist: one is through the intestinal barrier and the other is by direct reflux from the sphincter of Oddi. This study was undertaken to explore the relationship between the effectiveness of intestinal barrier and the formation of pigment gallstones in hamsters.Thirty-two hamsters were divided into an experimental and a control group, with 16 hamsters in each group. A low protein and high cellulose diet was given for 6 weeks to induce the formation of pigment gallstones in the experimental group (PS) and a normal diet was given to the control group (CON). Morphological changes, changes in the levels of serum endotoxin and diamine oxidase, and changes in the numbers of B lymphocytes, plasma cells and secretory immunoglobin A (sIgA) in the intestinal mucosa were assessed after 6 weeks.Four hamsters died during lithogenesis and body weight decreased in the PS group. Pigment gallstones were found in 11 hamsters at the end of the experiment, giving a lithogenesis rate of 91.67%. The serum endotoxin level before and after gallstone formation in the PS group was 0.2960+/-0.1734 U/ml and 8.2964+/-4.6268 U/ml, respectively (P0.05). The blood diamine oxidase level before and after gallstone formation in the PS group was 2.6333+/-0.8037 U/ml and 3.3642+/-0.9545 U/ml, respectively (P0.05). The numbers of B lymphocytes, plasma cells and sIgA in the intestinal mucosa in the PS group were 71.56+/-2.89, 68.65+/-2.09 and 27.56+/-1.07, respectively, and were significantly decreased compared with the corresponding values in the CON group (94.25+/-3.69, 93.47+/-3.98 and 42.57+/-1.96, respectively, P0.05).A low protein and high cellulose diet can markedly reduce intestinal barrier function and facilitate the formation of pigment gallstones. The decrease of intestinal barrier function may take part in the formation of pigment gallstones.

The effect of "intestinal transit" has become a new field of interest in the study of the pathogenesis of cholesterol gallstones. This study was undertaken to further test this notion and ascertain the relationship between impaired intestinal transit function and cholesterol gallstones.A total of 64 hamsters were divided into 2 groups, experimental and control. Each was subdivided into 4 subgroups for sacrifice at different time. A high-cholesterol diet and a standard diet were fed to each group. The geometric center, which represents the intestinal transit function was calculated.The growth of all hamsters was normal. Cholesterol gallstones were found in 2 hamsters at the end of the 4th week. The geometric center values for the experimental and control groups were 2.3891+/-0.3923 vs. 2.7730+/-0.5283, at the end of week 3; 1.8148+/-0.4312 vs. 3.2294+/-1.1613 at week 4; 1.8451+/-0.3700 vs. 2.9075+/-0.3756 at week 5; and 1.8025+/-0.3413 vs. 3.0920+/-0.5622 at week 6.A high cholesterol diet can significantly reduce the intestinal transit function and facilitate the formation of cholesterol gallstones.

Background: NF-κb is a transcription factor in eukaryotic cells that binds to inhibitor protein κB (IκB) in the cytoplasm. Once stress responses occur, IκB is phosphorylated and degraded by the proteasome. Upon dissociation with IκB, activated NF-κB enters the nucleolus and induces the expression of mdr1. MDR-1 encodes the P-glycoprotein (P-gp), which is an ATP-dependent drug efflux pump which lowers intracellular drug concentration resulting in drug resistance. Bortezomib (VELCADE®) is an anti-cancer drug that is a first-in-class proteasome inhibitor and is indicated in treatment of multiple myeloma (MM) patients. However, its role in myeloid leukemia therapy, is still being evaluated. In this study, we observed the effect of bortezomib on the expression of NF-κB AIκB and P-gp in daunorubicin (DNR) resistant cell line K562/DNR, a myeloid cell line; we also discussed the molecular mechanism and functional characteristics of reversing resistance by bortezomib and provided experimental basis to overcome multi-drug resistance in myeloid leukemia. Methods: Resistance of cell line will be evaluated by MTT; After treating K562/DNR for 36h with DNR (100‚•g/ml) alone or combined with bortezomib at different concentration (0.4 mg/L A4 mg/L or 40 mg/L), the expression levels of NF-κB AIκB and P-gp, the activity of NF-κB p65 and the apoptosis rates of cells will be measured by Western blot followed by ELISA and flow cytometry, respectively. After treating K562/DNR for 12h, 24h and 36h with DNR (100 mg/ml) alone or combined with bortezomib (4 mg/L), the same indexes will also be measured; Statistical analysis: With SPSS software, the two group means were compared by t-test and the two sample rates were compared by χ2-test. Results: After treating K562/DNR for 36h with DNR alone or combined with bortezomib at different concentrations, apoptosis rates were measured by flow cytometry. As a single agent, botezomib at concenration of 0.4 mg/L and 4 mg/L did not result in an increase in the rate of apoptosis. However, an increase in apoptosis rate was observed with bortezomib 40 mg/L. In contrast, a combination of DNR and bortezomib resulted in significant increases in apoptosis rate at all doses of bortezomib. Moreover, a dose response was observed. After treating K562/DNR for 12h A24h and 36h with DNR alone or combined with bortezomib, we utilized Western blot to assess the intracellular level of NF-κB AP-gp and IκB. Compared with negative control, DNR as a single agent increased the level of NF-κB AP-gp and decreased the level of IκB. After the addition of bortezomib, the level of NF-κB AP-gp decreased while IκB level increased; furthermore, the effect increased by prolonging the treating time. Conclusion: Based on our observations bortezomib may reverse drug resistance of K562/DNR cell line to DNR. Under optimized conditions, the effect of reversing resistance follows a dose-dependent manner and a time-dependent manner and increases with increasing the concentrations of bortezomib and duration of cellular exposure.