P-glycoprotein (P-gp)-mediated drug-drug interactions are important factors causing adverse effects of drugs in clinical use. The aim of this study was to determine whether trantinterol (also known as SPFF), a novel ?2-adrenoceptor agonist, was a P-gp inhibitor or substrate. The results showed that trantinterol was not a substrate of P-gp but increased rhodamine 123 (Rho 123) uptake by MDCK-MDR1 cells and decreased the efflux transport of both Rho 123 and cyclosporine A (CsA) in bi-directional transport studies across MDCK-MDR1 cell monolayers. This suggested that trantinterol was a P-gp inhibitor but not a P-gp substrate. The mechanism of inhibition was investigated in the P-gp-Glo assay system where it was found that trantinterol inhibited P-gp ATPase activity in a dose-dependent manner. A subsequent study using the antibody binding assay with the conformation-sensitive P-gp-specific antibody UIC2 confirmed that trantinterol decreased UIC2 binding at 10 ?M in contrast to the competitive inhibitor, verapamil. This suggested that trantinterol was a non-competitive inhibitor of P-gp. Finally, a pharmacokinetic study in rat showed that trantinterol significantly increased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of digoxin and paclitaxel (PAC), and the Cmax of cyclosporine A (CsA). In summary, trantinterol is a potent non-competitive P-gp inhibitor which may increase the bioavailability of other P-gp substrate drugs co-administered with it.
The attrition rate of functioning allografts beyond the first year has not improved despite improved immunosuppression, suggesting that nonimmune mechanisms could be involved. Notably, glomerulopathies may account for about 40% of failed kidney allografts beyond the first year of engraftment, and glomerulosclerosis and progression to ESRD are caused by podocyte depletion. Model systems demonstrate that nephrectomy can precipitate hypertrophic podocyte stress that triggers progressive podocyte depletion leading to ESRD, and that this process is accompanied by accelerated podocyte detachment that can be measured in urine. Here, we show that kidney transplantation "reverse nephrectomy" is also associated with podocyte hypertrophy and increased podocyte detachment. Patients with stable normal allograft function and no proteinuria had levels of podocyte detachment similar to levels in two-kidney controls as measured by urine podocyte assay. By contrast, patients who developed transplant glomerulopathy had 10- to 20-fold increased levels of podocyte detachment. Morphometric studies showed that a subset of these patients developed reduced glomerular podocyte density within 2 years of transplantation due to reduced podocyte number per glomerulus. A second subset developed glomerulopathy by an average of 10 years after transplantation due to reduced glomerular podocyte number and glomerular tuft enlargement. Reduced podocyte density was associated with reduced eGFR, glomerulosclerosis, and proteinuria. These data are compatible with the hypothesis that podocyte depletion contributes to allograft failure and reduced allograft half-life. Mechanisms may include immune-driven processes affecting the podocyte or other cells and/or hypertrophy-induced podocyte stress causing accelerated podocyte detachment, which would be amenable to nonimmune therapeutic targeting.
The rotation invariance of the classical disc-based moments, such as Zernike moments (ZMs), pseudo-Zernike moments (PZMs), and orthogonal Fourier-Mellin moments (OFMMs), makes them attractive as descriptors for the purpose of recognition tasks. However, less work has been performed for the generalization of these moment functions. In this paper, four general forms are developed to obtain a class of disc-based generalized radial polynomials that are orthogonal over the unit circle. These radial polynomials are scaled to ensure numerical stability, and some useful properties are discussed for potential applications they could be used in. Then, these scaled radial polynomials are used as kernel functions to construct a series of unit disc-based generalized orthogonal moments (DGMs). The variation of parameters in DGMs can form various types of orthogonal moments: generalized Zernike moments (GZMs), generalized pseudo-Zernike moments (GPZMs), generalized Fourier- Mellin moments (GOFMMs), and so on. The classical ZMs, PZMs and OFMMs correspond to a special case of these three generalized moments for which the free parameter = 0. Each member of this family will share some excellent properties for image representation and recognition tasks, such as orthogonality and rotation invariance. Additionally, we have also developed two algorithms, the so-called m-recursive and n-recursive methods for the computation of these proposed radial polynomials in order to improve the numerical stability. Experimental results show that the proposed methods are superior to the classical disc-based moments in terms of image representation capability and classification accuracy.
The primary function of Leydig cells is to secrete testosterone, which is critical in the regulation of male reproduction and development. Low levels of testosterone will lead to male hypogonadism. Stem cell-derived Leydig cell transplantation may be a promising alternative therapy for male hypogonadism. Thus far, others have reported that Leydig-like cells can be derived from mesenchymal stem cells (MSCs), embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). However, the efficiency of the differentiating Leydig cells remains low, and progress toward generating functional adult Leydig cells (ALCs) is limited. Herein, we describe a robust method of directing differentiation of mouse embryonic stem cells (mESCs) into Leydig-like cells in vitro by over-expression of the transcription factor SF-1 and treatment with a combination of 8 Br-cAMP and forskolin. These differentiated cells express mRNA encoding the steroidogenic enzymes, and produce progesterone and testosterone. Importantly, when transplanted into male rats that had their original Leydig cells selectively eliminated by ethylene dimethanesulfonate (EDS), these in vitro-derived Leydig-like cells further developed into functional ALCs that rescued serum testosterone levels. These data provide evidence that mouse embryonic stem cells can be induced to differentiate into Leydig-like cells in vitro, which can develop in the in vivo microenvironment.
SK channels are existed in hearts of mouse, rat, and human. Biochemical evidence indicates that SK2 channels are expressed more in atrial than in ventricular tissue. SK channels are highly sensitive to the calcium concentration of the pipette solution. In the present study, performed whole-cell patch clamp was used to detect the calcium sensitivity of small conductance Ca(2+)-activated K+ channels (SK) currents between sinus ryhthm (SR) and auricular fibrillation (AF).
A Brønsted acid promoted C-C bond cleavage method for the synthesis of novel 2-amino-5-aroylmethylthiazole derivatives has been directly developed from 1,4-enediones and thioureas through self-sequenced thio-Michael-addition, intramolecular selective cyclization, dehydration/aromatization, and C-C bond cleavage reactions. It is noteworthy that this reaction has significant advantages in simple reagents, under environmentally benign conditions and with excellent yields. This highly efficient method is also a highly attractive alternative for the preparation of PLTP, CETP inhibitors and novel biheterocycles.
Context: Betatrophin has recently attracted increasing interests as a potential ?-cell regenerative therapy in diabetes. However, differences in betatrophin profiles in patients with type 2 diabetes mellitus (T2DM) remain unclear. Objective: To examine circulating betatrophin levels in subjects with different glucose tolerance status and its correlation with insulin resistance. Design, Setting and Participants: Serum betatrophin levels were measured using ELISA in age-, sex-, BMI- and blood lipids- matched subjects with normal glucose tolerance (NGT) (n=137), isolated impaired fasting glucose (IFG) (n=69), isolated impaired glucose tolerance (IGT) (n=120) and newly diagnosed T2DM (n=112) from the Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal (REACTION) study. Results: Serum betatrophin levels were elevated in patients with T2DM compared to subjects with NGT, isolated IFG or isolated IGT (798.6 ± 42.5 vs. 692.7 ± 29.0, P < 0.05; vs. 682.7 ± 43.0, P < 0.05; vs. 646.8 ± 34.3, P < 0.01). Betatrophin levels positively correlated with index of homeostasis model assessment of insulin resistance (HOMA-IR) (partial r = 0.11); inversely correlated with quantitative insulin sensitivity check index (QUICKI) (partial r = -0.11), the Gutt insulin sensitivity index (ISIG) (partial r = -0.12) and the Matsuda insulin sensitivity index (ISIM) (partial r = -0.11) after controlling for age, sex, BMI and blood lipid in all participants (all P values < 0.05). Conclusion: Circulating betatrophin levels are increased in patients with T2DM and associated with indexes of insulin resistance.
In our study, the function of the third-order branches of the mesentenc artery was measured by microvascular ring technique, which can be used to detect microvascular function in some disease related to microvascular dysfunction.
Three cyclotides were isolated from the whole plant of Viola yedoensis in this study. The two, vary peptide E and cycloviolacin Y5, were previously reported, and a novel cycloviolacin VY1 was characterized according to the interpretation of MS/MS fragmentation of peptides which were produced from the reduced and alkylated parent peptide with the digestion of Endo Lys-C, trypsin and chymotrypsin, separately. The stability of remarkable resistance to proteolytic degradation by trypsin and chymotrypsin, and that of thermal denaturation was confirmed again. Besides, the IC50 value of cycloviolacin VYI against influenza A H1N1 virus was (2.27 +/- 0.20) microg x mL(-1). It is the first cyclotide reported with anti-influenza A H1N1 virus activity in vitro assay.
Osteosarcoma is a high-grade malignant bone tumor. Loss of inhibitor of growth 2 (ING2) expression has been demonstrated in numerous types of cancers. However, no study has shown the relationship between ING2 expression and osteosarcoma. In the present study, we confirmed that the levels of ING2 mRNA and protein were lower in cancer tissues than these levels in normal tissues. Loss of nuclear ING2 protein was significantly associated with a decreased survival time of patients. Osteosarcoma cells were transfected with ING2 protein without a nuclear localization signal or intact ING2 protein to examine the effects of exogenous expression of ING2 in vitro. Compared to the control cells, intact ING2-expressing cells exhibited increased apoptosis, G1 phase arrest and senescence. Taken together, these results suggest that ING2 acts as a tumor suppressor in osteosarcoma.
? Background: The prognostic value of pulmonary hypertension at the start of peritoneal dialysis (PD) in patient survival is unclear. ? Methods: We conducted a retrospective study of incident patients who initiated PD therapy from January 2007 to December 2011, and followed up through June 2013. Pulmonary hypertension was defined as an estimated systolic pulmonary artery pressure (PAP) of ? 35 mm Hg using echocardiography. Clinical parameters and laboratory findings were compared between patients with and without pulmonary hypertension and a logistic regression model was elaborated. Patient outcomes (all-cause and cardiovascular mortality) were recorded during follow-up. Survival curves were constructed by the Kaplan-Meier method, and the influences of pulmonary hypertension on outcomes were analyzed by Cox regression models. ? Results: Pulmonary hypertension was prevalent in 99 (16.0%) of the 618 patients studied. The independent risk factors for pulmonary hypertension were female (odds ratio [OR] = 2.12; 95% confidence interval [CI]: 1.29 - 3.46), left atrial diameter (OR = 1.15; 95% CI: 1.10 - 1.20), left ventricular ejection fraction (OR = 0.97; 95% CI: 0.95 - 0.99), and serum sodium (OR = 0.94; 95% CI: 0.89 - 0.99). Over a median follow-up of 29.4 months, 93 patients (15.0%) died, 59.1% of them due to cardiovascular disease. Kaplan-Meier survival analysis showed that patients with pulmonary hypertension had worse overall rates of survival and cardiovascular death-free survival than those without pulmonary hypertension. After multivariate adjustment, pulmonary hypertension was independently associated with increased risk for both all-cause and cardiovascular mortality, with hazard ratios (HRs) of 2.10 (95% CI: 1.35 - 3.27) and 2.60 (95% CI: 1.48 - 4.56), respectively. ? Conclusions: The prevalence of pulmonary hypertension at the start of PD was common and associated with increased risk of both all-cause and cardiovascular mortality in incident PD patients.
Our understanding of Hepatitis E virus (HEV) has changed enormously over the past 30 years, from a waterborne infection causing outbreaks of acute hepatitis in developing countries to an infection of global distribution causing a range of hepatic and extra-hepatic illness. However, the key proteins playing important parts in the virus infection were still unknown. Understanding the changes of cellular proteins in these cells exposed to HEV is helpful for elucidating molecular mechanisms associated with function alterations of HEV-infected susceptible cells. In the present study, a comparative gel-based proteomic analysis was employed to study the changes in cellular proteins of A549 exposed to HEV in vitro to provide novel information for understanding the functional alterations of A549 induced by HEV infection.
Cytokine gene single nucleotide polymorphisms (SNPs) are involved in the genesis and progression of hepatocellular carcinoma (HCC). We hypothesized that combined effects of cytokine gene SNPs and SNP-SNP interactions are associated with HCC risk. Six SNPs in cytokine genes (IL-2, IFN-?, IL-1?, IL-6, and IL-10) were genotyped in a study of 720 Chinese HCC cases and 784 cancer-free controls. Although none of these SNPs individually had a significant effect on the risk of HCC, we found that the combined effects of these six SNPs may contribute to HCC risk (OR=1.821, 95% CI=1.078-3.075). This risk was pronounced among smokers, drinkers, and hepatitis B virus carriers. A SNP-SNP interaction between IL-2-330 and IFN-?-1615 was associated with an increased HCC risk (OR=1.078, 95% CI=1.022-1.136). In conclusion, combined effects of SNPs and SNP-SNP interactions in cytokine genes may contribute to HCC risk.
Radiation therapy is an important treatment for head and neck squamous cell carcinoma (HNSCC). However, how to promote radiation sensitivity in HNSCC remains a challenge. This study aimed to investigate the radiosensitizing effects of fenofibrate on HNSCC and explore the underlying mechanisms. HNSCC cell lines CNE-2 and KB were subjected to ionizing radiation (IR), in the presence or absence of fenofibrate treatment. Cell growth and survival, apoptosis and cell cycle were evaluated. In addition, CNE-2 cells were xenografted into nude mice and subjected to IR and/ or fenofibrate treatment. The expression of cyclinB and CDK1 was detected by Western blotting. Our results showed that fenofibrate efficiently radiosensitized HNSCC cells and xenografts in mice, and induced apoptosis and G2/M arrest via reducing the activity of the CDK1/cyclinB1 kinase complex. These data suggest that fenofibrate could be a promising radiosensitizer for HNSCC radiotherapy.
Three series of xanthone sulfonamides were synthesized, and their inhibitory activities against acyl-CoA: cholesterol acyltransferase (ACAT) were evaluated. Results showed that most of the title compounds exhibited strong inhibitory activity against ACAT, of which compounds 1c, 1e, 1f, 2d, 2e, and 3d were proved to be more active than the positive control Sandoz 58-035. Computational docking experiments indicated that the interaction between inhibitors and ACAT contained the H-bond interaction, the hydrophobic interaction, and the narrow hydrophobic cleft.
Liposarcoma (LPS) is the most common soft tissue sarcoma and accounts for approximately 20% of all mesenchymal malignancies, often occurring in deep soft tissue of retroperitoneal space. Accurate preoperative diagnosis is therefore necessary. We explored whether computed tomography (CT) could be used to differentiate between the various types of retroperitoneal liposarcoma (RPLS).
HIV coinfection accelerates disease progression in chronic hepatitis C and reduces sustained antiviral responses (SVR) to interferon-based therapy. New direct-acting antivirals (DAAs) promise higher SVR rates, but the selection of preexisting resistance-associated variants (RAVs) may lead to virologic breakthrough or relapse. Thus, pretreatment frequencies of RAVs are likely determinants of treatment outcome but typically are below levels at which the viral sequence can be accurately resolved. Moreover, it is not known how HIV coinfection influences RAV frequency. We adopted an accurate high-throughput sequencing strategy to compare nucleotide diversity in HCV NS3 protease-coding sequences in 20 monoinfected and 20 coinfected subjects with well-controlled HIV infection. Differences in mean pairwise nucleotide diversity (?), Tajima's D statistic, and Shannon entropy index suggested that the genetic diversity of HCV is reduced in coinfection. Among coinfected subjects, diversity correlated positively with increases in CD4(+) T cells on antiretroviral therapy, suggesting T cell responses are important determinants of diversity. At a median sequencing depth of 0.084%, preexisting RAVs were readily identified. Q80K, which negatively impacts clinical responses to simeprevir, was encoded by more than 99% of viral RNAs in 17 of the 40 subjects. RAVs other than Q80K were identified in 39 of 40 subjects, mostly at frequencies near 0.1%. RAV frequency did not differ significantly between monoinfected and coinfected subjects. We conclude that HCV genetic diversity is reduced in patients with well-controlled HIV infection, likely reflecting impaired T cell immunity. However, RAV frequency is not increased and should not adversely influence the outcome of DAA therapy.
Simulation results of the widely used temperature index snowmelt model are greatly influenced by input air temperature data. Spatially sparse air temperature data remain the main factor inducing uncertainties and errors in that model, which limits its applications. Thus, to solve this problem, we created new air temperature data using linear regression relationships that can be formulated based on MODIS land surface temperature data. The Soil Water Assessment Tool model, which includes an improved temperature index snowmelt module, was chosen to test the newly created data. By evaluating simulation performance for daily snowmelt in three test basins of the Amur River, performance of the newly created data was assessed. The coefficient of determination (R (2)) and Nash-Sutcliffe efficiency (NSE) were used for evaluation. The results indicate that MODIS land surface temperature data can be used as a new source for air temperature data creation. This will improve snow simulation using the temperature index model in an area with sparse air temperature observations.
Failure of remyelination in diseases, such as multiple sclerosis (MS), leads to permanent axonal damage and irreversible functional loss. The mechanisms controlling remyelination are currently poorly understood. Recent studies implicate the cyclin-dependent kinase 5 (Cdk5) in regulating oligodendrocyte (OL) development and myelination in CNS. In this study, we show that Cdk5 is also an important regulator of remyelination. Pharmacological inhibition of Cdk5 inhibits repair of lysolecithin lesions. This inhibition is a consequence of Cdk5 disruption in neural cells because remyelination in slice cultures is blocked by Cdk5 inhibitors, whereas specific deletion of Cdk5 in OLs inhibits myelin repair. In CNP-Cre;Cdk5(fl/fl) conditional knock-out mouse (Cdk5 cKO), myelin repair was delayed significantly in response to focal demyelinating lesions compared with wild-type animals. The lack of myelin repair was reflected in decreased expression of MBP and proteolipid protein and a reduction in the total number of myelinated axons in the lesion. The number of CC1(+) cells in the lesion sites was significantly reduced in Cdk5 cKO compared with wild-type animals although the total number of oligodendrocyte lineage cells (Olig2(+) cells) was increased, suggesting that Cdk5 loss perturbs the transition of early OL lineage cell into mature OL and subsequent remyelination. The failure of remyelination in Cdk5 cKO animals was associated with a reduction in signaling through the Akt pathway and an enhancement of Gsk-3? signaling pathways. Together, these data suggest that Cdk5 is critical in regulating the transition of adult oligodendrocyte precursor cells to mature OLs that is essential for myelin repair in adult CNS.
The crude powder of the fruit of Arctium lappa L. (ALF) has previously been reported to attenuate experimental colitis in mice. But, its main effective ingredient and underlying mechanisms remain to be identified. In this study, ALF was extracted with ethanol, and then successively fractionated into petroleum ether, ethyl acetate, n-butanol and water fraction. Experimental colitis was induced by dextran sulfate sodium (DSS) in mice. Among the four fractions of ALF, the ethyl acetate fraction showed the most significant inhibition of DSS-induced colitis in mice. The comparative studies of arctigenin and arctiin (the two main ingredients of ethyl acetate fraction) indicated that arctigenin rather than arctiin could reduce the loss of body weight, disease activity index and histological damage in the colon. Arctigenin markedly recovered the loss of intestinal epithelial cells (E-cadherin-positive cells) and decreased the infiltration of neutrophils (MPO-positive cells) and macrophages (CD68-positive cells). Arctigenin could down-regulate the expressions of TNF-?, IL-6, MIP-2, MCP-1, MAdCAM-1, ICAM-1 and VCAM-1 at both protein and mRNA levels in colonic tissues. Also, it markedly decreased the MDA level, but increased SOD activity and the GSH level. Of note, the efficacy of arctigenin was comparable or even superior to that of the positive control mesalazine. Moreover, it significantly suppressed the phosphorylation of MAPKs and the activation of NF-?B, including phosphorylation of I?B? and p65, p65 translocation and DNA binding activity. In conclusion, arctigenin but not arctiin is the main active ingredient of ALF for attenuating colitis via down-regulating the activation of MAPK and NF-?B pathways.
We examine the influence of strategic choice on working capital configurations and observe how the relationship between working capital ratio and operational performance differs depending on strategy. By clustering the strategic factors of the wholesale and retail industry, we find three categories of strategies: terminal market strategy, middle market strategy, and hybrid strategy. Using the panel data of the listed companies of the wholesale and retail industry as our sample, we analyze the differences in the ways companies configure working capital, the speed with which working capital adjusts to its target, and the effects of working capital on performance for companies that make different strategic choices. The empirical results suggest that working capital is configured and adjusted to its target in different ways under different competitive strategic choices. This effect is finally transferred to influence the relationship between working capital configuration and operational performance.
The expression of membrane-bound complement regulatory proteins (mCRPs) that inhibit the complement system in normal tissues is essential for self-protection against an autologous immune reaction. However, the expression patterns of mCRPs, including CD46, CD55, and CD59, are inconsistent in different types of cancer cells.
Background: The purpose of our study is to identify serum protein biomarkers for node-positive oral squamous cell carcinoma (OSCC). Biomarkers indicating lymph node metastasis provides valuable classification methodology to optimize treatment plans for patients with OSCC. Methods: Quantitative serum proteomic analysis of OSCCs with either node-positive or node-negative disease was performed with tandem mass spectrometry and isobaric tagging for relative and absolute quantitation (iTRAQ). Immunoassays were used to validate a panel of candidate protein biomarkers and receiver operating characteristic analysis was used to evaluate the performance of the candidate biomarkers. Results: A total of 282 serum proteins were quantified between node-positive and node-negative OSCCs with the proteomic approach. Four candidate biomarkers, gelsolin, fibronectin, angiotensinogen and haptoglobin, were validated in an independent group of patients with node-positive or node-negative OSCC. The best candidate biomarker, gelsolin, yielded a receiver operating characteristic value of 89 % for node-positive OSCC, although the sample size for validation is relatively small. Fibronectin, gelsolin and angiotensinogen were also found to be differentially expressed between cancer cell lines of node-positive and node-negative cancer origin. Conclusion: Our studies suggest that testing of serum protein biomarkers might help detect lymph node metastasis of oral cancer. Due to limited sample size in our studies, long-term longitudinal studies with large populations of individuals with oral cancer are needed to validate these potential biomarkers. Head Neck, 2014.
MicroRNAs are evolutionary conserved single stranded non-coding RNAs with immense ability to posttranscriptionally regulate gene expression via complementary base pairing with mRNAs of more than 50% protein encoding genes. They play diverse roles in physiological and pathophysiological processes such as normal development and cancer pathogenesis respectively. Recent investigations have focused on the identification and characterization of microRNAs aberrantly expressed in cancer and their target molecules that are critically involved in the initiation, progression and development of carcinogenesis as possible diagnostic, prognostic and theranostic (Integration of biomarker use as diagnostic tools and target-specific therapies to enhance selective and individualized therapy) tools to augment conventional cancer therapeutic armamentarium. In this mini review, we bring to focus the intricate interactions between microRNAs aberrantly expressed in hepatocarcinogenesis and their interactions with the transforming growth factor beta (TGF-?)/Small mother against decapentaplegic (Smad) and the mitogen activated protein kinases (MAPKs) signaling pathways. Importantly, we highlight microRNA-Specific targets as possible biomarkers for prognosis, diagnosis and as therapeutic targets for hepatocellular carcinoma (HCC) while at the same time exploring new directions for future investigations.
The in vivo and in vitro immunostimulating properties of chitosan oligosaccharide (COS) prepared by enzymatic hydrolysis of chitosan and the mechanisms mediating the effects were investigated. Our data showed that the highly active chitosanase isolated could hydrolyze chitosan to the polymerization degree of 3-8. The resulting COS was an efficient immunostimulator. COS markedly enhanced the proliferation and neutral red phagocytosis by RAW 264.7 macrophages. The production of nitric oxide (NO) and tumor necrosis factor alpha (TNF-?) by macrophages was significantly increased after incubation with COS. Oral administration of COS in mice could increase spleen index and serum immunoglobin G (IgG) contents. COS was labeled with FITC to study the pinocytosis by macrophages. Results showed that FITC-COS was phagocyted by macrophages and anti-murine TLR4 antibody completely blocked FITC-COS pinocytosis. RT-PCR indicated that COS treatment of macrophages significantly increased TLR4 and inducible nitric oxide synthase (iNOS) mRNA levels. When cells were pretreated with anti-murine TLR4 antibody, the effect of COS on TLR4 and iNOS mRNA induction was decreased. COS-induced NO secretion by macrophages was also markedly decreased by anti-murine TLR4 antibody pretreatment. In conclusion, the present study revealed that COS possesses potent immune-stimulating properties by activating TLR4 on macrophages.
The specific mechanism underlying the role of putative stem cell marker aldehyde dehydrogenase 1 (ALDH1) playing in development and progression of breast cancer is currently unclear. Transforming growth factor ? (TGF?) signaling pathway is reported to be activated in most cancers. Thus a study was initiated to explore possible differences and correlation of ALDH1 and TGF?2 expression in the most common malignant and benign tumors of the breast in Chinese women. Samples of 75 breast cancer tissues, 30 paracancerous normal tissues, and 39 fibroadenoma breast tissues were investigated for the expression of ALDH1 and TGF?2 using immunohistochemistry. The positive rates of ALDH1 and TGF?2 protein were 62.67% and 66.67%, respectively, in breast cancer tissues, which were significantly higher than that in normal fibroadenoma breast (P<0.05) and paracancerous tissues (P<0.01). ALDH1 and TGF?2 status were significantly associated with tumor histological grade and receptor status (P<0.05). Expression of ALDH1 was found to be positively correlative to TGF?2 in breast cancer (r = 0.33, P<0.01). Expression of both proteins remained significantly associated with reduced overall survival (OS) by univariate analysis (P<0.05). Multivariate Cox regression analysis showed that ALDH1 expression, tumor stage, and lymph node status are independent prognostic factors in invasive breast cancer patients. Thus ALDH1 and TGF?2 play important roles in the development of breast cancer. The ALDH1 phenotype is an independent predictor of poor prognosis, and TGF?2 signaling pathway activation might be involved in the pathological regulation of ALDH1 in breast cancer.
Hypoxia is a widespread phenomenon present in many human solid tumors and is associated with a poor prognosis and therapy resistance. Here, we tested the feasibility of melittin, a major component of bee venom, on radiosensitization of hypoxic head and neck squamous cell carcinoma (HNSCC). CNE-2 and KB cells were treated with melittin and radiation response was determined. Cell viability, cytotoxicity and apoptosis induction were examined by CCK-8 assay, colony formation assay, and flow cytometry. Expression of hypoxia-inducible factor 1-alpha (HIF-1?) and vascular endothelial growth factor (VEGF) proteins were assessed using western blotting. Additionally, we also examined the effect of melittin on tumor growth and radiosensitivity in vivo using a xenograft model of HNSCC. Treatment with melittin resulted in cell growth inhibition, induction of cell apoptosis, and reduction of HIF-1? and VEGF expression, which has been linked to hypoxia cell radioresistance. In addition, intraperitoneal injection of melittin significantly reduced the growth of HNSCC tumors in CNE-2 tumor-bearing mice. These data suggest that melittin enhances radiosensitivity of HNSCC under hypoxia condition, and this is associated with the suppression of HIF-1? expression. Melittin appears to be a potential radiotherapy sensitization agent due to its significant antihypoxia activity.
In recent years, increasing evidence suggests a potential importance of telomere biology in type 2 diabetes. The aim of this study was to determine whether sitagliptin, a medicine generally used in diabetes, can influence the telomere and telomerase in newly diagnosed type 2 diabetic patients.
Leydig cells are the primary source of testosterone in the testes, and their steroidogenic function is strictly controlled by the hypothalamus-pituitary-gonad axis. Emerging evidence has indicated that fibroblast growth factors play a role in regulating stem Leydig cell development and steroidogenesis, but little is known about the regulatory mechanism. Using a seminiferous tubule culture system, we demonstrated that basic fibroblast growth factor (bFGF) can promote stem Leydig cell proliferation and commitment toward differentiation in testosterone-producing Leydig cells. However, these promoting effects decreased with an increase in the bFGF dose. Previous studies have reported that bFGF inhibits luteinizing hormone (LH)-stimulated androgen production by downregulating the mRNA expression of steroidogenic genes in immature Leydig cells. However, the expression levels of 677 microRNAs did not change significantly during the LH-mediated process of testosterone synthesis. Five microRNAs (miR-29a, -29c, -142-3p, -451 and -335) were identified, and their expression in immature Leydig cells was regulated simultaneously by bFGF and LH. These results suggested that the inhibition of LH-stimulated androgen production may be modulated by a change in bFGF-mediated microRNA expression, which further impacts the signaling pathway of testosterone biosynthesis and steroidogenic gene expression.
Fluorescent carbon nanoparticles (F-CNPs) as a new kind of fluorescent nanoparticles, have recently attracted considerable research interest in a wide range of applications due to their low-cost and good biocompatibility. The fluorescent detection of metal ions is one of the most important applications. In this review, we first present the general detection mechanism of F-CNPs for the fluorescent detection of metal ions, including fluorescence turn-off, fluorescence turn-on, fluorescence resonance energy transfer (FRET) and ratiometric response. We then focus on the recent advances of F-CNPs in the fluorescent detection of metal ions, including Hg(2+), Cu(2+), Fe(3+), and other metal ions. Further, we discuss the research trends and future prospects of F-CNPs. We envision that more novel F-CNPs-based nanosensors with more accuracy and robustness will be widely used to assay and remove various metal ions, and there will be more practical applications in coming years.
Although 2-imino-1H-imidazol-5(2H)-ones have important biological activities in metabolism, their synthesis has rarely been investigated. Quinoxalines as "privileged scaffolds" in medicinal chemistry have been extensively investigated, but the development of novel and efficient synthetic methods remains very attractive. Herein, we have developed two copper-catalyzed domino reactions for the synthesis of 2-imino-1H-imidazol-5(2H)-ones and quinoxalines involving C?C bond-cleavage with a 1,3-dicarbonyl unit as a leaving group. The domino sequence for the synthesis of 2-imino-1H-imidazol-5(2H)-ones includes aza-Michael addition, intramolecular cyclization, C?C bond-cleavage, 1,2-rearrangement, and aerobic dehydrogenation reaction, whereas the domino sequence for the synthesis of quinoxalines includes aza-Michael addition, intramolecular cyclization, elimination reaction, and C?C bond-cleavage reaction. The two domino reactions have significant advantages including high efficiency, mild reaction conditions, and high tolerance of various functional groups.
Tanshinone II-A sodium sulfonate (DS-201), a water-soluble derivative of Tanshinone II-A, has been found to induce vascular relaxation and activate BKCa channels. The aim of this study was to explore the mechanisms underlying the action of DS-201 on BKCa channels.
Inflammatory myofibroblastic tumors are rare, and those located in the extremities without bone involvement are even rarer. We present the case of a 61-year-old Chinese male patient with an inflammatory myofibroblastic tumor of the right thigh. It was excised and a histopathologic examination revealed an inflammatory myofibroblastic tumor. This case is presented by virtue of its rare location.
Serum proteomic analysis can be a valuable approach for the discovery of protein biomarkers for early detection or monitoring of a disease. In this study, two analytical methods were compared for quantification of serum proteins in patients with oral cancer. In the first approach, we quantified serum proteins between oral squamous cell carcinoma (OSCC) and healthy control subjects by performing in-solution digestion of serum proteins, isobaric tags for relative and absolute quantification (iTRAQ) labeling of the resulting peptides, strong cation exchange (SCX) fractionation of labeled peptides and finally capillary liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis of the peptides. In the second approach, we first separated serum proteins with SDS-PAGE. The gel-separated proteins were then digested with trypsin and the resulting peptides were labeled with iTRAQ and analyzed with LC-MS/MS for protein quantification. A total of 319 serum proteins were quantified with the first proteomic approach whereas a total of 281 proteins were quantified by the second proteomic approach. Most of the proteins were identified and quantified by both approaches, suggesting that these methods are similarly effective for serum proteome analysis. This study provides compelling evidence that quantitative serum proteomic analysis of OSCC is a valuable approach for identifying differentially expressed proteins in cancer patients' circulation systems that may be used as potential biomarkers for disease detection. Further validation in large oral cancer patient populations may lead to a simple and low invasive clinical tool for OSCC diagnosis or monitoring.
The deuterohemin-peptide conjugate (DhHP-6) is a microperoxidase mimetic, which has demonstrated substantial benefits in vivo as a scavenger of reactive oxygen species. This paper reports the development of a sensitive and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the determination of DhHP-6 in rat plasma using triptorelin as an internal standard (IS). 50?L plasma was used in sample preparation, and a simple protein precipitation procedure with acetonitrile was involved. Satisfactory peak shapes of analyte and IS were obtained on an Agilent HC-C18 column by using a gradient elution with 10mM ammonium acetate-0.5% formic acid (v:v) and acetonitrile, there was no significant interference impacting the determination. A calibration curve obtained from this method was linear within the concentration range 10-3000ng/mL with intra- and inter-day precisions of 4.2-6.8% and 3.2-8.9%, respectively and accuracy of -1.3% to 2.1%. The recovery was above 80% with low matrix effects. The method was successfully applied to support a preclinical pharmacokinetic study in rat.
The aim of this research was to study effects of drying methods on the tasty compounds of Pleurotus eryngii, a common commercial edible fungus. In order to maximally maintain the taste of P. eryngii, several different drying methods, including hot air, vacuum, microwave, freeze drying and naturally air-drying, were compared. Results showed that freeze drying and hot air were capable of the conservation of the taste compounds maximally in P. eryngii, followed by natural air drying and vacuum, while microwave drying was not suitable for P. eryngii due to the loss of taste compounds. Moreover, concentrations of free amino acids in freeze drying were significantly reduced, so as to 5'-nucleotides in hot air drying. In addition, the umami concentration of the sample using hot air dry was significantly (p<0.05) higher than that using microwave.
The proatherogenic effect of low-density lipoprotein cholesterol (LDL-C) and antiatherogenic effect of high-density lipoprotein cholesterol (HDL-C) have been confirmed in general population. But controversy arises among coronary artery disease (CAD) patients. The goal of this study was to identify the association of different lipid measurements with CAD prognosis. The study cohort included 1916 CAD patients who were 40-85 years of age. Cox proportional hazards regression models were used to estimate the association of baseline 6 lipid factors and 3 ratios with all-cause and cardiovascular (CVD) mortality. During a median follow-up of 3.1 years, 147 deaths were recorded, 113 of which were due to CVD. When lipid factors were categorized, HDL-C showed a U-shape association with all-cause and CVD mortality after adjustment for major CVD risk factors. Serum LDL-C, apoB, LDL/HDL ratio, and apoB/apoA-I ratio were positively, and apoA-I level was inversely associated with the risk of CVD mortality. After further pairwise comparison of lipid-related risk, LDL/HDL ratio and LDL-C had stronger association with all-cause and CVD mortality than other proatherogenic measurements among Chinese CAD patients.
Intractable central post-stroke pain (CPSP) is one of the most common sequelae of stroke, but has been inadequately studied to date. In this study, we first determined the relationship between the lesion site and changes in mechanical or thermal pain sensitivity in a rat CPSP model with experimental thalamic hemorrhage produced by unilateral intra-thalamic collagenase IV (ITC) injection. Then, we evaluated the efficacy of gabapentin (GBP), an anticonvulsant that binds the voltage-gated Ca(2+) channel ?2? and a commonly used anti-neuropathic pain medication. Histological case-by-case analysis showed that only lesions confined to the medial lemniscus and the ventroposterior lateral/medial nuclei of the thalamus and/or the posterior thalamic nucleus resulted in bilateral mechanical pain hypersensitivity. All of the animals displaying CPSP also had impaired motor coordination, while control rats with intra-thalamic saline developed no central pain or motor deficits. GBP had a dose-related anti-allodynic effect after a single administration (1, 10, or 100 mg/kg) on day 7 post-ITC, with significant effects lasting at least 5 h for the higher doses. However, repeated treatment, once a day for two weeks, resulted in complete loss of effectiveness (drug tolerance) at 10 mg/kg, while effectiveness remained at 100 mg/kg, although the time period of efficacious analgesia was reduced. In addition, GBP did not change the basal pain sensitivity and the motor impairment caused by the ITC lesion, suggesting selective action of GBP on the somatosensory system.
The aim of this work was to establish a specific and sensitive method to comprehensively investigate and compare chemical constituents of Fuzi-Gancao herb pair (FG), consisting of Aconitum carmichaelii Debeaux (Fuzi, Chinese) and Roast Radix Glycyrrhizae (Glycyrrhiza glabra L., Gancao, in Chinese) and Fuzi alone to explore the underlying interaction mechanism of FG.
Firearms identification imaging systems help solve crimes by comparing newly acquired images of cartridge casings or bullets to a database of images obtained from past crime scenes. We formulate an optimization problem that bases its matching decisions not only on the similarity between pairs of images, but also on the time and spatial location of each new acquisition and each database entry. The objective is to maximize the detection probability subject to a constraint on the false positive rate. We use data on all cartridge casings matches detected in Israel during 2006-2008 to estimate most of the model parameters. We estimate matching accuracy from two different studies and predict that the optimal use of extraneous information would increase the detection probability from 0.931 to 0.987 and from 0.707 to 0.844, respectively. These improvements are achieved by favoring pairs of images that are closer together in space and time.
Secreted protein acidic and rich in cysteine (SPARC) is involved in regulating cell adhesion, proliferation, migration, and tissue remodeling. We performed a meta-analysis to evaluate the association between SPARC expression and the clinicopathologic features and outcomes of gastric cancer patients.
Gridded precipitation data are becoming an important source for driving hydrologic models to achieve stable and valid simulation results in different regions. Thus, evaluating different sources of precipitation data is important for improving the applicability of gridded data. In this study, we used three gridded rainfall datasets: 1) National Centers for Environmental Prediction - Climate Forecast System Reanalysis (NCEP-CFSR); 2) Asian Precipitation - Highly-Resolved Observational Data Integration Towards Evaluation (APHRODITE); and 3) China trend - surface reanalysis (trend surface) data. These are compared with monitoring precipitation data for driving the Soil and Water Assessment Tool in two basins upstream of Three Gorges Reservoir (TGR) in China. The results of one test basin with significant topographic influence indicates that all the gridded data have poor abilities in reproducing hydrologic processes with the topographic influence on precipitation quantity and distribution. However, in a relatively flat test basin, the APHRODITE and trend surface data can give stable and desirable results. The results of this study suggest that precipitation data for future applications should be considered comprehensively in the TGR area, including the influence of data density and topography.
Castration-resistant progression of prostate cancer after androgen deprivation therapies remains the most critical challenge in the clinical management of prostate cancer. Resurgent androgen receptor (AR) activity is an established driver of castration-resistant progression, and upregulation of the full-length AR (AR-FL) and constitutively-active AR splice variants (AR-Vs) has been implicated to contribute to the resurgent AR activity. We reported previously that ginsenoside 20(S)-protopanaxadiol-aglycone (PPD) can reduce the abundance of both AR-FL and AR-Vs. In the present study, we further showed that the effect of PPD on AR expression and target genes was independent of androgen. PPD treatment resulted in a suppression of ligand-independent AR transactivation. Moreover, PPD delayed castration-resistant regrowth of LNCaP xenograft tumors after androgen deprivation and inhibited the growth of castration-resistant 22Rv1 xenograft tumors with endogenous expression of AR-FL and AR-Vs. This was accompanied by a decline in serum prostate-specific antigen levels as well as a decrease in AR levels and mitoses in the tumors. Notably, the 22Rv1 xenograft tumors were resistant to growth inhibition by the next-generation anti-androgen enzalutamide. The present study represents the first to show the preclinical efficacy of PPD in inhibiting castration-resistant progression and growth of prostate cancer. The findings provide a rationale for further developing PPD or its analogues for prostate cancer therapy.
A supersonic separator has been introduced to remove water vapour from natural gas. The mechanisms of the upstream and downstream influences are not well understood for various flow conditions from the wellhead and the back pipelines. We used a computational model to investigate the effect of the inlet and outlet flow conditions on the supersonic separation process. We found that the shock wave was sensitive to the inlet or back pressure compared to the inlet temperature. The shock position shifted forward with a higher inlet or back pressure. It indicated that an increasing inlet pressure declined the pressure recovery capacity. Furthermore, the shock wave moved out of the diffuser when the ratio of the back pressure to the inlet one was greater than 0.75, in which the state of the low pressure and temperature was destroyed, resulting in the re-evaporation of the condensed liquids. Natural gas would be the subsonic flows in the whole supersonic separator, if the mass flow rate was less than the design value, and it could not reach the low pressure and temperature for the condensation and separation of the water vapor. These results suggested a guidance mechanism for natural gas supersonic separation in various flow conditions.
Cell fate and function can be regulated and reprogrammed by intrinsic genetic program, extrinsic factors and niche microenvironment. Direct reprogramming has shown many advantages in the field of cellular reprogramming. Here we tried the possibility to generate corneal endothelia (CE) -like cells from human adipose-derived stem cells (ADSCs) by the non-genetic direct reprogramming of recombinant cell-penetrating proteins Oct4/Klf4/Sox2 (PTD-OKS) and small molecules (purmorphamine, RG108 and other reprogramming chemical reagents), as well as biomimetic platforms of simulate microgravity (SMG) bioreactor. Co-cultured with corneal cells and decellularized corneal ECM, Reprogrammed ADSCs revealed spherical growth and positively expressing Nanog for RT-PCR analysis and CD34 for immunofluorescence staining after 7 days-treatment of both purmorphamine and PTD-OKS (P-OKS) and in SMG culture. ADSCs changed to CEC polygonal morphology from spindle shape after the sequential non-genetic direct reprogramming and biomimetic platforms. At the same time, induced cells converted to weakly express CD31, AQP-1 and ZO-1. These findings demonstrated that the treatments were able to promote the stem-cell reprogramming for human ADSCs. Our study also indicates for the first time that SMG rotary cell culture system can be used as a non-genetic means to promote direct reprogramming. Our methods of reprogramming provide an alternative strategy for engineering patient-specific multipotent cells for cellular plasticity research and future autologous CEC replacement therapy that avoids complications associated with the use of human pluripotent stem cells.
Osteoporotic vertebral fractures (OVFs) are the common disease found in elderly population. Neurological deficit in OVFs is rare despite the involved posterior cortex of the fractured vertebral body, severe kyphotic deformity, or the instability at the fracture site. OVF with resulting neurological deficit was considered as a contraindication for vertebral augmentation techniques. We reported a rare case of a 75-year-old woman with L1, L2 osteoporotic vertebral fractures and L5/S1 disc herniation who presented with back pain and radicular pain extending along the posterior aspect of the left leg. Physical examination showed slight weakness of her flexor hallucis longus and absence of ankle jerk on her left leg. The result of a straight leg-raising test was limited to an angle of 50 degrees. The radiographs showed that the nerve root was compressed by the retropulsed bone fragment of the L2 vertebral body and a herniated disc at the level of L5/S1 on the left side. After L1 and L2 kyphoplasty the radicular pain as well as the back pain was completely disappeared. At her two-year follow-up examination, the patient was completely symptom free and reported no radicular pain. This case suggested that minimally invasive techniques such as kyphoplasty or vertebroplasty are effective in certain OVF patients with neurological deficit. Radicular pain could be caused by osteoporotic fracture that involves the posterior cortex of the vertebral body. Understanding the anatomy of nerve roots and pathogenetic mechanism of radicular pain is particularly important for treatment option.
Recently, several studies assessed the effectiveness of Tai Chi for Parkinson's disease (PD), but the role of Tai Chi in the management of PD remained controversial. Therefore, the purpose of this systematic review is to evaluate the evidence on the efficacy of Tai Chi for PD.
By consuming mulberry leaves covered with pollen from nearby genetically engineered, insect-resistant rice lines producing Cry proteins derived from Bacillus thuringiensis (Bt), larvae of the domestic silkworm, Bombyx mori (Linnaeus) (Lepidoptera: Bombyxidae), could be exposed to insecticidal proteins. Laboratory experiments were conducted to assess the potential effects of Cry1C- or Cry2A-producing transgenic rice (T1C-19, T2A-1) pollen on B. mori fitness. In a short-term assay, B. mori larvae were fed mulberry leaves covered with different densities of pollen from Bt rice lines or their corresponding near isoline (control) for the first 3 d and then were fed mulberry leaves without pollen. No effect was detected on any life table parameter, even at 1800 pollen grains/cm(2) leaf, which is much higher than the mean natural density of rice pollen on leaves of mulberry trees near paddy fields. In a long-term assay, the larvae were fed Bt and control pollen in the same way but for their entire larval stage (approximately 27 d). Bt pollen densities ? 150 grains/cm(2) leaf reduced 14-d larval weight, increased larval development time, and reduced adult eclosion rate. ELISA analyses showed that 72.6% of the Cry protein was still detected in the pollen grains excreted with the feces. The low exposure of silkworm larvae to Cry proteins when feeding Bt rice pollen may be the explanation for the relatively low toxicity detected in the current study. Although the results demonstrate that B. mori larvae are sensitive to Cry1C and Cry2A proteins, the exposure levels that harmed the larvae in the current study are far greater than natural exposure levels. We therefore conclude that consumption of Bt rice pollen will pose a low to negligible risk to B. mori.
A poly(ionic liquid) with a rather low glass transition temperature of -57°C was synthesized via free radical polymerization of an acrylate-type ionic liquid monomer. It exhibits fluidic behavior in a wide temperature range from room temperature to the threshold of the thermal decomposition. We demonstrate that it could act as a unique type of macromolecular solvent to dissolve various compounds and polymers and separate substances. In addition, this polyelectrolyte could serve successfully as reaction medium for catalysis and colloid particle synthesis. The synergy in the solvation and stabilization properties is a striking character of this polymer to downsize the in situ generated particles.
The reduction in podocyte density to levels below a threshold value drives glomerulosclerosis and progression to ESRD. However, technical demands prohibit high-throughput application of conventional morphometry for estimating podocyte density. We evaluated a method for estimating podocyte density using single paraffin-embedded formalin-fixed sections. Podocyte nuclei were imaged using indirect immunofluorescence detection of antibodies against Wilms tumor-1 or transducin-like enhancer of split 4. To account for the large size of podocyte nuclei in relation to section thickness, we derived a correction factor given by the equation CF=1/(D/T+1), where T is the tissue section thickness and D is the mean caliper diameter of podocyte nuclei. Normal values for D were directly measured in thick tissue sections and in 3- to 5-?m sections using calibrated imaging software. D values were larger for human podocyte nuclei than for rat or mouse nuclei (P<0.01). In addition, D did not vary significantly between human kidney biopsies at the time of transplantation, 3-6 months after transplantation, or with podocyte depletion associated with transplant glomerulopathy. In rat models, D values also did not vary with podocyte depletion, but increased approximately 10% with old age and in postnephrectomy kidney hypertrophy. A spreadsheet with embedded formulas was created to facilitate individualized podocyte density estimation upon input of measured values. The correction factor method was validated by comparison with other methods, and provided data comparable with prior data for normal human kidney transplant donors. This method for estimating podocyte density is applicable to high-throughput laboratory and clinical use.
To evaluate the combined effect of premedication of parecoxib sodium and local infiltration of ropivocaine on postoperative shoulder pain and incisional pain in patients undergoing diagnostic hysteroscopy and laparoscopy.
Objectives. To determine the effect of nicotine stimulation on collagen-induced arthritis (CIA), especially on Th17 cells, and the influence of activated acetylcholine receptor signaling on the induction and function of in vitro-cultured Th17 cells. Methods. Mice were divided into control and experimental (nicotine) group, and PBS or nicotine-PBS was orally administered from Day 21 to Day 28. Phenotypic changes in spleen CD4(+) cells were measured by flow cytometry. ?7nAChR expression in Th17 cells was detected using flow cytometry, western blotting and real-time PCR. Purified Th17 cells were further stimulated with nicotine. The cytometric bead array (CBA) assay was employed to measure TNF-? levels in mice serum and IL-17A levels in the supernatants of nicotine-treated cell cultures. Results. Compared with their counterparts, mice receiving oral nicotine showed a delayed progress of arthritis and more attenuated signs of histological changes. Moreover, serum TNF? levels were lower in the nicotine-treated group. Spleen IL-17 level of nicotine-treated mice was lower than that of the control group, and the mRNA expression of pro-inflammatory cytokines (IL-17A and IL-6) in splenocytes were also lower than that of the control group. ?7nAChR expression was detected on in vitro-cultured IL-17A(+) cells. Cells treated with 10 (- 6) M nicotine expressed lower IL-17A levels. Similarly, supernatants from nicotine-treated cell cultures also showed lower IL-17A levels. Conclusions. Nicotine stimulation attenuated signs and severity of arthritis in mice. Activation of nicotine acetylcholine receptors on in vitro-cultured Th17 cells decreased their pro-inflammatory function, which may play a potential role in alleviating arthritis in mice.
(-)-Tulipalin B and (+)-6-tuliposide B were confirmed to inhibit MurA in vitro. However, contrary to fosfomycin, these compounds showed potent inhibitory activities against MurA overexpressing Escherichia coli, especially in the presence of UDP-GlcNAc. These observations suggest that these compounds induced bacterial cell death not through a MurA malfunction, but in such a MurA-mediated indirect manner as the inhibition of other Mur enzymes.
Through investigating the effect of the angiotensin receptor blocker (ARB) losartan on the number of endothelial progenitor cells (EPCs) and blood flow-mediated endothelium-dependent function (FMD) in the peripheral blood of patients with coronary heart disease (CHD), we found that FMD was improved and the number of circulating EPCs increased in the ARB treatment group (P <0.05). In addition, the increase in the number of EPCs was positively correlated with the improvement of FMD in the ARB treatment group (r = 0.52, P <0.01). These findings suggest that losartan may mobilize EPCs in the peripheral blood, improving endothelial function in CHD.
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