Search

Crocin, extracted and purified from Gardenia jasminoids Ellis in our laboratory, has been reported to have antioxidative, hypolipidaemic and anti-atherosclerorotic effects. However, the underlying molecular mechanisms by which crocin acts as a cytoprotective agent remain to be elucidated. In the present study, we examined the mechanisms of crocin, the digentiobiosyl ester of crocetin, on bovine aortic endothelial cell apoptosis induced by hydrogen peroxide (H2O2). The cells were obtained from the thoracic aorta of newborn calves, and apoptosis was induced by 200 µM H2O2. Before addition of H2O2, the cells were pretreated with different concentrations of crocin for 6 hr. After incubation of the cells with H2O2, a comparative reverse transcriptase–polymerase chain reaction-based repeated amplification protocol assay was used to determine the ratio of bcl-2/bax mRNA expression, and cells loaded with fluo-3/AM were subjected to laser scanning confocal microscopy for detection of intracellular calcium ([Ca2+]i) levels. Treatment of the cells with H2O2 alone decreased the ratio of bcl-2/bax expression to almost twice of those of untreated cells (from 0.33 ± 0.05 to 0.16 ± 0.02). In the presence of 1 and 10 µM crocin, the ratios were enhanced when compared with H2O2 alone respectively (from 0.16 ± 0.02 to 0.58 ± 0.04, 1.18 ± 0.13). The treatment of cells with crocin alone had little effect on the value of this ratio. In the presence or absence of extracellular Ca2+, H2O2 could induce intracellular calcium elevation not only in the elevation presence of extracellular Ca2+ (Hanks), but also without extracellular calcium present (D-Hanks). But the extent of [Ca2+]i under conditions lacking extracellular calcium is less. Crocin concentration dependently inhibited the [Ca2+]i elevation induced by H2O2 under these two conditions. Our data suggest that crocin may exert anti-atherosclerotic effects by increasing the expression ratio of bcl-2/bax, as a result, inhibiting the bovine aortic endothelial cell apoptosis that plays an important role in the initiation and progression of atherosclerosis. [ABSTRACT FROM AUTHOR]

RRR-α-tocopherol ether linked acetic acid analog (α-TEA), is a potential chemotherapeutic agent for ovarian cancer. Pro-death and pro-life signaling pathways were studied to understand the anti-cancer actions of α-TEA on cisplatin-sensitive (A2780S) and -resistant (A2780/cp70R) human ovarian cancer cells. Both cell lines were refractory to Fas; whereas, α-TEA sensitized them to Fas signaling. α-TEA increased levels of Fas message, protein and membrane-associated Fas. Neutralizing antibodies to Fas or Fas L partially blocked α-TEA-induced apoptosis. α-TEA induced prolonged activation of c-Jun N-terminal kinase (JNK) and its substrate c-Jun; Bax conformational change; and cleavage of Bid and caspases-8, -9 and -3. Chemical inhibitors of JNK, and caspases blocked α-TEA-induced apoptosis. α-TEA decreased phosphorylation of protein kinase B (Akt/PKB) and extracellular signal-regulated kinase (ERK1/2), as well as cellular FLICE-like inhibitory protein (c-FLIP) and Survivin protein levels. Knockdown of Akt and ERK activity using phosphoinositide- 3-kinase (PI3K) and mitogen-activated protein kinase kinase (MKK1) inhibitors enhanced α-TEA-induced apoptosis. Over-expression of constitutively active Akt2 and MKK1 blocked α-TEA-induced apoptosis. Collectively, data show α-TEA to be a potent apoptotic inducer of both cisplatin-sensitive and -resistant human ovarian cancer cells via activating death receptor Fas signaling and suppressing anti-apoptotic AKT and ERK targets. [ABSTRACT FROM AUTHOR]

From start-up, growth, maturity to decline, a company will experience a complicated process, in which the company needs to change its anticipated objective, structure and business model with the variation of environment, in order to survive and gain sustainable development. Based on an enterprise's life-cycle theory, this paper makes use of both qualitative and quantitative models to do an empirical study on measurement of the life-cycle of 1135 Chinese public companies from 1991 to 2002, both FoxPro and SAS programs are used to process data. At the end of the paper, the author comes up with a company's value goals and relevant competence strategies in every stage of life cycle, with the purpose to promote the Chinese public companies' sustainable development. [ABSTRACT FROM AUTHOR]

Background: The impact of uridine diphosphate glucuronosyltransferase 1A7 (UGT1A7) polymorphisms on genetic susceptibility to digestive system cancer has received close attention since the discovery by Guillemette, the polymorphisms of which may alter enzyme activity. To clarify the allele frequency distribution and its association with risk of colorectal cancer, a population-based case–control study was carried out in Chinese population. Methods: A total of 140 patients with colorectal cancer and 280 cancer-free frequency-matched controls from a follow-up cohort population established in 1989, were enrolled. For the UGT1A7 polymorphisms analysis, polymerase chain reaction (PCR)-based genotyping techniques including semi-nested PCR, allele-specific PCR and PCR-restriction fragment length polymorphism (RFLP) were developed. Results: The variant allele frequencies in patients and controls were 50.0% and 38.6%, respectively, which were significantly associated with risk of colorectal cancer (odds ratio [OR]: 1.59; 95% confidence interval [CI]: 1.19–2.13). For the variant genotypes analysis, *2/*2 and *3/*3 exhibited a significant association with risk of colorectal cancer (OR: 7.80, 95%CI: 2.66–22.87; OR: 3.47, 95%CI: 1.51–7.97, respectively). Stratification analysis indicated that in previous–current cigarette smoking (cigarette smoking history), current cigarette smoking (current cigarette smoking status), previous–current alcohol drinking (alcohol drinking history) or current alcohol drinking individuals (current alcohol drinking status), the risk developing colorectal cancer increased: OR (95%CI), 2.81 (0.97–8.11), 3.39 (1.19–9.67), 2.89 (0.99–8.46) and 3.14 (1.09–9.09), respectively. Conclusions: UGT1A7 polymorphisms may have a significant modifying effect on colorectal cancer risk, which may interact with environmental factors, cigarette smoking and alcohol drinking in colorectal carcinogenesis. [ABSTRACT FROM AUTHOR]

Background: The pollution of drinking water, e.g. from rivers and pools, has long been recognized to be associated with an increased risk for colorectal cancer (CRC), but there are few direct prospective cohort studies related to person-years on the relative risks of different sources of drinking water for CRC, hence the reason for our study. Methods: Based on a screening for CRC among residents aged 30 years and over in Jiashan County, Zhejiang Province, China, a total of 64,115 residents were classified into five cohorts by their source of drinking water and followed-up from 1st May 1990 to 1st January 2001. Person-years was calculated for every cohort member and Poisson regression was used to control potential confounding variables including demographic variables and smoking history, and to attain crude and adjusted relative risks based on person-years. Results: A trend was seen toward increasing incidence rates for CRC from the drinking water sources of municipal, river, ditch, mixed water to well in turn as shown by relative risk rates of 29.61, 32.67, 33.45, 40.87 and 58.67 per 100,000 inhabitants. Only the role in risk of well water was significantly different from municipal water (P < 0.05). After the confounding variables were adjusted, the significant risk from well water could be seen for colon cancer, rectal cancer as well as CRC. The relative risks were 1.741 [95% confidence interval (CI) 1.001-3.029], 2.228 (95% CI 1.432-3.466) and 2.022 (95% CI 1.432-2.854), respectively. Conclusion: Drinking well water over a long period was identified as playing a role in the risk for CRC, especially for rectal cancer. [ABSTRACT FROM AUTHOR]

Abstract Study objective: To asses the association between alcohol consumption and the risk of colorectal cancer (CRC) in the Chinese population. Design: A population-based prospective cohort study was initiated from the colorectal cancer screening population in Jiashan County in 19891990. The drinking habits of individuals were investigated with demographic information. Setting: A cohort study was followed-up from 1st May 1990 to 1st January 2001 and censored at the date of diagnosis of CRC, at death from any causes, or at 1st January 2001, whichever came first, and the person-time was computed. Participants: Two hundred and forty two CRC patients were diagnosed during the study period and 64,100 individuals finished the follow-up. Results: The distribution of sex, smoking status, occupation, education level and marital status were all significantly different among different drinking habits at baseline. When the above factors were adjusted, no significant association was observed between alcohol consumption and the risk of CRC. Exclusion of individuals diagnosed cancer less than 1 year after the examination date did not alter the strength of an alcoholCRC relationship. Further analysis in sex strata also did not show a significant relationship. Conclusions: Alcohol drinking may not be associated with a higher risk of CRC in the Chinese population. [ABSTRACT FROM AUTHOR]

We investigated whether dissimilar biochemical fractions originating in anatomically discrete sections of the pomegranate (Punica granatum) fruit might act synergistically against proliferation, metastatic potential, and phosholipase A2 (PLA2) expression of human prostate cancer cells in vitro. Proliferation of DU 145 human prostate cancer cells was measured following treatment with a range of therapeutically active doses of fermented pomegranate juice polyphenols (W) and sub-therapeutic doses of either pomegranate pericarp (peel) polyphenols (P) or pomegranate seed oil (Oil). Invasion across Matrigel by PC-3 human prostate cancer cells was measured following treatment with combinations of W, P and Oil such that the total gross weight of pomegranate extract was held constant. Expression of PLA2, associated with invasive potential, was measured in the PC-3 cells after treatment with the same dosage combinations as per invasion. Supra-additive, complementary and synergistic effects were proven in all models by the Kruskal-Wallis non-parametric H test at p < 0.001 for the proliferation tests, p < 0.01 for invasion, and p < 0.05 for PLA2 expression. Proliferation effects were additionally evaluated with CompuSyn software median effect analysis and showed a concentration index CI < 1, confirming synergy. The results suggest vertical as well as the usual horizontal strategies for discovering pharmacological actives in plants. [ABSTRACT FROM AUTHOR]

Vitamin E is a term that describes a group of compounds with similar yet unique chemical structures and biological activities. One interesting property possessed by certain vitamin E compounds-namely, delta-tocotrienol, RRR-alpha-tocopheryl succinate [vitamin E succinate (VES), a hydrolyzable ester-linked succinic acid analogue of RRR-alpha-tocopherol], and a novel vitamin E analogue referred to as alpha-TEA (alpha-tocopherol ether linked acetic acid analogue, which is a stable nonhydrolyzable analogue of RRR-alpha-tocopherol)-is their ability to induce cancer cells but not normal cells to undergo a form of cell death called apoptosis. In contrast, the parent compound, RRR-alpha-tocopherol, also referred to as natural or authentic vitamin E and known for its antioxidant properties, does not induce cancer-cell apoptosis. Efforts to understand how select vitamin E forms can induce cancer cells to undergo apoptosis have identified several nonantioxidant biological functions, including restoration of pro-death transforming growth factor-beta and Fas signaling pathways. Recent studies with alpha-TEA show it to be a potent inducer of apoptosis in a wide variety of epithelial cancer cell types, including breast, prostate, lung, colon, ovarian, cervical, and endometrial in cell culture, and to be effective in significantly reducing tumor burden and metastasis in a syngeneic mouse mammary tumor model, as well as xenografts of human breast cancer cells. Studies also show that alpha-TEA, in combination with the cyclooxygenase-2 inhibitor celecoxib and the chemotherapeutic drug 9-nitro-camptothecin decreases breast cancer animal model tumor burden and inhibits metastasis significantly better than do single-agent treatments. [ABSTRACT FROM AUTHOR]

Vitamin E derivative, RRR-α-tocopheryl succinate (vitamin E succinate, VES), is a potent pro-apoptotic agent, inducing apoptosis by restoring both transforming growth factor-β (TGF-β) and Fas (CD95) apoptotic signaling pathways that contribute to the activation of c-Jun N-terminal kinase (JNK)-mediated apoptos is. Objectives of these studies were to characterize signaling events involved in the pro-apoptotic actions of a naturally occurring form of vitamin E, δ-tocotrienol, and a novel vitamin E analog, α-tocopherol ether acetic acid analog [α-TEA; 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxyacetic acid]. Like VES, α-TEA and δ-tocotrienol induced estrogen-nonresponsive MDA-MB-435 and estrogen-responsive MCF-7 human breast cancer cells to undergo high levels of apoptosis in a concentration- and time-dependent fashion. Like VES, the two compounds induced either no o1" lower levels of apoptosis in normal human mammary epithelial cells and immortalized but nontumorigenic human MCF-10A cells. The pro-apoptotic mechanisms triggered by the structurally distinct α-TEA and δ-tocotrienol were identical to those previously reported for VES, that is, α-TEA-and δ-tocotrienol-induced apoptosis involved up-regulation of TGF-β receptor II expression and TGF-β-, Fas- and JNK-signaling pathways. These data provide a better understanding of the anticancer actions of a dietary form of vitamin E (δ-tocotrienol) and a novel nonhydrolyzable vitamin E analog (α-TEA). [ABSTRACT FROM AUTHOR]

Abstract 3-Phosphoinositide-dependent protein kinase 1 (PDK1) is a pivotal regulator in the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway that have been shown to play key roles in the functional development of B and T cells via activation of AGC protein kinases during hematopoiesis. However, the role of PDK1 in HSCs has not been fully defined. Here we specifically deleted the PDK1 gene in the hematopoietic system and found that PDK1-deficient HSCs exhibited impaired function and defective lineage commitment abilities. Lack of PDK1 caused HSCs to be less quiescent and to produce a higher number of phenotypic HSCs and fewer progenitors. PDK1-deficient HSCs were also unable to reconstitute the hematopoietic system. Notably, HSC function was more dependent on PDK1 than on mTORC2, which indicates that PDK1 plays a dominant role in the Akt-mediated regulation of HSC function. PDK1-deficient HSCs also exhibited reduced ROS levels, and treatment of PDK1-deficient HSCs with L-butathioninesulfoximine in vitro elevated the low ROS level and promoted colony formation. Therefore, PDK1 appears to contribute to HSC function partially via regulating ROS levels.

Hematopoietic stem cells constitute a unique subpopulation of blood cells that can give rise to all types of mature cells in response to physiological demands. However, the intrinsic molecular machinery that regulates this transformative property remains elusive. In this paper, we demonstrate that small GTPase Rheb1 is a critical regulator of proliferation and differentiation of hematopoietic stem cells in vivo. Rheb1 deletion led to increased phenotypic hematopoietic stem cell/hematopoietic progenitor cell proliferation under a steady state condition. Over-proliferating Rheb1-deficient hematopoietic stem cells were severely impaired in functional repopulation assays, and they failed to regenerate the blood system when challenged with hematopoietic ablation by sublethal irradiation. In addition, it was discovered that Rheb1 loss resulted in a lack of maturation of neutrophils / caused neutrophil immaturation by reducing mTORC1 activity, and that activation of the mTORC1 signaling pathway by mTOR activator 3BDO partially restored the maturation of Rheb1-deficient neutrophils. Rheb1 deficiency led to a progressive enlargement of the hematopoietic stem cell population and an eventual excessive myeloproliferation in vivo, including an overproduction of peripheral neutrophils and an excessive expansion of extramedullary hematopoiesis. Moreover, low RHEB expression was correlated with poor survival in acute myeloid leukemia patients with normal karyotype. Our results, therefore, demonstrate a critical and unique role for Rheb1 in maintaining proper hematopoiesis and myeloid differentiation.

Summary: We previously reported the generation of integration-free induced pluripotent stem cells from adult peripheral blood (PB) with an improved episomal vector (EV) system, which uses the spleen focus-forming virus U3 promoter and an extra factor BCL-XL (B). Here we show an ∼100-fold increase in efficiency by optimizing the vector combination. The two most critical factors are: (1) equimolar expression of OCT4 (O) and SOX2 (S), by using a 2A linker; (2) a higher and gradual increase in the MYC (M) to KLF4 (K) ratio during the course of reprogramming, by using two individual vectors to express M and K instead of one. The combination of EV plasmids (OS + M + K + B) is comparable with Sendai virus in reprogramming efficiency but at a fraction of the cost. The generated iPSCs are indistinguishable from those from our previous approach in pluripotency and phenotype. This improvement lays the foundation for broad applications of episomal vectors in PB reprogramming. : In this article, Zhang, Cheng, and colleagues show that the use of two episomal vectors to express MYC and KLF4 leads to an ∼100-fold increase in reprogramming of human PB MNCs to pluripotency. This improved episomal vector system is comparable with Sendai virus in generating integration-free iPSCs but at a fraction of the cost. Keywords: human induced pluripotent stem cells, peripheral blood mononuclear cells, episomal vectors, sendai viral vectors

Abstract Background The constitutive hyper-activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways has frequently been associated with acute myeloid leukemia (AML). While many inhibitors targeting these pathways have been developed, the anti-leukemic effect was not as robust as expected. As part of the molecular link between PI3K/Akt and mTOR kinase, the role of Rheb1 in AML remains unexplored. Our study aims to explore the role of Rheb1 in AML and estimate whether Rheb1 could be a potential target of AML treatment. Methods The expressions of Rheb1 and other indicated genes were analyzed using real-time PCR. AML mouse model was established by retrovirus transduction. Leukemia cell properties and related signaling pathways were dissected by in vitro and in vivo studies. The transcriptional changes were analyzed via gene chip analysis. Molecular reagents including mTOR inhibitor and mTOR activator were used to evaluate the function of related signaling pathway in the mouse model. Results We observed that Rheb1 is overexpressed in AML patients and the change of Rheb1 level in AML patients is associated with their median survival. Using a Rheb1-deficient MLL-AF9 murine AML model, we revealed that Rheb1 deletion prolonged the survival of AML mice by weakening LSC function. In addition, Rheb1 deletion arrested cell cycle progression and enhanced apoptosis of AML cells. Furthermore, while Rheb1 deletion reduced mTORC1 activity in AML cells, additional rapamycin treatment further decreased mTORC1 activity and increased the apoptosis of Rheb1 Δ/Δ AML cells. The mTOR activator 3BDO partially rescued mTORC1 signaling and inhibited apoptosis in Rheb1 Δ/Δ AML cells. Conclusions Our data suggest that Rheb1 promotes AML progression through mTORC1 signaling pathway and combinational drug treatments targeting Rheb1 and mTOR might have a better therapeutic effect on leukemia.

Presents information on a study which developed a method to prepare ceramic coatings by making use of plasma energy produced from the pulsed discharge between electric conductor and aqueous electrolyte. Methodology of the study; Results and discussion on the study; Conclusions.

TET1/2/3 are methylcytosine dioxygenases that regulate cytosine hydroxymethylation. Tet1/2 are abundantly expressed in HSC/HPCs and are implicated in hematological malignancies. Tet2 deletion in mice causes myeloid malignancies, while Tet1-null mice develop B cell lymphoma after an extended period of latency. Interestingly, TET1/2 are often concomitantly downregulated in acute B-lymphocytic leukemia. Here, we investigated the overlapping and non-redundant functions of Tet1/2 using Tet1/2 double-knockout (DKO) mice. DKO and Tet2−/− HSC/HPCs show overlapping and unique 5hmC and 5mC profiles. DKO mice exhibit strikingly decreased incidence and delayed onset of myeloid malignancies in comparison to Tet2−/− mice and in contrast develop lethal B cell malignancies. Transcriptome analysis of DKO tumors reveals expression changes in many genes dysregulated in human B cell malignancies, including LMO2, BCL6, and MYC. These results highlight the critical roles of TET1/2 individually and together in the pathogenesis of hematological malignancies.

Fanconi anemia is a complex heterogeneous genetic disorder with a high incidence of bone marrow failure, clonal evolution to acute myeloid leukemia and mesenchymal-derived congenital anomalies. Increasing evidence in Fanconi anemia and other genetic disorders points towards an interdependence of skeletal and hematopoietic development, yet the impact of the marrow microenvironment in the pathogenesis of the bone marrow failure in Fanconi anemia remains unclear. Here we demonstrated that mice with double knockout of both Fancc and Fancg genes had decreased bone formation at least partially due to impaired osteoblast differentiation from mesenchymal stem/progenitor cells. Mesenchymal stem/progenitor cells from the double knockout mice showed impaired hematopoietic supportive activity. Mesenchymal stem/progenitor cells of patients with Fanconi anemia exhibited similar cellular deficits, including increased senescence, reduced proliferation, impaired osteoblast differentiation and defective hematopoietic stem/progenitor cell supportive activity. Collectively, these studies provide unique insights into the physiological significance of mesenchymal stem/progenitor cells in supporting the marrow microenvironment, which is potentially of broad relevance in hematopoietic stem cell transplantation.

Discusses the mechanism of action of vitamin E as tumor cell growth inhibitors. Structure and nomenclature of vitamin E compounds; Apoptotic activity of vitamin E compounds; Vitamin E succinate induction of apoptosis of human cancer cells.

SUMMARY Fluorescent proteins (FPs) have great utility in identifying specific cell populations and in studying cellular dynamics in the mouse. To quantify the factors that determine both the expression and relative brightness of FPs in mouse embryonic stem cells (mESCs) and in mice, we generated eight different FP-expressing ROSA26 alleles using recombinase-mediated cassette exchange (RMCE). These alleles enabled us to analyze the effects on FP expression of a translational enhancer and different 3′-intronic and/or polyadenylation sequences, as well as the relative brightness of five different FPs, without the confounding position and copy number effects that are typically associated with randomly inserted transgenes. We found that the expression of a given FP can vary threefold or more depending on the genetic features present in the allele. The optimal FP expression cassette contained both a translational enhancer sequence in the 5′-untranslated region (UTR) and an intron-containing rabbit β-globin sequence within the 3′-UTR. The relative expressed brightness of individual FPs varied up to tenfold. Of the five different monomeric FPs tested, Citrine (YFP) was the brightest, followed by Apple, eGFP, Cerulean (CFP) and Cherry. Generation of a line of Cherry-expressing mice showed that there was a 30-fold variation of Cherry expression among different tissues and that there was a punctate expression pattern within cells of all tissues examined. This study should help investigators make better-informed design choices when expressing FPs in mESCs and mice.

The development of early B cells, which are generated from hematopoietic stem cells (HSCs) in a series of well-characterized stages in bone marrow (BM), represents a paradigm for terminal differentiation processes. Akt is primarily regulated by phosphorylation at Thr308 by PDK1 and at Ser473 by mTORC2, and Akt signaling plays a key role in hematopoiesis. However, the role of mTORC2 in the development of early B cells remains poorly understood. In this study, we investigated the functional role of mTORC2 by specifically deleting an integral component, Rictor, in a hematopoietic system. We demonstrated that the deletion of Rictor induced an aberrant increase in the FoxO1 and Rag-1 proteins in BM B cells and that this increase was accompanied by a significant decrease in the abundance of B cells in the peripheral blood (PB) and the spleen, suggesting impaired development of early B cells in adult mouse BM. A BM transplantation assay revealed that the B cell differentiation defect induced by Rictor deletion was not affected by the BM microenvironment, thus indicating a cell-intrinsic mechanism. Furthermore, the knockdown of FoxO1 in Rictor-deleted HSCs and hematopoietic progenitor cells (HPCs) promoted the maturation of B cells in the BM of recipient mice. In addition, we revealed that treatment with rapamycin (an mTORC1 inhibitor) aggravated the deficiency in B cell development in the PB and BM. Taken together, our results provide further evidence that Rictor regulates the development of early B cells in a cell-intrinsic manner by modifying the expression of FoxO1 and Rag-1.

BACKGROUND: Bone marrow microenvironment (niche) plays essential roles in the fate of hematopoietic stem cells (HSCs). Intracellular and extracellular redox metabolic microenvironment is one of the critical factors for the maintenance of the niche. Cytochrome P450 reductase (CPR) is an obligate electron donor to all microsomal cytochrome P450 enzymes (P450 or CYP), and contributes to the redox metabolic process. However, its role in maintaining HSCs is unknown. OBJECTIVE: To examine the effects of low CPR expression on HSCs function using a mouse model of globally suppressed Cpr gene expression (Cpr Low, CL mice). METHODS: Hematopoietic cell subpopulations in bone marrow (BM) and peripheral blood (PB) from WT and CL mice were examined for their repopulation and differentiation ability upon BM competitive transplantation and enriched HSC (LKS(+)) transplantation. Effects of low CPR expression on hematopoiesis were examined by transplanting normal BM cells into CL recipients. Reactive oxygen species (ROS), cell cycle, and apoptosis in CL mice were analyzed by flow cytometry for DCF-DA fluorescence intensity, Ki67 protein, and Annexin-V, respectively. RESULTS: The levels of ROS in BM cells, HPCs and HSCs were comparable between CL and WT mice. In comparison to WT mice, the number of LT-HSCs or ST-HSCs was lower in CL mice while CMPs, GMPs and MEPs in CL mice were higher than that in WT control. Competitive transplantation assay revealed enhanced repopulation capacity of HSCs with low CPR expression, but no difference in differentiation potential upon in vitro experiments. Furthermore, lymphoid differentiation of donor cells decreased while their myeloid differentiation increased under CL microenvironment although the overall level of donor hematopoietic repopulation was not significantly altered. CONCLUSIONS: Our studies demonstrate that suppressing CPR expression enhances the repopulation efficiency of HSCs and a low CPR expression microenvironment favors the differentiation of myeloid over lymphoid lineage cells.

Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome that is characterized by pure red-cell aplasia and associated physical deformities. It has been proven that defects of ribosomal proteins can lead to this disease and that RPS19 is the most frequently mutated gene in DBA patients. Previous studies suggest that p53-dependent genes and pathways play important roles in RPS19-deficient embryos. However, whether there are other vital factors linked to DBA has not been fully clarified. In this study, we compared the whole genome RNA-Seq data of zebrafish embryos injected with RPS19 morpholino (RPS19 MO), RPS19 and p53 morpholino simultaneously (RPS19+p53 MO) and control morpholino (control). We found that genes enriched in the functions of hematological systems, nervous system development and skeletal and muscular disorders had significant differential expression in RPS19 MO embryos compared with controls. Co-inhibition of p53 partially alleviates the abnormalities for RPS19-deficient embryos. However, the hematopoietic genes, which were down-regulated significantly in RPS19 MO embryos, were not completely recovered by the co-inhibition of p53. Furthermore, we identified the genome-wide p53-dependent and -independent genes and pathways. These results indicate that not only p53 family members but also other factors have important impacts on RPS19-deficient embryos. The detection of potential pathogenic genes and pathways provides us a new paradigm for future research on DBA, which is a systematic and complex hereditary disease.

All pancreatic endocrine cell types arise from a common endocrine precursor cell population, yet the molecular mechanisms that establish and maintain the unique gene expression programs of each endocrine cell lineage have remained largely elusive. Such knowledge would improve our ability to correctly program or reprogram cells to adopt specific endocrine fates. Here, we show that the transcription factor Nkx6.1 is both necessary and sufficient to specify insulin-producing beta cells. Heritable expression of Nkx6.1 in endocrine precursors of mice is sufficient to respecify non-beta endocrine precursors towards the beta cell lineage, while endocrine precursor- or beta cell-specific inactivation of Nkx6.1 converts beta cells to alternative endocrine lineages. Remaining insulin(+) cells in conditional Nkx6.1 mutants fail to express the beta cell transcription factors Pdx1 and MafA and ectopically express genes found in non-beta endocrine cells. By showing that Nkx6.1 binds to and represses the alpha cell determinant Arx, we identify Arx as a direct target of Nkx6.1. Moreover, we demonstrate that Nkx6.1 and the Arx activator Isl1 regulate Arx transcription antagonistically, thus establishing competition between Isl1 and Nkx6.1 as a critical mechanism for determining alpha versus beta cell identity. Our findings establish Nkx6.1 as a beta cell programming factor and demonstrate that repression of alternative lineage programs is a fundamental principle by which beta cells are specified and maintained. Given the lack of Nkx6.1 expression and aberrant activation of non-beta endocrine hormones in human embryonic stem cell (hESC)-derived insulin(+) cells, our study has significant implications for developing cell replacement therapies.

Ten new cembrane-based diterpenes, locrassumins A–G (1–7), (–)-laevigatol B (8), (–)-isosarcophine (9), and (–)-7R,8S-dihydroxydeepoxysarcophytoxide (10), were isolated from a South China Sea collection of the soft coral Lobophytum crassum, together with eight known analogues (11–18). The structures of the new compounds were determined by extensive spectroscopic analysis and by comparison with previously reported data. Locrassumin C (3) possesses an unprecedented tetradecahydrobenzo[3,4]cyclobuta[1,2][8]annulene ring system. Compounds 1, 7, 12, 13, and 17 exhibited moderate inhibition against lipopolysaccharide (LPS)-induced nitric oxide (NO) production with IC50 values of 8–24 μM.

The authors comment on a study by A. J. Mitchell and D. Lawrence which claims that schizophrenics and people with other mental illnesses have lower invasive coronary intervention rates following acute coronary syndrome. According to the authors, the main limitation of the study by Mitchell and Lawrence is that the data analyzed were from observational studies conducted in the U.S. They add that, despite this limitation, it emphasizes the need for more research on low quality of care.

An abstract of the article "Vitamin E and Cancer," by Kimberly Kline and colleagues is presented.

C-reactive protein (CRP) can increase up to 1000-fold in blood and form complexes with very low density lipoproteins (VLDL). These complexes are associated with worse outcomes for septic patients, and this suggests a potential pathological role in sepsis. Complex formation is heightened when CRP is over 200 mg/l and levels are associated with the severity of sepsis and blood bacterial culture positivity. Using a mouse bacteremia model, blood bacterial clearance can be delayed by i.v. injection of CRP-VLDL complexes. Complexes are more efficiently taken up by activated U937 cells in vitro and Kupffer cells in vivo than VLDL alone. Both in vitro-generated and naturally occurring CRP-VLDL complexes reduce phagocytosis of bacteria by activated U937 cells. Fcg and scavenger receptors are involved and a competitive mechanism for clearance of CRP-VLDL complexes and bacteria is demonstrated. Interaction of phosphocholine groups on VLDL with CRP is the major driver for complex formation and phosphocholine can disrupt the complexes to reverse their inhibitory effects on phagocytosis and bacterial clearance. Increased formation of CRP-VLDL complexes is therefore harmful and could be a novel target for therapy in sepsis. [ABSTRACT FROM AUTHOR]

Antipsychotic medications can induce cardiovascular and metabolic abnormalities (such as obesity, hyperglycemia, dyslipidemia and the metabolic syndrome) that are associated with an increased risk of type 2 diabetes mellitus and cardiovascular disease. Controversy remains about the contribution of individual antipsychotic drugs to this increased risk and whether they cause sudden cardiac death through prolongation of the corrected QT interval. Although some drug receptor-binding affinities correlate with specific cardiovascular and metabolic abnormalities, the exact pharmacological mechanisms underlying these associations remain unclear. Antipsychotic agents with prominent metabolic adverse effects might cause abnormalities in glucose and lipid metabolism via both obesity-related and obesity-unrelated molecular mechanisms. Despite existing guidelines and recommendations, many antipsychotic-drug-treated patients are not assessed for even the most easily measurable metabolic and cardiac risk factors, such as obesity and blood pressure. Subsequently, concerns have been raised over the use of these medications, especially pronounced in vulnerable pediatric patients, among whom their use has increased markedly in the past decade and seems to have especially orexigenic effects. This Review outlines the metabolic and cardiovascular risks of various antipsychotic medications in adults and children, defines the disparities in health care and finally makes recommendations for screening and monitoring of patients taking these agents. [ABSTRACT FROM AUTHOR]