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Introduction: Endothelial dysfunction indicates blood vessel injury and is a risk factor for cardiovascular diseases. Blueberry has been approved for its benefits on human health, especially on cardiovascular function. However, its effect on endothelial function remains unclear. We conducted a systematic review and meta-analysis to explore the impact of blueberries on endothelial function in adults. Methods: We searched PubMed, Web of Science, Embase, and the Cochrane Library, 16 studies were included in the systematic review, and 11 were used for the meta-analysis. Data associated with endothelial function were extracted and pooled as mean differences (MD) with 95% confidence intervals (CI). Results: Blueberry consumption significantly improved flow-mediated dilation (FMD) by 1.50% (95% CI: 0.81, 2.20; I2 = 87%) and reactive hyperemia index (RHI) by 0.26 (95% CI: 0.09, 0.42; I2 = 72%). A significant decrease in diastolic blood pressure (DBP) was also observed (MD: -2.20 mm Hg; 95% CI: -4.13, -0.27; I2 = 11%). Subgroup analysis indicated a significant decrease in blood pressure (Systolic blood pressure [SBP]: -3.92 mmHg; 95% CI: -6.88, -0.97; I2 = 20% and DBP: -2.20 mmHg; 95% CI: -4.13, -0.27; I2 = 11%) in the smoking population. However, SBP levels (MD: -1.43 mm Hg; 95% CI: -3.11, 0.26; I2 = 20%) and lipid status (high-density lipoprotein cholesterol [HDL-C]: 0.06; 95% CI: -0.04, 0.16; I2 = 77%; low-density lipoprotein cholesterol [LDL-C]: 0.05; 95% CI: -0.14, 0.24; I2 = 0%) did not significantly improve. Conclusion: Blueberry intervention improved endothelial function and DBP. Subgroup analysis revealed a notable improvement in blood pressure among the smoking population. However, no significant effects were observed on SBP, HDL-C, and LDL-C levels. Future research should delve into the mechanisms of endothelial improvement and verify blood pressure reduction in specific subpopulations through large-scale trials. [ABSTRACT FROM AUTHOR]

Early-life human gut microbiome is a pivotal driver of gut homeostasis and infant health. However, the viral component (known as “virome”) remains mostly unexplored. Here, we establish the Early-Life Gut Virome (ELGV), a catalog of 160,478 non-redundant DNA and RNA viral sequences from 8130 gut virus-like particles (VLPs) enriched or bulk metagenomes in the first three years of life. By clustering, 82,141 viral species are identified, 68.3% of which are absent in existing databases built mainly from adults, and 64 and 8 viral species based on VLPs-enriched and bulk metagenomes, respectively, exhibit potentials as biomarkers to distinguish infants from adults. With the largest longitudinal population of infants profiled by either VLPs-enriched or bulk metagenomic sequencing, we track the inherent instability and temporal development of the early-life human gut virome, and identify differential viruses associated with multiple clinical factors. The mother-infant shared virome and interactions between gut virome and bacteriome early in life are further expanded. Together, the ELGV catalog provides the most comprehensive and complete metagenomic blueprint of the early-life human gut virome, facilitating the discovery of pediatric disease-virome associations in future. [ABSTRACT FROM AUTHOR]

Objective: To summarise current evidence evaluating the effects of human milk on the risk of bronchopulmonary dysplasia (BPD) in preterm infants.Design: We searched for studies on human milk and BPD in English and Chinese databases on 26 July 2017. Furthermore, the references of included studies were also screened. The inclusion criteria in this meta-analysis were the following: (1) preterm infants (<37 weeks); (2) human milk; (3) comparing with formula feeding; (4) the outcome included BPD; and (5) the type of study was randomised controlled trial (RCT) or cohort study.Result: A total of 17 cohort studies and 5 RCTs involving 8661 preterm infants met our inclusion criteria. The ORs and 95% CIs of six groups were as follows: 0.78 (0.68 to 0.88) for exclusive human milk versus exclusive formula group, 0.77 (0.68 to 0.87) for exclusive human milk versus mainly formula group, 0.76 (0.68 to 0.87) for exclusive human milk versus any formula group, 0.78 (0.68 to 0.88) for mainly human milk versus exclusive formula group, 0.83 (0.69 to 0.99) for mainly human milk versus mainly formula group and 0.82 (0.73 to 0.93) for any human milk versus exclusive formula group. Notably, subgroup of RCT alone showed a trend towards protective effect of human milk on BPD but no statistical significance.Conclusion: Both exclusive human milk feeding and partial human milk feeding appear to be associated with lower risk of BPD in preterm infants. The quality of evidence is low. Therefore, more RCTs of this topic are needed. [ABSTRACT FROM AUTHOR]

Objective: To determine the comparative efficacy and safety of corticosteroids in the prevention of bronchopulmonary dysplasia (BPD) in preterm infants.Study Design: We systematically searched PubMed, EMBASE and the Cochrane Library. Two reviewers independently selected randomised controlled trials (RCTs) of postnatal corticosteroids in preterm infants. A Bayesian network meta-analysis and subgroup analyses were performed.Results: We included 47 RCTs with 6747 participants. The use of dexamethasone at either high dose or low dose decreased the risk of BPD (OR 0.29, 95% credible interval (CrI) 0.14 to 0.52; OR 0.58, 95% CrI 0.39 to 0.76, respectively). High-dose dexamethasone was more effective than hydrocortisone, beclomethasone and low-dose dexamethasone. Early and long-term dexamethasone at either high dose or low dose decreased the risk of BPD (OR 0.11, 95% CrI 0.02 to 0.4; OR 0.37, 95% CrI 0.16 to 0.67, respectively). There were no statistically significant differences in the risk of cerebral palsy (CP) between different corticosteroids. However, high-dose and long-term dexamethasone ranked lower than placebo and other regimens in terms of CP. Subgroup analyses indicated budesonide was associated with a decreased risk of BPD in extremely preterm and extremely low birthweight infants (OR 0.60, 95% CrI 0.36 to 0.93).Conclusions: Dexamethasone can reduce the risk of BPD in preterm infants. Of the different dexamethasone regimens, aggressive initiation seems beneficial, while a combination of high-dose and long-term use should be avoided because of the possible adverse neurodevelopmental outcome. Dexamethasone and inhaled corticosteroids need to be further evaluated in large-scale RCTs with long-term follow-ups. [ABSTRACT FROM AUTHOR]

The assembly of prereplicative complex (pre-RC) during G1 phase must be tightly controlled to sustain cell proliferation and maintain genomic stability. Mechanisms to prevent pre-RC formation in G2/M and S phases are well appreciated, whereas how cells ensure efficient pre-RC assembly during G1 is less clear. Here we report that cyclin K regulates pre-RC formation. We find that cyclin K expression positively correlates with cell proliferation, and knockdown of cyclin K or its cognate kinase CDK12 prevents the assembly of pre-RC in G1 phase. Mechanistically we uncover that cyclin K promotes pre-RC assembly by restricting cyclin E1 activity in G1. We identify a cyclin K-dependent, novel phosphorylation site in cyclin E1 that disrupts its interaction with CDK2. Importantly, this antagonistic relationship is largely recapitulated in cyclin E1-overexpressing tumors. We discuss the implications of our findings in light of recent reports linking cyclin K and CDK12 to human tumorigenesis. [ABSTRACT FROM AUTHOR]

Bergmann glia facilitate granule neuron migration during development and maintain the cerebellar organization and functional integrity. At present, molecular control of Bergmann glia specification from cerebellar radial glia is not fully understood. In this report, we show that ZEB2 (aka, SIP1 or ZFHX1B), a Mowat-Wilson syndrome-associated transcriptional regulator, is highly expressed in Bergmann glia, but hardly detectable in astrocytes in the cerebellum. The mice lacking Zeb2 in cerebellar radial glia exhibit severe deficits in Bergmann glia specification, and develop cerebellar cortical lamination dysgenesis and locomotion defects. In developing Zeb2-mutant cerebella, inward migration of granule neuron progenitors is compromised, the proliferation of glial precursors is reduced, and radial glia fail to differentiate into Bergmann glia in the Purkinje cell layer. In contrast, Zeb2 ablation in granule neuron precursors or oligodendrocyte progenitors does not affect Bergmann glia formation, despite myelination deficits caused by Zeb2 mutation in the oligodendrocyte lineage. Transcriptome profiling identified that ZEB2 regulates a set of Bergmann glia-related genes and FGF, NOTCH, and TGFβ/BMP signaling pathway components. Our data reveal that ZEB2 acts as an integral regulator of Bergmann glia formation ensuring maintenance of cerebellar integrity, suggesting that ZEB2 dysfunction in Bergmann gliogenesis might contribute to motor deficits in Mowat-Wilson syndrome. [ABSTRACT FROM AUTHOR]

White matter injury (WMI) often results in cognitive impairment, behavioral disorders, and cerebral palsy and thus imposes a tremendous burden on society. The cells in brain white matter mainly comprise oligodendrocytes (OLs), astrocytes, and microglia. The dysregulation of OLs development is the pathological hallmark of WMI. Recent studies have demonstrated that microRNAs (miRNAs or miRs) participate in the regulation of OLs development, and the dysregulation of this process represents the pathogenesis of WMI. This review summarizes the progress made in this field that will help clinicians and researchers understand the molecular etiology of WMI and develop miRNAs as new agents for the prevention and treatment of WMI. [ABSTRACT FROM AUTHOR]

Clinically, temozolomide (TMZ) is widely used in glioblastoma (GBM) treatment. However, the toxicity of TMZ may influence the quality of patient life. Thus, novel treatment options for sensitizing GBM cells to TMZ chemotherapy are necessary. Aurora-A is widely expressed in GBM and correlated with poor prognosis. It has been proven to be an effective target for gene therapy and chemotherapy. In the present study, short hairpin (sh)RNA targeting Aurora-A was employed to knockdown Aurora-A expression in GBM cells. Cell Counting Kit-8 assays, flow cytometry, colony formation assays, invasion assays and tube formation assays were used to determine the effects of Aurora-A knockdown when combined with TMZ treatment. A U251 subcutaneous cancer model was established to evaluate the efficacy of combined therapy. The results of the present study indicated that the proliferation, colony formation, invasion and angiogenesis of GBM cells were significantly inhibited by combined therapy when compared with TMZ treatment alone. In vivo results demonstrated that knockdown of Aurora-A significantly (P=0.0084) sensitizes GBM cells to TMZ chemotherapy. The results of the present study demonstrated that knockdown of Aurora-A in GBM cells enhances TMZ sensitivity in vitro and in vivo. Therefore, Aurora-A knockdown may be a novel treatment option for decreasing TMZ toxicity and improving patient quality of life. [ABSTRACT FROM AUTHOR]

There is increasing evidence that microRNAs (miRNAs) are able to play a key role in the diagnosis and therapy of cancer. miRNA-99a (miR-99a), which is downregulated in several human malignancies, has been reported as a potential tumor suppressor. However, to the best of our knowledge, the expression and function of miR-99a has not been investigated in human non-small cell lung cancer (NSCLC) at present. The aim of the current study was to evaluate the association between NSCLC and miR-99a. miR-99a expression was analyzed in 15 pairs of NSCLC and non-cancerous tissue samples by reverse transcription-quantitative polymerase chain reaction. In addition, the NSCLC A549 and H1299 cell lines were transfected with miR-99a mimics, and the effect of miR-99a on the cell cycle, cell proliferation, migration and colony formation of A549 and H1299 cells was investigated. It was found that the level of miR-99a expression was significantly downregulated in NSCLC tissues and that ectopic overexpression of miR-99a significantly inhibited the growth of A549 and H1299 cells. Additionally, ectopic overexpression of miR-99a inhibited A549 and H1299 cell migration and invasion by inhibiting epithelial to mesenchymal transition. The downregulation of insulin-like growth factor 1 receptor (IGF-1R) by miR-99a and knockdown of IGF-1R mediated by siRNA were each found to phenocopy the effect of miR-99a overexpression in NSCLC. To the best of our knowledge, the present study demonstrated for the first time that, in NSCLC, miR-99a is downregulated and thus regulates proliferation, colony formation and migration through the IGF-1R pathway, which indicates that miR-99a is a diagnostic biomarker for NSCLC. [ABSTRACT FROM AUTHOR]

Background: Congenital heart disease (CHD) is one of the most prevalent birth defects. Housing renovations are a newly recognized source of indoor environmental pollution that is detrimental to health. A growing body of research suggests that maternal occupational exposure to renovation materials may be associated with an increased risk of giving birth to fetuses with CHD. However, the effect of indoor housing renovation exposure on CHD occurrence has not been reported. Methods: A multi-hospital case-control study was designed to investigate the association between maternal periconceptional housing renovation exposure and the risk of CHD for offspring. In total, 346 cases and 408 controls were enrolled in this study from four hospitals in China. Exposure information was based on a questionnaire given to women during pregnancy. The association between housing renovation exposure and CHD occurrence was assessed by estimating odds ratios (OR) with logistic regression models adjusted for potential confounders. Results: The risk for CHD in offspring was significantly associated with maternal exposure to housing renovations (AOR: 1.89, 95% CI: 1.29-2.77). There were similar risks for cardiac defects with or without extra-cardiac malformation (AOR of 2.65 and 1.76, respectively). Maternal housing renovation exposure may increase the fetus' risk of suffering from conotruncal defect or anomalous venous return. There were significant risks for cardiac defects if the pregnant woman moved into a new house within one month after decoration at either 3 months before pregnancy (AOR: 2.38, 95% CI: 1.03 to 5.48) or during first trimester (AOR: 4.00, 95% CI: 1.62 to 9.86). Conclusions: Maternal exposure to housing renovations may have an increased risk of giving birth to fetuses with some selected types of CHD. This relationship was stronger for women who moved into a newly decorated house. However, considering the limited number of subjects and the problem of multiple exposures, more research is needed to clarify the effects seen here. [ABSTRACT FROM AUTHOR]

Background: Previous reports on the prevalence of neural tube defects (NTDs) in China did not include cases of NTDs that were less than 28 weeks of gestational age (GA) and hence did not accurately reflect the total prevalence of NTDs or the geographic and urban-rural disparities in their prevalence. This article includes cases of NTDs that were less than 28 weeks of GA. Methods: Data used in this study were collected from 2006 to 2008 using a nationwide hospital-based registry, the Chinese Birth Defects Monitoring Network. The total prevalence ratio (PR) of NTDs and their subtypes, the ratios of PR (PRR), and 95% confidence intervals (CI) were used to analyse geographic disparities at both the regional (north, south) and provincial levels and to analyse disparities between rural and urban areas. Results: Overall, the total PR of NTDs was 14.0 per 10,000 births. The PRR of NTDs of rural women between the north and south region was 2.26 (95% CI: 2.04-2.52), which was much higher than that of urban women (PRR: 1.56, 95% CI: 1.41-1.72). The three subtypes of NTDs had different geographic distribution at the level of province. The urban-rural PRR of NTDs was 2.14 (95% CI: 1.94-2.34) in the north but only 1.47 (95% CI: 1.31-1.66) in the south. Conclusions: There is a high total prevalence of NTDs, which remains one of the major public health concerns in China. Eliminating the geographic and urban-rural disparities in the disease burden is a priority for future intervention. [ABSTRACT FROM AUTHOR]

Background: Intrauterine balloon aortic valvuloplasty (IUBAV) has been used for critical aortic stenosis. However, it is necessary to determine the fetal impairments such as preterm birth after this approach and to find a way to prevent or reduce them. Methods: In the present study, we evaluated the therapeutic value of indomethacin (IDM) and dexamethasone (DXS) on reducing the preterm birth rate in experimental goats after IUBAV. Results: Our results indicated that the administration of IDM/DXS significantly reduced the rate of premature birth. IDM/DXS treatment led to preservation of myocardial ultrastructure with less damage, and amelioration of the fetal and placental circulation. Furthermore, we found that norepinephrine (NE) level was positively associated with the degree of myocardial damage. IDM/DXS administration led to a significant decrease of operation-induced increase of NE levels, which may be associated with the protective effects of IDM/DXS. Lastly, we found that the administration of IDM/DXS did not induce the risk of ductus arteriosus closure or slow down fetal growth. Conclusions: Our results indicate that IDM/DXS promotes a better gestational outcome at least partially by reducing stress response during and after the operation of IUBAV in the goat model. IDM/DXS may be a useful application in human patients during IUBAV intervention. [ABSTRACT FROM AUTHOR]

Background: An outbreak of urinary stones related to consumption of melamine-tainted milk products (MTMP) occurred in China in 2008. The aim of the present study was to evaluate such children to identify their clinical features and risk factors. Methods: Renal ultrasound was performed for 7328 children who presented to a Sichuan teaching hospital between 13 September and 15 October 2008 due to concern of such stones. Clinical data, family information, feeding history and urinary stones were analyzed. Results: Of the 7328 children, 189 (2.58%) had ultrasound findings of urinary stones, and 51 were admitted. Age (mean ± SD) was 27.4 ± 25.5 months, and 101 were male and 88, female. The odds ratio (OR) for urinary stones for infants and young children (1-3 years) as compared to older children (>3 years), was 2.42 (95% confidence interval [CI], 1.64-3.56; P < 0.0001) and 1.95 (95%CI, 1.31-2.89; P < 0.0011), respectively. Independent risk factors associated with urinary stones included consumption of MTMP with melamine at >5500 mg/kg (OR, 13.3; 95%CI, 6.8-26.1, P < 0.0001) as compared to that with melamine at <200 mg/kg, and younger father ( P = 0.0006). On logistic regression, the only risk factor associated with inpatient care was lower family income per person (OR, 4.4; 95%CI, 1.2-15.9, P = 0.02). Repeat ultrasound for 51 children at mean follow up of 15.3 ± 8.9 days found that 33 passed out all stones, which was associated with a larger number of smaller stones ( P = 0.003). Urinary stones contained melamine and uric acid, but no cyanuric acid. Conclusions: MTMP-associated urinary stones were more frequent in young children and more severe in children from poorer families. [ABSTRACT FROM AUTHOR]

Congenital heart disease (CHD) is a common cardiac disorder in humans. Despite many advances in the understanding of CHD and the identification ofmany associated genes, the fundamental etiology for the majority of cases remains unclear. The planar cell polarity (PCP) signaling pathway, responsible for tissue polarity in Drosophila and gastrulation movements and cardiogenesis in vertebrates, has been shown to play multiple roles during cardiac differentiation and development. The disrupted function of PCP signaling is connected to some CHDs. Here, we summarize our current understanding of how PCP factors affect the pathogenesis of CHD. [ABSTRACT FROM AUTHOR]

Integrin αvβ8 plays an important role in cerebral vascular development. It has been proven that αvβ8 is a key factor for transforming growth factor-β1 (TGF-β1) activation in epithelial cells. However, it is not clear whether αvβ8 can activate TGF-β1 and play a role in protection during neonatal hypoxic-ischemic brain injury. In this study, we investigated the relationship between αvβ8 and TGF-β1 activation, and thus the effects of TGF-β1 activation in the protection of neurons after hypoxia-ischemia (HI). Astrocytes and neurons from rat brains were cultured and then subjected to oxygen–glucose deprivation to generate HI model in vitro. β8 expression was determined using immunocytochemistry, western blot, and reverse-transcriptase polymerase chain reaction. TGF-β1 activation was determined by TGF-β bioassay in a tested cell (astrocyte) and a reporter cell co-culture system. The pro-apoptotic protein, cleaved caspase-3, and the anti-apoptotic protein, Bcl-2 and Bcl-xL, were detected using western blot. Cellular apoptosis was detected with TUNEL. We found that β8 expression was stronger in astrocytes than that in neurons under normoxia. HI resulted in a rapid and persistent increase of β8 expression in astrocytes, but only in a slight and transient increase in neurons. Astrocytes β8 could induce TGF-β1 leading to upregulation of Bcl-2 and Bcl-xL, and thus attenuated neuronal apoptosis. The present findings suggest that β8 protecting the brain against neonatal HI injury through TGF-β1 signaling pathway, which may have implications for the treatment of HI brain injury. [ABSTRACT FROM AUTHOR]

Background: Glucocorticoid (GC) resistance is frequently seen in acute lymphoblastic leukemia of T-cell lineage (T-ALL). In this study we investigate the potential and mechanism of using rapamycin to restore the sensitivity of GC-resistant T-ALL cells to dexamethasone (Dex) treatment. Methods: Cell proliferation was detected by 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT) assay. Fluorescence-activated cell sorting (FACS) analysis was used to analyze apoptosis and cell cycles. Western blot analysis was performed to test the expression of the downstream effector proteins of mammalian target of rapamycin (mTOR), the cell cycle regulatory proteins, and apoptosis associated proteins. Results: 10 nM rapamycin markedly increased GC sensitivity in GC-resistant T-ALL cells and this effect was mediated, at least in part, by inhibition of mTOR signaling pathway. Cell cycle arrest was associated with modulation of G1-S phase regulators. Both rapamycin and Dex can induce up-regulation of cyclin-dependent kinase (CDK) inhibitors of p21 and p27 and co-treatment of rapamycin with Dex resulted in a synergistic induction of their expressions. Rapamycin did not obviously affect the expression of cyclin A, whereas Dex induced cyclin A expression. Rapamycin prevented Dex-induced expression of cyclin A. Rapamycin had a stronger inhibition of cyclin D1 expression than Dex. Rapamycin enhanced GC-induced apoptosis and this was not achieved by modulation of glucocorticoid receptor (GR) expression, but synergistically up-regulation of pro-apoptotic proteins like caspase-3, Bax, and Bim, and down-regulation of anti-apoptotic protein of Mcl-1. Conclusion: Our data suggests that rapamycin can effectively reverse GC resistance in T-ALL and this effect is achieved by inducing cell cycles arrested at G0/G1 phase and activating the intrinsic apoptotic program. Therefore, combination of mTOR inhibitor rapamycin with GC containing protocol might be an attracting new therapeutic approach for GC resistant T-ALL patients. [ABSTRACT FROM AUTHOR]

The proapoptotic function of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) phosphatase has been linked to its capacity to antagonize the phosphatidylinositol-3-kinase–Akt signaling pathway. Previous studies have shown that the Forkhead transcriptional factor (FOXO3a) is a critical effector of the PTEN-mediated tumor suppressor. However, whether the PTEN–Akt–FOXO3a pathway is involved in neuronal apoptosis in developing rat brain after hypoxia–ischemia (HI) is unclear. In this study, we generated an HI model using postnatal day 10 rats. Immunohistochemistry and western blot were used to detect the expression of total and phosphorylated PTEN, Akt, and FOXO3a, as well as its target gene Bim. We found that dephosphorylation of PTEN was accompanied by dephosphorylation of Akt and FOXO3a, which induced FOXO3a translocation into the nucleus and upregulated the expression of Bim. Furthermore, we found that PTEN inhibition by bisperoxovanadium significantly increased the phosphorylation of Akt and FOXO3a, decreased the nuclear translocation of FOXO3a, and inhibited Bim expression after HI. Moreover, the downregulation of Bim caused by PTEN inhibition attenuated cellular apoptosis in developing rat brain. Our findings suggest that the PTEN–Akt–FOXO3a pathway is involved in neuronal apoptosis in neonatal rat brain after HI. Agents targeting PTEN may offer a promise to rescue neurons from HI brain damage. [ABSTRACT FROM AUTHOR]

BACKGROUND: Normal stem cells usually express a low level of telomerase activity that serves to stabilize the chromosomes during cell division and helps prevent cell senescence. Human telomerase reverse transcriptase (hTERT) is a rate-limiting enzyme that dictates the activity of human telomerase and thus decides the life span of cells. The expression of hTERT and its roles in β-thalassemia major are unclear, however. STUDY DESIGN AND METHODS: hTERT mRNA expression in bone marrow (BM) CD34+ cells from 25 children with β-thalassemia major and 15 control subjects was investigated using real-time reverse transcription polymerase chain reaction (RT-PCR) analysis. The serum erythropoietin (sEPO) and hemoglobin (Hb) levels in peripheral blood were also determined. The relationship between hTERT and sEPO as well as Hb was then examined. RESULTS: It was found that hTERT mRNA expression was significantly up regulated in BM CD34+ cells from patients with β-thalassemia major. Furthermore, a significantly positive correlation was found between hTERT mRNA and sEPO (r = 0.771, p < 0.001). A significantly inverse correlation, however, was found between hTERT mRNA and Hb concentration (r = −0.929, p < 0.001). CONCLUSION: Our findings suggest that severe anemia with low Hb concentration might up regulate hTERT expression of BM CD34+ cells and sEPO levels in patients with β-thalassemia major. [ABSTRACT FROM AUTHOR]

Abstract  The synchronization of the circadian signals to external or suprachiasmatic nucleus stimulation in the peripheral clocks is essential for maintaining the usual function of human body. However, aging will disrupt the synchronization of peripheral circadian rhythms, thus leading to some age-associated diseases. Up to now, little is known about the modification of the oscillatory rhythms in aged cells. A recent report showed that cell senescence in vascular human smooth muscle cells (HSMCs) altered circadian rhythms by a dysregulation of rhythmic gene expression. Furthermore, this alteration could be reversed by telomerase reconstitution. To test whether telomerase reconstitution can restore disrupted circadian rhythm in other types of senescent cells, we used fibroblasts as cell models to profoundly investigate the relationship between cell senescence and circadian rhythm modulation. We found that the response of rhythmic gene expression to serum stimulation was markedly attenuated in senescent fibroblasts, telomerase-reconstituted fibroblasts reset the circadian oscillation of rhythmic gene expression, and the activation of pERK-CREB and p38-CREB pathways might be involved in the circadian rhythm resetting. These findings suggested that telomerase reconstitution might be a good way to reset synchronization of peripheral circadian rhythms disrupted in senescent tissues. [ABSTRACT FROM AUTHOR]

Abstract  Telomerase reconstitution shows great potential for cell treatment and tissue engineering. Although the effects of telomerase on cell lifespan are well documented, the effects of telomerase on cellular biological characteristics, such as cellular migration, are relatively unknown. In this study, we tried to investigate if telomerase is involved in the regulation of fibroblast migration and the mechanism behind it. We found that when stimulated with a chemokine, CXCL12, the rate of migration was significantly higher in fibroblasts with telomerase reconstitution than that in fibroblasts without. Furthermore, the CXCL12 receptor, CXCR4, and multiple down-stream factors (Rho family members), were upregulated in the telomerase reconstituted fibroblasts. We concluded for the first time that telomerase reconstitution increased fibroblast migration through activation of CXCL12/CXCR4 axis and Rho family. The finding that fibroblasts with telomerase reconstitution have enhanced migration may have broad implications for cell therapy. [ABSTRACT FROM AUTHOR]

Hypoxia inducible factor 1α (HIF-1α) is a key regulator of cellular oxygen homeostasis. However, the regulation of HIF-1α in neonates with hypoxia–ischemia (HI) is not clear. Under normoxic conditions, the extracellular signal-related protein kinase (ERK) pathway has been shown to be involved in the activation of HIF-1α in cell lines. Therefore, we hypothesized that the ERK pathway is involved in the activation of HIF-1α and its target genes in the developing rat brain following HI. To test this hypothesis, we set up an HI model by ligating the right common carotid artery followed by hypoxia using postnatal day 10 rats. Rat brains from HI and sham controls were collected to detect the expression of HIF-1α, its target gene, vascular endothelial growth factor (VEGF), and ERK using immunohistochemistry, Western blot analysis, and RT-PCR. We found that the expression of HIF-1α protein was significantly upregulated at 4 h and peaked at 8 h after HI compared with sham controls. Accordingly, VEGF was similarly upregulated. However, the expression of total ERK (Erk1/2) had no obvious changes. Even though the phosphorylated form of ERK, p-Erk1/2, was upregulated and peaked at 4 h after HI, it is earlier than that seen in HIF-1α expression. Furthermore, the induction of HIF-1α protein, but not its mRNA, could be significantly inhibited by Erk1/2 pathway specific inhibitor, U0126. Our findings suggest that Erk1/2 pathway is involved in the regulation of HIF-1α and VEGF in the developing rat brain after HI. The Erk1/2 pathway may work as a potential target for therapeutic intervention in neonates with HI. [ABSTRACT FROM AUTHOR]