Protective Effect of L-Carnitine and Coenzyme Q10 on CCl4-Induced Liver Injury in Rats

This study provides an information about the mechanisms of liver injury induced by CCl4, and determines the influence of administration of L-carnitine or/and CoQ10 as prophylactic agents against CCl4 deteriorative effect. The study was carried out on 80 adult male albino rats divided into eight groups, 10 animals each, as follows: four normal groups (control, treated with L-carnitine, treated with CoQ10, and treated with a combination of Lcarnitine and CoQ10) and four liver injury groups treated with CCl4 (control, treated with L-carnitine, treated with CoQ10, and treated with a combination of L-carnitine and CoQ10). Liver injury was induced by s.c. injection of a single dose of CCl4 (1 ml/kg). L-carnitine (50 mg/kg/day) was given i.p. for four successive days 24 hours before CCl4 injection, and CoQ10 (200 mg/kg) was given as a single i.p. dose 24 hours before CCl4 injection. Animals were sacrificed 24 hours after CCl4 injection, blood samples were withdrawn and liver tissue samples were homogenized. The levels of the following parameters were determined: hepatic reduced glutathione, serum ALT and AST, hepatic lipid peroxides, hepatic vitamin C, hepatic and serum total protein, serum albumin, serum sialic acid, serum nitrite, and serum and hepatic total LDH activities and LDH isoenzymes. The obtained data revealed that CCl4 injection produced a significant decrease in reduced glutathione content, vitamin C, total protein and albumin levels. However, there was a significant increase in serum ALT and AST activities, lipid peroxides, sialic acid, nitric oxide, serum and hepatic total LDH activities. On the other hand, groups treated with L-carnitine or/and CoQ10 prior to CCl4 injection showed an improvement in most parameters when compared with cirrhotic control group. It has been concluded that L-carnitine and coenzyme Q10 have a pronounced prophylactic effect against liver damage induced by halogenated alkanes such as carbon tetrachloride

Effects of Long-term Use of Depo-medroxyprogesterone Acetate on Lipid Metabolism in Nepalese Women

Various synthetic progestogens that are used as contraceptives have been reported to influence lipid and lipoprotein fractions differently. Depo-medroxyprogesterone acetate (DMPA), a synthetic progestogen, is used by Nepalese women as a contraceptive agent. Our study aims to determine the effects of long-term use of DMPA on lipid metabolism. We performed this study on 60 healthy Nepalese women who had been using DMPA for more than 2 yr and age- and weight-matched control subjects who were not using hormonal contraceptives. Fasting blood samples were collected from the subjects for the estimation of total cholesterol (TC) and triglyceride (TG) levels, and the levels of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were estimated using the Friedewald's equation. TC and LDL-C levels in DMPA users were significantly higher than those in non-users. Our study concluded that DMPA use induces lipid metabolism changes that can increase the risk of cardiovascular diseases

Role of quercetin and arginine in ameliorating nano zinc oxide-induced nephrotoxicity in rats

BACKGROUND: Nanoparticles are small-scale substances (<100 nm) with unique properties. Therefore, nanoparticles pose complex health risk implications. The objective of this study was to detect whether treatment with quercetin (Qur) and/or arginine (Arg) ameliorated nephrotoxicity induced by two different doses of nano zinc oxide (n-ZnO) particles. METHOD: ZnO nanoparticles were administered orally in two doses (either 600 mg or 1 g/Kg body weight/day for 5 conscutive days) to Wister albino rats. In order to detect the protective effects of the studied antioxidants against n-ZnO induced nepherotoxicity, different biochemical parameters were investigated. Moreover, histopathological examination of kidney tissue was performed. RESULTS: Nano zinc oxide-induced nephrotoxicity was confirmed by the elevation in serum inflammatory markers including: tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6); and C-reactive protein (CRP). Moreover, immunoglobulin (IGg), vascular endothelium growth factor (VEGF), and nitric oxide (NO) were significantly increased in rat serum. Serum urea and creatinine levels were also significantly increased in rats intoxicated with n-ZnO particles compared with the control group. Additionally, a significant decrease in the non-enzymatic antioxidant reduced glutathione (GSH) was shown in kidney tissues and serum glucose levels were increased. These biochemical findings were supported by a histopathological examination of kidney tissues, which showed that in the animals that received a high dose of n-ZnO, numerous kidney glomeruli underwent atrophy and fragmentation. Moreover, the renal tubules showed epithelial desquamation, degeneration and necrosis. Some renal tubules showed casts in their lumina. Severe congestion was also observed in renal interstitium. These effects were dose dependent. Cotreatment of rats with Qur and/or Arg along with n-ZnO significantly improved most of the deviated tested parameters. CONCLUSIONS: The data show that Qur has a beneficial effect against n-ZnO oxidative stress and related vascular complications. Also, its combination with Arg proved to be even more effective in ameliorating nano zinc oxide nephrotoxicity

Single-Cell Expression Analyses during Cellular Reprogramming Reveal an Early Stochastic and a Late Hierarchic Phase

SummaryDuring cellular reprogramming, only a small fraction of cells become induced pluripotent stem cells (iPSCs). Previous analyses of gene expression during reprogramming were based on populations of cells, impeding single-cell level identification of reprogramming events. We utilized two gene expression technologies to profile 48 genes in single cells at various stages during the reprogramming process. Analysis of early stages revealed considerable variation in gene expression between cells in contrast to late stages. Expression of Esrrb, Utf1, Lin28, and Dppa2 is a better predictor for cells to progress into iPSCs than expression of the previously suggested reprogramming markers Fbxo15, Fgf4, and Oct4. Stochastic gene expression early in reprogramming is followed by a late hierarchical phase with Sox2 being the upstream factor in a gene expression hierarchy. Finally, downstream factors derived from the late phase, which do not include Oct4, Sox2, Klf4, c-Myc, and Nanog, can activate the pluripotency circuitry

Reprogramming Factor Stoichiometry Influences the Epigenetic State and Biological Properties of Induced Pluripotent Stem Cells

We compared two genetically highly defined transgenic systems to identify parameters affecting reprogramming of somatic cells to a pluripotent state. Our results demonstrate that the level and stoichiometry of reprogramming factors during the reprogramming process strongly influence the resulting pluripotency of iPS cells. High expression of Oct4 and Klf4 combined with lower expression of c-Myc and Sox2 produced iPS cells that efficiently generated “all-iPSC mice” by tetraploid (4n) complementation, maintained normal imprinting at the Dlk1-Dio3 locus, and did not create mice with tumors. Loss of imprinting (LOI) at the Dlk1-Dio3 locus did not strictly correlate with reduced pluripotency though the efficiency of generating “all-iPSC mice” was diminished. Our data indicate that stoichiometry of reprogramming factors can influence epigenetic and biological properties of iPS cells. This concept complicates efforts to define a “generic” epigenetic state of iPSCs and ESCs and should be considered when comparing different iPS and ES cell lines.National Science Foundation (U.S.). Graduate Research Fellowship ProgramNational Institutes of Health (U.S.) (Grant 5-RO1-HDO45022)National Institutes of Health (U.S.) (Grant 5-R37-CA084198)National Institutes of Health (U.S.). (Grant 5-RO1-CA087869

Systematic Identification of Culture Conditions for Induction and Maintenance of Naive Human Pluripotency

Embryonic stem cells (ESCs) of mice and humans have distinct molecular and biological characteristics, raising the question of whether an earlier, “naive” state of pluripotency may exist in humans. Here we took a systematic approach to identify small molecules that support self-renewal of naive human ESCs based on maintenance of endogenous OCT4 distal enhancer activity, a molecular signature of ground state pluripotency. Iterative chemical screening identified a combination of five kinase inhibitors that induces and maintains OCT4 distal enhancer activity when applied directly to conventional human ESCs. These inhibitors generate human pluripotent cells in which transcription factors associated with the ground state of pluripotency are highly upregulated and bivalent chromatin domains are depleted. Comparison with previously reported naive human ESCs indicates that our conditions capture a distinct pluripotent state in humans that closely resembles that of mouse ESCs. This study presents a framework for defining the culture requirements of naive human pluripotent cells.Simons Foundation (Grant SFLIFE 286977)National Institutes of Health (U.S.) (Grant RO1-CA084198)National Science Foundation (U.S.). Graduate Research FellowshipJerome and Florence Brill Graduate Student Fellowshi

Validation of Rearrangement Break Points Identified by Paired-End Sequencing in Natural Populations of Drosophila melanogaster

Several recent studies have focused on the evolution of recently duplicated genes in Drosophila. Currently, however, little is known about the evolutionary forces acting upon duplications that are segregating in natural populations. We used a high-throughput, paired-end sequencing platform (Illumina) to identify structural variants in a population sample of African D. melanogaster. Polymerase chain reaction and sequencing confirmation of duplications detected by multiple, independent paired-ends showed that paired-end sequencing reliably uncovered the break points of structural rearrangements and allowed us to identify a number of tandem duplications segregating within a natural population. Our confirmation experiments show that rates of confirmation are very high, even at modest coverage. Our results also compare well with previous studies using microarrays (Emerson J, Cardoso-Moreira M, Borevitz JO, Long M. 2008. Natural selection shapes genome wide patterns of copy-number polymorphism in Drosophila melanogaster. Science. 320:1629–1631. and Dopman EB, Hartl DL. 2007. A portrait of copy-number polymorphism in Drosophila melanogaster. Proc Natl Acad Sci U S A. 104:19920–19925.), which both gives us confidence in the results of this study as well as confirms previous microarray results

Systematic Identification of Balanced Transposition Polymorphisms in Saccharomyces cerevisiae

High-throughput techniques for detecting DNA polymorphisms generally do not identify changes in which the genomic position of a sequence, but not its copy number, varies among individuals. To explore such balanced structural polymorphisms, we used array-based Comparative Genomic Hybridization (aCGH) to conduct a genome-wide screen for single-copy genomic segments that occupy different genomic positions in the standard laboratory strain of Saccharomyces cerevisiae (S90) and a polymorphic wild isolate (Y101) through analysis of six tetrads from a cross of these two strains. Paired-end high-throughput sequencing of Y101 validated four of the predicted rearrangements. The transposed segments contained one to four annotated genes each, yet crosses between S90 and Y101 yielded mostly viable tetrads. The longest segment comprised 13.5 kb near the telomere of chromosome XV in the S288C reference strain and Southern blotting confirmed its predicted location on chromosome IX in Y101. Interestingly, inter-locus crossover events between copies of this segment occurred at a detectable rate. The presence of low-copy repetitive sequences at the junctions of this segment suggests that it may have arisen through ectopic recombination. Our methodology and findings provide a starting point for exploring the origins, phenotypic consequences, and evolutionary fate of this largely unexplored form of genomic polymorphism