NAD(P)H: Quinone Oxidoreductase 1 Deficiency Conjoint with Marginal Vitamin C Deficiency Causes Cigarette Smoke Induced Myelodysplastic Syndromes

BACKGROUND: The etiology of myelodysplastic syndromes (MDS) is largely unknown. Exposure to cigarette smoke (CS) is reported to be associated with MDS risk. There is inconsistent evidence that deficiency of NAD(P)H-quinone: oxidoreductase 1 (NQO1) increases the risk of MDS. Earlier we had shown that CS induces toxicity only in marginal vitamin C-deficient guinea pigs but not in vitamin C-sufficient ones. We therefore considered that NQO1 deficiency along with marginal vitamin C deficiency might produce MDS in CS-exposed guinea pigs. METHODOLOGY AND PRINCIPAL FINDINGS: Here we show that CS exposure for 21 days produces MDS in guinea pigs having deficiency of NQO1 (fed 3 mg dicoumarol/day) conjoint with marginal vitamin C deficiency (fed 0.5 mg vitamin C/day). As evidenced by morphology, histology and cytogenetics, MDS produced in the guinea pigs falls in the category of refractory cytopenia with unilineage dysplasia (RCUD): refractory anemia; refractory thrombocytopenia that is associated with ring sideroblasts, micromegakaryocytes, myeloid hyperplasia and aneuploidy. MDS is accompanied by increased CD34(+) cells and oxidative stress as shown by the formation of protein carbonyls and 8-oxodeoxyguanosine. Apoptosis precedes MDS but disappears later with marked decrease in the p53 protein. MDS produced in the guinea pigs are irreversible. MDS and all the aforesaid pathophysiological events do not occur in vitamin C-sufficient guinea pigs. However, after the onset of MDS vitamin C becomes ineffective. CONCLUSIONS AND SIGNIFICANCE: CS exposure causes MDS in guinea pigs having deficiency of NQO1 conjoint with marginal vitamin C deficiency. The syndromes are not produced in singular deficiency of NQO1 or marginal vitamin C deficiency. Our results suggest that human smokers having NQO1 deficiency combined with marginal vitamin C deficiency are likely to be at high risk for developing MDS and that intake of a moderately large dose of vitamin C would prevent MDS

Biosorption of Acid dye by Jackfruit Leaf Powder: Isotherm, kinetics and Response surface methodology studies

A green adsorbent derived from Jackfruit leaf powder (JLP) was used to eliminate Acid Yellow 99 (AY 99) dye from an aqueous medium in this study. We checked the effect of pH, biomass dosage, and temperature (process parameters) on the adsorption potential of AY 99 was explored using the CCD model integrating the RSM approach. At a pH of 2.5, biosorbent dosage of 4 gL-1, and a 30°C temperature, maximum removal was preferred. ANOVA was incorporated to observe the importance of experimental variables and their interactions. The solution pH (A) and biomass dose (C) had the greatest effects on the decolorization of AY 99, according to the findings. ANOVA was used to identify the most important factors, which included two independent variables (A and C) and two quadratic model terms (A2 and C2). The kinetic data were effectively interpreted using a pseudo 2nd order with film diffusion model combination, indicating the chemisorptions phenomenon. Following the model of Langmuir isotherm, the utmost capacity for adsorption was determined to be 418.15 mg g-1 in terms of initial dye concentration. The findings of the maximum adsorption capacity showed that JLP could be employed as a useful adsorbent to eliminate AY 99 from its aqueous medium

Redox Regulation of Mitochondrial Fission Protein Drp1 by Protein Disulfide Isomerase Limits Endothelial Senescence.

Mitochondrial dynamics are tightly controlled by fusion and fission, and their dysregulation and excess reactive oxygen species (ROS) contribute to endothelial cell (EC) dysfunction. How redox signals regulate coupling between mitochondrial dynamics and endothelial (dys)function remains unknown. Here, we identify protein disulfide isomerase A1 (PDIA1) as a thiol reductase for the mitochondrial fission protein Drp1. A biotin-labeled Cys-OH trapping probe and rescue experiments reveal that PDIA1 depletion in ECs induces sulfenylation of Drp1 at Cys644, promoting mitochondrial fragmentation and ROS elevation without inducing ER stress, which drives EC senescence. Mechanistically, PDIA1 associates with Drp1 to reduce its redox status and activity. Defective wound healing and angiogenesis in diabetic or PDIA1+/- mice are restored by EC-targeted PDIA1 or the Cys oxidation-defective mutant Drp1. Thus, this study uncovers a molecular link between PDIA1 and Drp1 oxidoreduction, which maintains normal mitochondrial dynamics and limits endothelial senescence with potential translational implications for vascular diseases associated with diabetes or aging.This research was supported by NIH R01HL135584 (to M.U.-F.), NIH R21HL112293 (to M.U.-F.), NIH R01HL133613 (to T.F. and M.U.-F.), NIH R01HL116976 (to T.F. and M.U.-F.), NIH R01HL070187 (to T.F.), NIH R01HL112626 (to J.K.), Department of Veterans Affairs Merit Review Grant 2I01BX001232 (to T.F.), AHA 16GRNT31390032 (to M.U.-F.), AHA 15SDG25700406 (to S.V.), AHA 16POST27790038 (to A.D.), and NIH T32HL07829 (to R.C.). We thank Mr. Kyle Taylor at Keyence Corporation for assisting with taking images using the Keyence microscope; Dr. John O’Bryan at UIC for assisting with the BiFC assays; Dr. Leslie Poole at Wake Forest University for providing DCP-Bio1, as well as Dr. Jody Martin and the Center for Cardiovascular Research-supported Vector Core Facility at UIC for amplifying adenoviruses.S

Copper Transport Protein Antioxidant-1 Promotes Inflammatory Neovascularization via Chaperone and Transcription Factor Function

Supplementary information accompanies this paper at http://www.nature.com/srepCopper (Cu), an essential micronutrient, plays a fundamental role in inflammation and angiogenesis; however, its precise mechanism remains undefined. Here we uncover a novel role of Cu transport protein Antioxidant-1 (Atox1), which is originally appreciated as a Cu chaperone and recently discovered as a Cu-dependent transcription factor, in inflammatory neovascularization. Atox1 expression is upregulated in patients and mice with critical limb ischemia. Atox1-deficient mice show impaired limb perfusion recovery with reduced arteriogenesis, angiogenesis, and recruitment of inflammatory cells. In vivo intravital microscopy, bone marrow reconstitution, and Atox1 gene transfer in Atox1(-/-) mice show that Atox1 in endothelial cells (ECs) is essential for neovascularization and recruitment of inflammatory cells which release VEGF and TNFα. Mechanistically, Atox1-depleted ECs demonstrate that Cu chaperone function of Atox1 mediated through Cu transporter ATP7A is required for VEGF-induced angiogenesis via activation of Cu enzyme lysyl oxidase. Moreover, Atox1 functions as a Cu-dependent transcription factor for NADPH oxidase organizer p47phox, thereby increasing ROS-NFκB-VCAM-1/ICAM-1 expression and monocyte adhesion in ECs inflamed with TNFα in an ATP7A-independent manner. These findings demonstrate a novel linkage between Atox1 and NADPH oxidase involved in inflammatory neovascularization and suggest Atox1 as a potential therapeutic target for treatment of ischemic disease.SS is a British Heart Foundation (BHF) PhD student; GDA is BHF Chair in cardiac surgery and NIHR Senior Investigator; CE is a BHF Senior Research Fellow. Sources of Funding: This research was supported by NIH R01 HL070187 (T.F.), Department of Veterans Affairs Merit Review grant 1I01BX001232 (T.F.), R01HL116976 (T.F., M.U.-F.), NIH R01 HL077524 and HL077524-S1, R21HL112293 (to M.U.-F.), Ruth L. Kirschstein-National Service Research Award (Kirschstein-NRSA) T32 Training Grant (to G-F.C.), AHA Post-doctoral Fellowship 09POST2250151 (to N.U.), and 11POST5740006 (to V.S.).Peer-reviewedPublisher Versio

Variation in lip print pattern between two ethnic groups, Oraon tribals and Bengalee Hindus, residing in West Bengal, India

Lip print pattern (LPP) is unique to each individual. For decades, forensic experts have used LPP for personal identification to solve criminal cases. However, studies investigating ethnic variation in LPP are scanty. Our study wanted to investigate variation in LPP between two ethnic groups, Oraon tribals and Bengalee Hindus, residing in West Bengal, India. A total of 280 participants included 112 Oraons and168 Bengalee Hindus of both. Prints were taken using dark shaded lipstick and transparent cellophane tape and recorded into white A4 sheet. Prints were divided into four quadrants and examined by magnifying glass. For analysis of results, classification of Suzuki and Tsuchihashi was followed. A p value of 0.05 was considered to be statistically significant. It was observed that Type II pattern was dominant in first and second quadrants in both ethnic groups, irrespective of sex. Combination of Type II+III was found to be the most common pattern in males among both Oraons (16.2%) and Bengalee Hindus (12.2%) whereas in females Type II pattern (25.0%) among Oraons and Type III pattern among Bengalee Hindus (11.4%) was the most common. Chi square test showed statistically significant difference among females (p<0.05) and in third and fourth quadrants among males (p<0.01) of both ethnic groups. Our investigation clearly demonstrated sex and ethnic variations in LPP. Further studies are required to investigate ethnic variation in LPP among the various populations groups, both tribal as well as non-tribal, from different regions of India

Are H0H_0 and σ8\sigma_8 tensions generic to present cosmological data?

International audienceYes, for a wide range of cosmological models (ΛCDM, non-interacting w z CDM, w z WDM, or a class of interacting DMDE). Recently there have been attempts to solve the tension between direct measurements of H 0 and from respective low-redshift observables and indirect measurements of these quantities from observations of the cosmic microwave background (CMB). In this work we construct a quasi-model-independent framework that reduces to different classes of cosmological models under suitable choices of parameters. We test this parameterization against the latest Planck CMB data combined with recent measurements of baryon acoustic oscillations (BAO) and supernovae, and direct measurements of H 0. Our analysis reveals that a strong positive correlation between H 0 and σ 8 is more or less generic for most of the cosmological models. The present data slightly prefer a phantom equation of state for dark energy and a slightly negative effective equation of state for dark matter (a direct signature of interacting models), with a relatively high H 0 consistent with Planck+R16 data and simultaneously a consistent . Thus, even though the tensions cannot be fully resolved, a class of interacting models with phantom w DE get a slight edge over w z CDM for the present data. However, although they may resolve the tension between high-redshift CMB data and individual low-redshift data sets, these data sets have inconsistencies between them (e.g., between BAO and H 0, supernovae and BAO, and cluster counts and H 0)

Cytotoxic and Antioxidant Property of a Purified Fraction (NN-32) of Indian Naja Naja Venom on Ehrlich Ascites Carcinoma in BALB/c Mice

A cytotoxic and antioxidant protein (NN-32) from the Indian spectacled cobra Naja naja venom was identified and its probable mode of action on murine Ehrlich ascites carcinoma (EAC) was established. The venom purified through ion exchange chromatography produced several peaks, among which fraction 32 produced cytotoxic-cardiotoxic properties. This fraction (NN-32) showed a single peak (retention time 38.3 min) by HPLC using C4 column. The molecular mass determined by MALDI-MS, found to be 6.7 kDa and the first ten N-terminal sequence was determined (LKCNKLVPLF) by Edmann degradation method using applied Biosystem procise sequencer. It was observed that the sequence shared 100% homology with other cytotoxin cardiotoxin identified from the venom of Naja species. NN-32 showed cytotoxicity on EAC cells, increased survival time of inoculated EAC mice, reduced solid tumor volume and weight. NN-32 increased proapoptotic protein caspase 3 and 9 activity and Bax-Bcl2 ratio. It also increased the antioxidant markers glutathione, glutathione peroxidase, glutathione transferase, superoxide dismutase and catalase activity. NN-32 increased serum IL-10 level and decreased murine keratinocytederived chemokine level. The cardiotoxicity of NN-32 was established on isolated guinea pig auricle, where 100% irreversible blockade of auricular contraction was observed. Thus, it may be concluded that, NN-32 induced anticancer activity in EAC mice was partly mediated through its apoptogenic – antioxidant property