The FAS and FASL system plays a substantial role in apoptosis and immune escape of cells. Three polymorphisms located in the promoter regions of FAS (-1377G/A and -670A/G) and FASL (-844T/C) have been shown to alter the transcriptional activity of the genes, respectively. This study was conducted to evaluate the effects of these polymorphisms on the susceptibility of neuroblastoma in the Chinese population. A total of 203 patients with neuroblastoma and 411 controls were recruited in this case-control study. Polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) was applied for genotyping. Unconditional logistic regression was used to estimate cancer risk by calculating odds ratios (ORs) and their 95% confidence intervals (95% CIs). It was observed that significantly increased risks of neuroblastoma associated with FAS -1377G/A and FASL -844T/C polymorphisms, with ORs equal to 1.55 (95% CI, 1.10–2.20) for FAS -1377 A allele and 2.90 (95% CI, 2.04–4.12) for FASL -844CC genotype carriers compared with non-carriers, respectively. However, no association was found between the polymorphisms of FAS -670A/G and risk of neuroblastoma. In addition, the cumulative effect of FAS and FASL polymorphisms on risk of neuroblastoma was observed (P for trend = 2.502×10−10), with OR for the carriers of both FAS -1377A allele and FASL -844CC genotypes equaled to 3.95 (95% CI, 2.40–6.51). This work reveals that polymorphisms of FAS -1377G/A and FASL -844T/C but not FAS -670A/G are associated with risk of neuroblastoma in Chinese. These findings support the hypothesis that genetic polymorphism in FAS/FASL death system may influence individual susceptibility to neuroblastoma.
The six-membered ring of the title compound, C8H11NO3, adopts an envelope shape with the C atom in the meta position of the carbonyl representing the flap. This atom is disordered over two positions in an 0.865 (6): 0.135 (6) ratio. In the crystal, a two-dimensional supramolecular network parallel to the ac plane is built up from O—H⋯O and N—H⋯O hydrogen bonds.
The breast cancer stem cells (BCSC) play important roles in breast cancer occurrence, recurrence and metastasis. However, the role of estrogen signaling, a signaling pathway important in development and progression of breast cancer, in regulation of BCSC has not been well established. Previously, we identified and cloned a variant of estrogen receptor α, ER-α36, with a molecular weight of 36 kDa. ER-α36 lacks both transactivation domains AF-1 and AF-2 of the 66 kDa full-length ER-α (ER-α66) and mediates rapid estrogen signaling to promote proliferation of breast cancer cells. In this study, we aim to investigate the function and the underlying mechanism of ER-α36-mediated rapid estrogen signaling in growth regulation of the ER-positive breast cancer stem/progenitor cells. ER-positive breast cancer cells MCF7 and T47D as well as the variants with different levels of ER-α36 expression were used. The effects of estrogen on BCSC's abilities of growth, self-renewal, differentiation and tumor-seeding were examined using tumorsphere formation, flow cytometry, indirect immunofluorence staining and in vivo xenograft assays. The underlying mechanisms were also studied with Western-blot analysis. We found that 17-β-estradiol (E2β) treatment increased the population of ER-positive breast cancer stem/progenitor cells while failed to do so in the cells with knocked-down levels of ER-α36 expression. Cells with forced expression of recombinant ER-α36, however, responded strongly to E2β treatment by increasing growth in vitro and tumor-seeding efficiency in vivo. The rapid estrogen signaling via the AKT/GSK3β pathway is involved in estrogen-stimulated growth of ER-positive breast cancer stem/progenitor cells. We concluded that ER-α36-mediated rapid estrogen signaling plays an important role in regulation and maintenance of ER-positive breast cancer stem/progenitor cells.
Forest litter decomposition is a major component of the global carbon (C) budget, and is greatly affected by the atmospheric nitrogen (N) deposition observed globally. However, the effects of N addition on forest litter decomposition, in ecosystems receiving increasingly higher levels of ambient N deposition, are poorly understood.
We conducted a two-year field experiment in five forests along the western edge of the Sichuan Basin in China, where atmospheric N deposition was up to 82–114 kg N ha–1 in the study sites. Four levels of N treatments were applied: (1) control (no N added), (2) low-N (50 kg N ha–1 year–1), (3) medium-N (150 kg N ha–1 year–1), and (4) high-N (300 kg N ha–1 year–1), N additions ranging from 40% to 370% of ambient N deposition. The decomposition processes of ten types of forest litters were then studied. Nitrogen additions significantly decreased the decomposition rates of six types of forest litters. N additions decreased forest litter decomposition, and the mass of residual litter was closely correlated to residual lignin during the decomposition process over the study period. The inhibitory effect of N addition on litter decomposition can be primarily explained by the inhibition of lignin decomposition by exogenous inorganic N. The overall decomposition rate of ten investigated substrates exhibited a significant negative linear relationship with initial tissue C/N and lignin/N, and significant positive relationships with initial tissue K and N concentrations; these relationships exhibited linear and logarithmic curves, respectively.
This study suggests that the expected progressive increases in N deposition may have a potential important impact on forest litter decomposition in the study area in the presence of high levels of ambient N deposition.
We assessed the change over time in the contribution of maternal mortality to a life expectancy calculated between ages 15 and 49, or Reproductive-Aged Life Expectancy (RALE). Our goal was to estimate the increase in RALE in developed countries over the twentieth century and the hypothetical gains in African countries today by eliminating maternal mortality.
Analogous to life expectancy, RALE is calculated from a life table of ages 15 to 49. Specifically, RALE is the average number of years that women at age 15 would be expected to live between 15 and 49 with current mortality rates. Associated single decrement life tables of causes of death other than maternal mortality are explored to assess the possible gains in RALE by reducing or eliminating maternal mortality. We used population-based data from the Human Mortality Database and the Demographic and Health Surveys.
In developed countries, five years in RALE were gained over the twentieth century, of which approximately 10%, or half a year, was attributable to reductions in maternal mortality. In sub-Saharan African countries, the possible achievable gains fluctuate between 0.24 and 1.47 years, or 6% and 44% of potential gains in RALE.
Maternal mortality is a rare event, yet it is still a very important component of RALE. Averting the burden of maternal deaths could return a significant increase in the most productive ages of human life.
Persistent low-grade systemic inflammation has been increasingly recognized as a common pathological process, and an important contributing factor to cardiovascular diseases and its risk factor, metabolic syndrome. Immunoglobulin M is reactive to multiple autoantigens and is inferred to be important for autoimmunity, implying that immunoglobulin M may be a potential risk factor for metabolic syndrome. However, few epidemiological studies are available which are related to this potential link. Therefore, we designed a cross-sectional study of 9,379 subjects to evaluate the relationship between immunoglobulin M and metabolic syndrome in an adult population. Subjects who received health examinations were recruited from the Tianjin Medical University General Hospital-Health Management Center in Tianjin, China. Immunoglobulin M was determined with an immunonephelometric technique. Metabolic syndrome was defined according to the criteria of the American Heart Association scientific statements of 2009. Multiple logistic regression analysis was used to examine the relationships between the quartiles of immunoglobulin M and the prevalence of metabolic syndrome. After adjustment for covariates, the odds ratio of having metabolic syndrome in the fourth quartile compared with the first quartile of immunoglobulin M was 1.19 times for males (95% confidence interval, 1.002–1.41) and 1.39 times for females (95% confidence interval, 1.07–1.80). Immunoglobulin M levels also showed positive relationships with the ratio of elevated triglycerides and reduced high-density lipoprotein cholesterol in males. The study is the first to show that immunoglobulin M is independently related to metabolic syndrome and its individual components (elevated triglycerides and reduced high-density lipoprotein cholesterol) in males, whereas immunoglobulin M is independently related to metabolic syndrome in females but not to its individual components. Further studies are needed to explore the causality and the exact role of immunoglobulin M in metabolic syndrome.
In this article, we have examined the motility-related effects of weak power frequency magnetic fields (MFs) on the epidermal growth factor receptor (EGFR)-sensitive motility mechanism, including the F-actin cytoskeleton, growth of invasive protrusions and the levels of signal molecules in human amniotic epithelial (FL) cells. Without extracellular EGF stimulation, the field stimulated a large growth of new protrusions, especially filopodia and lamellipodia, an increased population of vinculin-associated focal adhesions. And, an obvious reduction of stress fiber content in cell centers was found, corresponding to larger cell surface areas and decreased efficiency of actin assembly of FL cells in vitro, which was associated with a decrease in overall F-actin content and special distributions. These effects were also associated with changes in protein content or distribution patterns of the EGFR downstream motility-related signaling molecules. All of these effects are similar to those following epidermal growth factor (EGF) stimulation of the cells and are time dependent. These results suggest that power frequency MF exposure acutely affects the migration/motility-related actin cytoskeleton reorganization that is regulated by the EGFR-cytoskeleton signaling pathway. Therefore, upon the MF exposure, cells are likely altered to be ready to transfer into a state of migration in response to the stimuli.
Optical differentiation and optical Hilbert transformation play important roles in communications, computing, information processing and signal analysis in optical domain offering huge bandwidth. Meanwhile, silicon-based photonic integrated circuit is one of the most promising candidates for all-optical signal processing due to its intrinsic advantages of low power consumption, compact footprint, ultra-high speed and compatibility with electronic integrated circuits. In this study, we analyze the interrelation between first-order optical differentiation and optical Hilbert transformation and then experimentally demonstrate a feasible integrated scheme which can simultaneously function as first-order optical differentiation and optical Hilbert transformation based on a single microdisk resonator. This finding may motivate the development of integrated optical signal processors.
Human telomeres, tandem repeats of TTAGGG nucleotides at the ends of chromosomes, are essential for maintaining genomic integrity and stability. Results of previous epidemiologic studies about the association of telomere length with risk of colorectal cancer (CRC) have been conflicting.
A case-control study was conducted in a Han population in Wuhan, central China. The relative telomere length (RTL) was measured in peripheral blood leukocytes (PBLs) using quantitative real-time polymerase chain reaction (PCR) in 628 CRC cases and 1,256 age and sex frequency matched cancer-free controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression models to evaluate the association between RTL and CRC risk.
Using median RTL in the controls as the cutoff, individuals with shorter RTL were associated with a significantly increased risk of CRC (adjusted OR = 1.27, 95%CI: 1.05–1.55). When participants were further categorized into 3 and 4 groups according to the tertile and quartile RTL values of controls, significant relationships were still observed between shorter RTL and increased CRC risk (OR per tertile = 1.13, 95%CI: 1.00–1.28, Ptrend = 0.045; OR per quartile = 1.12, 95%CI: 1.03–1.23, Ptrend = 0.012). In stratified analyses, significant association between shorter RTL and increased CRC risk was found in females, individuals younger than 60 years old, never smokers and never drinkers.
This study suggested that short telomere length in PBLs was significantly associated with an increased risk of CRC in Chinese Han population. Further validation in large prospective studies and investigation of the biologic mechanisms are warranted.
Astrocytes play a critical role in neurodegenerative diseases, including Alzheimer’s disease (AD). Previously, we showed that saturated free-fatty acid, palmitate (PA), upregulates BACE1 level and amyloidogenesis in primary rat neurons mediated by astrocytes. However, the molecular mechanisms by which conditioned media from PA-treated astrocytes upregulates BACE1 level in neurons are unknown. This study demonstrates that serine palmitoyltransferase (SPT) in the astrocytes increases ceramide levels, which enhances the release of cytokines that mediate the activation of neural and acidic sphingomyelinase (N-SMase and A-SMase) in the neurons, to propagate the deleterious effects of palmitate, i.e. BACE1 upregulation. In support of the relevance of SPT in AD, our lab recently measure and found SPT levels to be significantly upregulated in AD brains as compared to controls (Geekiyanage and Chan, 2011). Cytokines, namely TNFα and IL-1β, released into the conditioned media of PA-treated astrocytes activate N-SMase and A-SMase in the neurons. Neutralizing the cytokines in the PA-treated astrocyte conditioned media reduced BACE1 upregulation. However, inhibiting SPT in the astrocytes decreased the levels of both TNFα and IL-1β in the conditioned media, which in turn reduced the SMase activities and BACE1 level in primary neurons. Thus, our results suggest that the activation of the astrocytes by PA is mediated by SPT, and the activated astrocytes increases BACE1 level in the neurons, the latter is mediate by the SMases.
Alzheimer’s disease; Fatty acid; Sphingomyelinase; Serine palmitoyltransferase; Ceramide; TNFα; IL-1β
The macrophage scavenger receptor class A (SR-A) participates in the innate immune and inflammatory responses. This study examined the role of macrophage SR-A in myocardial ischemia/reperfusion (I/R) injury and hypoxia/reoxygenation (H/R)-induced cell damage. SR-A−/− and WT mice were subjected to ischemia (45 min) followed by reperfusion for up to 7 days. SR-A−/− mice showed smaller myocardial infarct size and better cardiac function than did WT I/R mice. SR-A deficiency attenuated I/R-induced myocardial apoptosis by preventing p53-mediated Bak-1 apoptotic signaling. The levels of microRNA-125b in SR-A−/− heart were significantly greater than in WT myocardium. SR-A is predominantly expressed on macrophages. To investigate the role of SR-A macrophages in H/R-induced injury, we isolated peritoneal macrophages from SR-A deficient (SR-A−/−) and wild type (WT) mice. Macrophages were subjected to hypoxia followed by reoxygenation. H/R markedly increased NF-κB binding activity as well as KC and MCP-1 production in WT macrophages but not in SR-A−/− macrophages. H/R induced caspase-3/7 and -8 activities and cell death in WT macrophages, but not in SR-A−/− macrophages. The levels of miR-125b in SR-A−/− macrophages were significantly higher than in WT macrophages. Transfection of WT macrophages with miR-125b mimics attenuated H/R-induced caspase-3/7 and -8 activities and H/R-decreased viability, and prevented H/R-increased p-53, Bak-1 and Bax expression. The data suggest that SR-A deficiency attenuates myocardial I/R injury by targeting p53-mediated apoptotic signaling. SR-A−/− macrophages contain high levels of miR-125b which may play a role in the protective effect of SR-A deficiency on myocardial I/R injury and H/R-induced cell damage.
microRNA-125b; Macrophage SR-A; hypoxia/reoxygenation; Myocardial I/R injury; apoptosis
Measures of nicotine dependence typically use the item average or total score from rating scales, such as the Nicotine Dependence Syndrome Scale (NDSS). Alternatively, item response theory (IRT) methods can provide useful item-specific information. IRT methods developed for longitudinal data can additionally provide information about item-specific changes over time.
We describe a longitudinal 2-parameter ordinal IRT model, and compare the results from this model with those from an IRT model for only the baseline item responses, and a conventional longitudinal analysis of the item-average NDSS score. We examined a 10-item, adolescent version of the NDSS at baseline, 6, 15, and 24 months for 1,097 9th or 10th graders.
IRT analysis of the baseline data revealed that the items “willing to go out of the house in a storm to find a cigarette,” “choose to spend money on cigarettes than lunch,” “function better after morning cigarette,” and “worth smoking in cold or rain,” were good items at distinguishing individuals’ levels of nicotine dependency. While the analysis of the averaged NDSS score indicated linear growth over time, the longitudinal IRT method revealed that only 5 out of the 10 items showed statistical increase over time.
Infrequently endorsed NDSS items were generally better able to distinguish higher levels of dependency. The endorsement of such items increased over time. Items that changed significantly over time reflected the general drive concept of dependence, as well as the total first overarching dimension of dependence.
We report an in vitro selection strategy to identify RNA sequences that mediate cap-independent translation initiation. This method entails the mRNA display of trillions of genomic fragments, selection for translation initiation, and high-throughput deep sequencing. We identified >12,000 translation enhancing elements (TEEs) in the human genome, generated a high-resolution map of human TEE bearing regions (TBRs), and validated the function of a subset of sequences in vitro and in cells.
Human Genome; Internal Ribosomal Entry Sites (IRES); mRNA Display
We hypothesized that loss of insulin-like growth factor binding protein 3 (IGFBP-3) signaling would produce neuronal changes in the retina similar to early diabetes.
To understand better the role of IGFBP-3 in the retina, IGFBP-3 knockout (KO) mice were evaluated for neuronal, vascular, and functional changes compared to wild-type littermates. We also cultured retinal endothelial cells (REC) in normoglycemia or hyperglycemia to determine the interaction between IGFBP-3 and TNF-α, as data indicate that both proteins are regulated by β-adrenergic receptors and respond antagonistically. We also treated some cells with Compound 49b, a novel β-adrenergic receptor agonist we have reported previously to regulate IGFBP-3 and TNF-α.
Electroretinogram analyses showed decreased B-wave and oscillatory potential amplitudes in the IGFBP-3 KO mice, corresponding to increased apoptosis. Retinal thickness and cell numbers in the ganglion cell layer were reduced in the IGFBP-3 KO mice. As expected, loss of IGFBP-3 was associated with increased TNF-α levels. When TNF-α and IGFBP-3 were applied to REC, they worked antagonistically, with IGFBP-3 inhibiting apoptosis and TNF-α promoting apoptosis. Due to their antagonistic nature, results suggest that apoptosis of REC may depend upon which protein (IGFBP-3 versus TNF-α) is active.
Taken together, loss of IGFBP-3 signaling results in a phenotype similar to neuronal changes observed in diabetic retinopathy in the early phases, including increased TNF-α levels.
IGFBP-3 KO mice have the early characteristics of diabetic retinopathy noted in rodents.
IGFBP-3; apoptosis; TNF-α
Insulin receptor substrate-2 (IRS-2), a signaling adaptor protein, was involved in two cancer-related pathways (the phosphatidylinositol 3′-kinase (PI3K) and the extracellular signal-regulated kinase (ERK) pathways). Several studies have evaluated the association between IRS2 rs1805097 (G>A) polymorphisms and the risk of colorectal and breast cancer. However, the results were inconsistent.
A meta-analysis of seven published case-control studies (4 studies with 4798 cases and 5478 controls for colorectal cancer and 3 studies with 2108 cases and 2507 controls for breast cancer) were conducted to assess the strength of association using crude odd ratios (ORs) with 95% confidence intervals (CIs). For colorectal cancer, no obvious associations were found for all genetic models (homozygote comparison OR = 0.96, 95%CI 0.85–1.08, Pheterogeneity = 0.97; heterozygote comparison: OR = 0.91, 95%CI 0.73–1.13, Pheterogeneity<0.01; dominant model: OR = 0.92, 95%CI 0.80–1.06, Pheterogeneity = 0.05; recessive model: OR = 1.02, 95%CI 0.91–1.14, Pheterogeneity = 0.60). In the subgroup analysis by ethnicity, control source and consistency of frequency with Hardy-Weinberg equilibrium (HWE), still no significant associations were observed. For breast cancer, also no obvious associations were found for all genetic models (homozygote comparison: OR = 0.95, 95%CI 0.71–1.26, Pheterogeneity = 0.10; heterozygote comparison: OR = 1.00, 95%CI 0.89–1.14, Pheterogeneity = 0.71; dominant model: OR = 0.98, 95%CI 0.87–1.10, Pheterogeneity = 0.55; recessive model: OR = 0.95, 95%CI 0.72–1.25, Pheterogeneity = 0.07). We performed subgroup analyses by sample size and did not find an association.
This meta-analysis indicated that IRS2 rs1805097polymorphism was not associated with colorectal and breast cancer risk.
In the X-ray repair cross-complementing group 1 (XRCC1) gene, a polymorphism, Arg399Gln (rs25487), has been shown to change neoconservative amino acid and thus result in alternation of DNA repair capacity. Numerous studies have investigated the association between Arg399Gln and breast cancer risk in the American population, but yielding inconsistent results. This study aimed to clarify the role of this polymorphism in susceptibility to breast cancer.
Literatures were searched in multiple databases including PubMed, Springer Link, Ovid, EBSCO and ScienceDirect databases up to April 2013. A comprehensive meta-analysis was conducted to estimate the overall odds ratio (OR), by integrating data from 18 case control studies of 10846 cases and 11723 controls in the American population.
Overall, significant association was observed between the Arg399Gln polymorphism and breast cancer risk under the random-effects model (OR for dominant model = 1.12, 95% CI: 1.02–1.24, Pheterogeneity = 0.003; OR for additive model = 1.07, 95% CI: 1.01–1.14, Pheterogeneity = 0.017). Further sensitivity analysis supported the robust stability of this current result by showing similar ORs before and after removal of a single study.
This meta-analysis suggests that the XRCC1 Arg399Gln polymorphism may significantly contribute to susceptibility of breast cancer in the American population.
To characterize the role of rare complete human knockouts in autism spectrum disorders (ASD), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a two-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (≤5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudo-autosomal regions on the X-chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together these results provide compelling evidence that rare autosomal and X-chromosome complete gene knockouts are important inherited risk factors for ASD.
The end-Permian mass extinction was followed by the formation of an enigmatic rock layer with a distinctive macroscopic spotted or dendroid fabric. This deposit has been interpreted as microbial reef rock, digitate dendrolite, digital thrombolite, dendritic thrombolite, or bacterial deposits. Agreement has been reached in considering them as microbialites, but not in their formation. This study has revealed that the spotted and dendroid microbialites were composed of numerous fossil casts formed by the planktic cyanobacterium, Microcystis, a coccoid genus that at the present-day commonly forms blooms in modern lakes, rivers, and reservoirs. The abundance of the fossils and the diagenesis they experienced has determined the macroscopic fabric: where they abundant, the rock appears as dendroid, otherwise, it appears as spotted. The ancient Microcystis bloom might produce toxin to kill other metazoans, and be responsible for the oceanic anoxia that has puzzled so many researchers for so many years.
The aberrantly expressed signal transducer and activator of transcription 3 (STAT3) predicts poor prognosis, primarily in estrogen receptor positive (ER(+)) breast cancers. Activated STAT3 is overexpressed in luminal A subtype cells. The mechanisms contributing to the prognosis and/or subtype relevant features of STAT3 in ER(+) breast cancers are through multiple interacting regulatory pathways, including STAT3-MYC, STAT3-ERα, and STAT3-MYC-ERα interactions, as well as the direct action of activated STAT3. These data predict malignant events, treatment responses and a novel enhancer of tamoxifen resistance. The inferred crosstalk between ERα and STAT3 in regulating their shared target gene-METAP2 is partially validated in the luminal B breast cancer cell line-MCF7. Taken together, we identify a poor prognosis relevant gene set within the STAT3 network and a robust one in a subset of patients. VEGFA, ABL1, LYN, IGF2R and STAT3 are suggested therapeutic targets for further study based upon the degree of differential expression in our model.
STAT3 transcriptional regulatory network; prognosis; TAM resistance; tumorigenesis; breast cancer
To explore whether hypoxia and interleukin 8 (IL-8) regulate the viability and apoptosis of cervical carcinomas cells and the possible mechanism. We evaluated the expression of hypoxia inducible factor-1α (HIF-1α), IL-8 and its receptors (CXCR1 and CXCR2) in cervical cancer and cervicitis tissues by immunohistochemistry. Then the effects of hypoxia and IL-8 on the viability and apoptosis of HeLa and SiHa cells were detected by the SRB and apoptosis assays. Here we observed that the expression of HIF-1α, IL-8 and CXCR1 in cervical cancer tissues was significantly higher than that in cervicitis tissues. Hypoxic condition stimulated the secretion of IL-8 and the expression of CXCR1 and CXCR2 on HeLa and SiHa cells. Recombinant human IL-8 enhanced the viability and reduced the apoptosis in HeLa and SiHa cells. HeLa and SiHa cells cultured in 1% oxygen showed the increased viability and apoptosis, and the former effect could be partly reversed by anti-human IL-8 neutralizing antibody. This data suggested that IL-8 secreted by cervical carcinomas cells induced by hypoxia can stimulate the viability of cervical carcinomas cells in an autocrine dependent manner, and contribute to the pathogenesis of cervical cancer.
Hypoxia; IL-8; cervical carcer cells; viabilty; apoptosis
Compound Danshen Tablet (CDT), a Traditional Chinese Medicine, has recently been reported to improve spatial cognition in a rat model of Alzheimer’s disease. However, in vivo neuroprotective mechanism of the CDT in models of spatial memory impairment is not yet evaluated. The present study is aimed to elucidate the cellular mechanism of CDT on Aβ25-35-induced cognitive impairment in mice.
Mice were randomly divided into 5 groups: the control group (sham operated), the Aβ25-35 treated group, the positive drug group, and large and small dosage of the CDT groups, respectively. CDT was administered at a dose of 0.81 g/kg and 0.405 g/kg for 3 weeks. The mice in the positive drug group were treated with 0.4 mg/kg of Huperzine A, whereas the mice of the control and Aβ25-35 treated groups were administrated orally with equivalent saline. After 7 days of preventive treatment, mice were subjected to lateral ventricle injection of Aβ25-35 to establish the mice model of Alzheimer’s disease. Spatial memory impairment was evaluated by Morris water maze test. Choline acetyltransferase (ChAT) contents in hippocampus and cortex were quantified by ELISA. The levels of cytokines, receptor of activated protein kinase C1 (RACK1) and brain-derived neurotrophic factor (BDNF) in hippocampus were measured by RT-PCR and ELISA.
The results showed that Aβ25-35 caused spatial memory impairment as demonstrated by performance in the Morris water maze test. CDT was able to confer a significant improvement in spatial memory, and protect mice from Aβ25-35-induced neurotoxicity. Additionally, CDT also inhibited the increase of TNF-α and IL-6 level, and increased the expression of choline acetyltransferase (ChAT), receptor of activated protein kinase C1 (RACK1) and brain-derived neurotrophic factor (BDNF) in brain as compared to model mice.
These findings strongly implicate that CDT may be a useful treatment against learning and memory deficits in mice by rescuing imbalance between cytokines and neurotrophins.
Compound danshen tablet; Spatial memory impairment; ChAT; RACK1; BDNF
Breast carcinoma is the most common female cancer with considerable metastatic potential. Discovery of new therapeutic approaches for treatment of metastatic breast cancer is still needed. Here, we reported our finding with niclosamide, an FDA approved anthelmintic drug. The potency of niclosamide on breast cancer was assessed in vitro and in vivo. In this investigation, we found that niclosamide showed a dramatic growth inhibition against breast cancer cell lines and induced apoptosis of 4T1 cells in a dose-dependent manner. Further, Western blot analysis demonstrated the occurrence of its apoptosis was associated with activation of Cleaved caspases-3, down-regulation of Bcl-2, Mcl-1 and Survivin. Moreover, niclosamide blocked breast cancer cells migration and invasion, and the reduction of phosphorylated STAT3Tyr705, phosphorylated FAKTyr925 and phosphorylated SrcTyr416 were also observed. Furthermore, in our animal experiments, intraperitoneal administration of 20 mg/kg/d niclosamide suppressed 4T1 tumor growth without detectable toxicity. Histological and immunohistochemical analyses revealed a decrease in Ki67-positive cells, VEGF-positive cells and microvessel density (MVD) and an increase in Cleaved caspase-3-positive cells upon niclosamide. Notably, niclosamide reduced the number of myeloid-derived suppressor cells (MDSCs) in tumor tissues and blocked formation of pulmonary metastases. Taken together, these results demonstrated that niclosamide may be a promising candidate for breast cancer.
Microarray technology has produced a huge body of time-course gene expression data and will continue to produce more. Such gene expression data has been proved useful in genomic disease diagnosis and drug design. The challenge is how to uncover useful information from such data by proper analysis methods such as significance analysis and clustering analysis. Many statistic-based significance analysis methods and distance/correlation-based clustering analysis methods have been applied to time-course expression data. However, these techniques are unable to account for the dynamics of such data. It is the dynamics that characterizes such data and that should be considered in analysis of such data. In this paper, we employ a nonlinear model to analyse time-course gene expression data. We firstly develop an efficient method for estimating the parameters in the nonlinear model. Then we utilize this model to perform the significance analysis of individually differentially expressed genes and clustering analysis of a set of gene expression profiles. The verification with two synthetic datasets shows that our developed significance analysis method and cluster analysis method outperform some existing methods. The application to one real-life biological dataset illustrates that the analysis results of our developed methods are in agreement with the existing results.
Control of systemic inorganic phosphate (Pi) levels is crucial for osteoid mineralization. Parathyroid hormone (PTH) mediates actions on phosphate homeostasis mostly by regulating the activity of the type 2 sodium-phosphate cotransporter (Npt2), and this action requires the PDZ protein NHERF1. Osteoblasts express Npt2 and in response to PTH enhance osteogenesis by increasing mineralized matrix. The regulation of Pi transport in osteoblasts is poorly understood. To address this gap we characterized PTH-dependent Pi transport and the role of NHERF1 in primary mouse calvarial osteoblasts. Under proliferating conditions osteoblasts express Npt2a, Npt2b, PTH receptor, and NHERF1. Npt2a mRNA expression was lower in calvarial osteoblasts from NHERF1-null mice. Under basal conditions Pi uptake in osteoblasts from wild-type mice was greater than that of knockout mice. PTH inhibited Pi uptake in proliferating osteoblasts from wild-type mice, but not in cells from knockout mice. In vitro induction of mineralization enhanced osteoblast differentiation and increased osterix and osteocalcin expression. Contrary to the results with proliferating osteoblasts, PTH increased Pi uptake and ATP secretion in differentiated osteoblasts from wild-type mice. PTH had no effect on Pi uptake or ATP release in differentiated osteoblasts from knockout mice. NHERF1 regulation of PTH-sensitive Pi uptake in proliferating osteoblasts is mediated by cAMP/PKA and PLC/PKC, while modulation of Pi uptake in differentiated osteoblasts depends only on cAMP/PKA signaling. The results suggest that NHERF1 cooperates with PTH in differentiated osteoblasts to increase matrix mineralization. We conclude that NHERF1 regulates PTH differentially affects Na-dependent Pi transport at distinct stages of osteoblast proliferation and maturation.
type 2 sodium-phosphate transporters; parathyroid hormone receptor; NHERF1; osteoblasts; inorganic phosphate