scholarly journals Genetic Analysis of Cytoprotective Functions Supported by Graded Expression of Keap1

2010 ◽  
Vol 30 (12) ◽  
pp. 3016-3026 ◽  
Author(s):  
Keiko Taguchi ◽  
Jonathan M. Maher ◽  
Takafumi Suzuki ◽  
Yukie Kawatani ◽  
Hozumi Motohashi ◽  
...  
Keyword(s):  
Acute Toxicity ◽  
Wild Type ◽  
Term Survival ◽  
Constitutive Activation ◽  
Oxidative Stresses ◽  
Adult Mice ◽  
Nrf2 Activation ◽  
Weaning Age ◽  
Old Mice

ABSTRACT Keap1 regulates Nrf2 activity in response to xenobiotic and oxidative stresses. Nrf2 is an essential regulator of cytoprotective genes. Keap1-null mice are lethal by weaning age due to malnutrition caused by severe hyperkeratosis of the upper digestive tract. Analysis of Keap1::Nrf2 double mutant mice revealed that currently recognizable phenotypes of Keap1-null mice are all attributable to constitutive activation of Nrf2. We previously reported that hepatocyte-specific Keap1 knockout (Keap1 flox/ −::Albumin-Cre) mice are viable and more resistant to acute toxicity of acetaminophen (APAP). In the current study, we found that the floxed Keap1 allele is hypomorphic and that Keap1 expression was decreased in all examined tissues of Keap1 flox/ − mice. Taking advantage of the hypomorphic phenotype of Keap1 flox/ − mice, we examined the effects of graded reduction of Keap1 expression in adult mice. When challenged with APAP, Keap1 flox/ − mice were more protected from mortality than wild-type and even Keap1 flox/ −::Albumin-Cre mice. In contrast, a decrease in Keap1 levels to less than 50% resulted in increased mortality in a study of 2-year-old mice. These results support our contention that the benefits of Nrf2 activation in acute toxicity are hormetic and that constitutive Nrf2 activation beyond a certain threshold is rather disadvantageous to long-term survival.

scholarly journals Flt3 Ligand–treated Neonatal Mice Have Increased Innate Immunity Against Intracellular Pathogens and Efficiently Control Virus Infections

2003 ◽  
Vol 197 (5) ◽  
pp. 575-584 ◽  
Author(s):  
Sabine Vollstedt ◽  
Marco Franchini ◽  
Hans P. Hefti ◽  
Bernhard Odermatt ◽  
Meredith O'Keeffe ◽  
...  
Keyword(s):  
B Cells ◽  
Bacterial Infections ◽  
Fold Increase ◽  
Virus Infections ◽  
Term Survival ◽  
Newborn Mice ◽  
Adult Mice ◽  
Control Virus ◽  
Simplex Virus

Flt-3 ligand (FL), a hematopoetic growth factor, increases the number of dendritic cells (DCs), B cells, and natural killer cells in adult mice but the effect in neonates was unknown. We show that FL treatment of newborn mice induced a >100-fold increase in the innate resistance against infection with herpes simplex virus type 1 and Listeria monocytogenes. This resistance required interferon (IFN)-α/β for viral and interleukin (IL)-12 for bacterial infections. Long-term survival after viral but not bacterial infection was increased ∼100-fold by FL treatment. After treatment, CD11c+/major histocompatibility complex type II+ and CD11c+/B220+ DC lineage cells were the only cell populations increased in the spleen, liver, peritoneum, and skin. DC induction was independent of IFNs, IL-2, -4, -7, -9, -15, and mature T and B cells. The data suggest that FL increases the number of DCs in neonates and possibly in other immune-compromised individuals, which in turn improves IFN-α/β– and IL-12–associated immune responses.

scholarly journals A Role for Single-Stranded Exonucleases in the Use of DNA as a Nutrient

2009 ◽  
Vol 191 (11) ◽  
pp. 3712-3716 ◽  
Author(s):  
Vyacheslav Palchevskiy ◽  
Steven E. Finkel
Keyword(s):  
Escherichia Coli ◽  
Bacterial Cells ◽  
Wild Type ◽  
Nutrient Source ◽  
Term Survival ◽  
Natural Competence ◽  
E Coli ◽  
Double Stranded Dna ◽  
Better Than

ABSTRACT Nutritional competence is the ability of bacterial cells to utilize exogenous double-stranded DNA molecules as a nutrient source. We previously identified several genes in Escherichia coli that are important for this process and proposed a model, based on models of natural competence and transformation in bacteria, where it is assumed that single-stranded DNA (ssDNA) is degraded following entry into the cytoplasm. Since E. coli has several exonucleases, we determined whether they play a role in the long-term survival and the catabolism of DNA as a nutrient. We show here that mutants lacking either ExoI, ExoVII, ExoX, or RecJ are viable during all phases of the bacterial life cycle yet cannot compete with wild-type cells during long-term stationary-phase incubation. We also show that nuclease mutants, alone or in combination, are defective in DNA catabolism, with the exception of the ExoX− single mutant. The ExoX− mutant consumes double-stranded DNA better than wild-type cells, possibly implying the presence of two pathways in E. coli for the processing of ssDNA as it enters the cytoplasm.

Comparison of the symbiotic and competition phenotypes of Sinorhizobium meliloti PHB synthesis and degradation pathway mutants

2005 ◽  
Vol 51 (7) ◽  
pp. 599-604 ◽  
Author(s):  
P Aneja ◽  
A Zachertowska ◽  
T C Charles
Keyword(s):  
Sinorhizobium Meliloti ◽  
Degradation Pathway ◽  
Nodule Occupancy ◽  
Wild Type ◽  
Term Survival ◽  
Mutant Strains ◽  
Key Factor ◽  
Carbon Excess ◽  
Synthesis And Degradation

The competitive abilities of Sinorhizobium meliloti mutant strains containing lesions in the PHB synthesis (phbC) and degradation (bdhA) pathways were compared. While the bdhA mutant showed no noticeable symbiotic defects on alfalfa host plants when inoculated alone, in mixed inoculation experiments it was found to be less competitive than the wild type for nodule occupancy. Long-term survival of the bdhA mutant on a carbon-limiting medium was not affected. However, when subjected to competition with the wild-type strain in periodic subculturing through alternating carbon-limiting and carbon-excess conditions, the bdhA mutant performed poorly. A more severe defect in competition for growth and nodule occupancy was observed with a mutant unable to synthesize PHB (phbC). These results indicate that the ability to efficiently deposit cellular PHB stores is a key factor influencing competitive survival under conditions of fluctuating nutrient carbon availability, whereas the ability to use these stores is less important.Key words: Sinorhizobium meliloti, PHB metabolism, competition.

scholarly journals Long-Term Survival of Campylobacter jejuni at Low Temperatures Is Dependent on Polynucleotide Phosphorylase Activity

2009 ◽  
Vol 75 (23) ◽  
pp. 7310-7318 ◽  
Author(s):  
Nabila Haddad ◽  
Christopher M. Burns ◽  
Jean Michel Bolla ◽  
Hervé Prévost ◽  
Michel Fédérighi ◽  
...  
Keyword(s):  
Campylobacter Jejuni ◽  
Low Temperatures ◽  
Survival Rates ◽  
Polynucleotide Phosphorylase ◽  
Wild Type ◽  
Term Survival ◽  
Poultry Products ◽  
Bacterial Gastroenteritis

ABSTRACT Campylobacter jejuni is a leading cause of bacterial gastroenteritis worldwide. Infection generally occurs after ingestion of contaminated poultry products, usually conserved at low temperatures. The mechanisms promoting survival of C. jejuni in the cold remain poorly understood despite several investigations. The present study provides insight into the survival mechanism by establishing the involvement of polynucleotide phosphorylase (PNPase), a 3′-5′ exoribonuclease with multiple biological functions in cold survival. The role of PNPase was demonstrated genetically using strains with altered pnp genes (which encode PNPase) created in C. jejuni F38011 and C. jejuni 81-76 backgrounds. Survival assays carried out at low temperatures (4 and 10°C) revealed a difference of 3 log CFU/ml between the wild-type and the pnp deletion (Δpnp) strains. This did not result from a general requirement for PNPase because survival rates of the strains were similar at higher growth temperatures (37 or 42°C). trans-Complementation with plasmid pNH04 carrying the pnp gene under the control of its natural promoter restored the cold survival phenotype to the pnp deletion strains (at 4 and 10°C) but not to the same level as the wild type. In this study we demonstrate the role of PNPase in low-temperature survival of C. jejuni and therefore attribute a novel biological function to PNPase directly related to human health.

scholarly journals The TALE Homeodomain Protein Pbx2 Is Not Essential for Development and Long-Term Survival

2004 ◽  
Vol 24 (12) ◽  
pp. 5324-5331 ◽  
Author(s):  
Licia Selleri ◽  
Jorge DiMartino ◽  
Jan van Deursen ◽  
Andrea Brendolan ◽  
Mrinmoy Sanyal ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Late Gestation ◽  
Homeodomain Protein ◽  
Mammalian Development ◽  
Term Survival ◽  
Long Term Survival ◽  
Embryonic Tissues ◽  
Adult Mice ◽  
Tale Homeodomain

ABSTRACT Pbx2 is one of four mammalian genes that encode closely related TALE homeodomain proteins, which serve as DNA binding partners for a subset of Hox transcription factors. The expression and contributions of Pbx2 to mammalian development remain undefined, in contrast to the essential roles recently established for family members Pbx1 and Pbx3. Here we report that Pbx2 is widely expressed during embryonic development, particularly in neural and epithelial tissues during late gestation. Despite wide Pbx2 expression, mice homozygous mutant for Pbx2 are born at the expected Mendelian frequencies and exhibit no detectable abnormalities in development and organogenesis or reduction of long-term survival. The lack of an apparent phenotype in Pbx2− /− mice likely reflects functional redundancy, since the Pbx2 protein is present at considerably lower levels than comparable isoforms of Pbx1 and/or Pbx3 in embryonic tissues. In postnatal bone marrow and thymus, however, Pbx2 is the predominant high-molecular-weight (MW)-isoform Pbx protein detectable by immunoblotting. Nevertheless, the absence of Pbx2 has no measurable effect on steady-state hematopoiesis or immune function in adult mice, suggesting possible compensation by low-MW-isoform Pbx proteins present in these tissues. We conclude that the roles of Pbx2 in murine embryonic development, organogenesis, hematopoiesis, immune responses, and long-term survival are not essential.

Long-term survival in primary glioblastoma revisited: The contribution of isocitrate dehydrogenase mutations.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2027-2027
Author(s):  
Michael Weller ◽  
Bettina Hentschel ◽  
Matthias Simon ◽  
Manfred Westphal ◽  
Gabriele Schackert ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Mgmt Promoter Methylation ◽  
Molecular Characteristics ◽  
Wild Type ◽  
Who Grade ◽  
Term Survival ◽  
Long Term Survival ◽  
Tp53 Mutations ◽  
Mgmt Promoter

2027 Background: The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in WHO grade 2/3 gliomas, but rare in primary glioblastomas, and associated with longer survival. Methods: We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival > 36 months (LTS-36), including 33 patients surviving > 60 months (LTS-60), with 259 patients surviving < 36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations and IDH1/2mutations were determined by standard techniques. Results: The rate of IDH1/2 mutations in LTS-36 patients was 34% (23/67 patients) as opposed to 4.3% in controls (11/257 patients). Long-term survivors with IDH1/2 -mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Among LTS-36 patients, wild-type TP53 status, MGMT promoter methylation, and absence of EGFR amplification, but not IDH1/2 mutation, were associated with prolonged survival. Among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had been treated initially with radiotherapy alone and had TP53 mutations less frequently. Conclusions: IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade 2/3 gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.

Midkine prevents ventricular remodeling and improves long-term survival after myocardial infarction

2009 ◽  
Vol 296 (2) ◽  
pp. H462-H469 ◽  
Author(s):  
Hiroharu Takenaka ◽  
Mitsuru Horiba ◽  
Hisaaki Ishiguro ◽  
Arihiro Sumida ◽  
Mayumi Hojo ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Ventricular Remodeling ◽  
Umbilical Vein ◽  
Left Ventricular ◽  
Wild Type ◽  
Long Term Effects ◽  
Term Survival ◽  
Deficient Mice

Cardiac remodeling is thought to be the major cause of chronic heart dysfunction after myocardial infarction (MI). However, molecules involved in this process have not been thoroughly elucidated. In this study we investigated the long-term effects of the growth factor midkine (MK) in cardiac remodeling after MI. MI was produced by ligation of the left coronary artery. MK expression was progressively increased after MI in wild-type mice, and MK-deficient mice showed a higher mortality. Exogenous MK improved survival and ameliorated left ventricular dysfunction and fibrosis not only of MK-deficient mice but also of wild-type mice. Angiogenesis in the peri-infarct zone was also enhanced. These in vivo changes induced by exogenous MK were associated with the activation of phosphatidylinositol 3-kinase (PI3K)/Akt and MAPKs (ERK, p38) and the expression of syndecans in the left ventricular tissue. In vitro experiments using human umbilical vein endothelial cells confirmed the potent angiogenic action of MK via the PI3K/Akt pathway. These results suggest that MK prevents the cardiac remodeling after MI and improves the survival most likely through an enhancement of angiogenesis. MK application could be a new therapeutic strategy for the treatment of ischemic heart failure.

scholarly journals Genetic elimination of prothrombin in adult mice is not compatible with survival and results in spontaneous hemorrhagic events in both heart and brain

Blood ◽  
2009 ◽  
Vol 113 (3) ◽  
pp. 696-704 ◽  
Author(s):  
Eric S. Mullins ◽  
Keith W. Kombrinck ◽  
Kathryn E. Talmage ◽  
Maureen A. Shaw ◽  
David P. Witte ◽  
...  
Keyword(s):  
Poly I:C ◽  
Compound Heterozygous ◽  
Bleeding Events ◽  
Spontaneous Bleeding ◽  
Term Survival ◽  
Vascular Integrity ◽  
Adult Mice ◽  
Hemorrhagic Events ◽  
Antimicrobial Function

Abstract Mice carrying a conditional prothrombin knockout allele (fIIlox) were established to develop an experimental setting for exploring the importance of thrombin in the maintenance of vascular integrity, the inflammatory response, and disease processes in adult animals. In the absence of Cre-mediated recombination, homozygous fIIlox/lox mice or compound heterozygous mice carrying one fIIlox allele and one constitutive-null allele were viable. Young adults exhibited neither spontaneous bleeding events nor diminished reproductive success. However, the induction of Cre recombinase in fIIlox mice using the poly I:C-inducible Mx1-Cre system resulted in the rapid and near-complete recombination of the fIIlox allele within the liver, the loss of circulating prothrombin, and profound derangements in coagulation function. Consistent with the notion that thrombin regulates coagulation and inflammatory pathways, an additional early consequence of reducing prothrombin was impaired antimicrobial function in mice challenged with Staphylococcus aureus peritonitis. However, life expectancy in unchallenged adults genetically depleted of prothrombin was very short (∼5-7 days). The loss of viability was associated with the development of severe hemorrhagic events within multiple tissues, particularly in the heart and brain. Unlike the constitutive loss of either clotting or platelet function alone, the conditional loss of prothrombin is uniformly not compatible with maintenance of hemostasis or long-term survival.

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