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At least 811 records · Page 45Linked to original sources
PubMed2006

Fibroblast growth factor receptor 1 (Fgfr1) is not essential for lens fiber differentiation in mice.

PURPOSE: The developing lens expresses at least three different FGF receptor genes (Fgfr1, Fgfr2, Fgfr3). Furthermore, FGFs have been shown to induce lens epithelial cells to differentiate into fiber cells both in vitro and in vivo. While the loss of Fgfr2 alone does not prevent fiber differentiation and the loss of Fgfr3 alone does not appear to affect lens development, the independent role of Fgfr1 in lens development has not been reported. These experiments were conducted to determine if Fgfr1 plays an independent, essential role in lens development. METHODS: To address this question, we took two complementary approaches. First, we employed the aphakia (ak) lens complementation system to show that Fgfr1 deficient embryonic stem (ES) cells were able to form a normal embryonic lens that maintains a normal pattern of crystallin gene expression. Second, we employed the Cre-loxP system to achieve lens-specific inactivation of Fgfr1. RESULTS: Fgfr1 null embryonic stem cells were able to rescue normal embryonic lens development in chimeric combination with aphakia mutant embryos. In addition, conditional deletion of Fgfr1 does not compromise lens development either before or after birth. CONCLUSIONS: The results of both approaches suggest that lens epithelial cell integrity, cell cycle regulation and lens fiber differentiation are intact in the Fgfr1 deficient lens. Overall, our results demonstrate that Fgfr1 is not cell autonomously essential for lens development and suggests functional redundancy among different FGF receptor genes with respect to lens fiber differentiation.

Alleles↗
PubMed1998

Status of trace elements in patients with idiopathic dilated cardiomyopathy in central Taiwan.

BACKGROUND: Sporadic cases of dilated cardiomyopathy (DCM) are often seen in central Taiwan. Though trace elements may play a role in the pathogenesis of idiopathic DCM, there are no reports concerning study of Taiwan's population in relation to trace elements in patients with DCM. METHODS: Serum selenium, zinc, copper and iron concentrations and blood glutathione peroxidase (GPX) activity were measured in 32 patients with DCM (24 males, 8 females; mean age, 44 +/- 14 years) and 31 age-matched normal volunteers (16 males, 15 females; mean age, 38 +/- 12 years). RESULTS: The average serum selenium concentration of 27.6 +/- 8.4 micrograms/l found in the DCM group was significantly lower than the average concentration of 47.2 +/- 14.7 micrograms/l in the normal group. Blood GPX activity was also significantly lower in the DCM group than in the normal group. Serum selenium concentration correlated well with blood GPX activity in the studied subjects. Serum copper and iron concentrations were significantly higher in the DCM group than in the normal group. There was no difference in serum zinc concentration between the two groups. CONCLUSIONS: Deficiency of serum selenium in association with a low blood GPX activity, and high serum copper and iron concentrations, are found in patients with idiopathic DCM in central Taiwan.

Adult↗
PubMed2025

Lentiviral-mediated gene complementation rescues pathogenic ABCA3 variants.

The ATP-binding cassette subfamily A member 3 (ABCA3) protein on the limiting membrane of lamellar bodies in alveolar type 2 (AT2) cells transports phospholipids required for pulmonary surfactant assembly. ABCA3 deficiency results from biallelic pathogenic variants in ABCA3 and causes progressive neonatal respiratory failure or childhood interstitial lung disease (chILD). Supportive/compassionate care or lung transplantation are the only current definitive treatments for ABCA3 deficiency and progressive respiratory failure. Complementing dysfunctional ABCA3 by gene addition has therapeutic potential. Previous studies show that repairing or complementing ABCA3 in induced pluripotent stem cell (iPSC)-derived AT2 cells rescues lamellar body morphology and surfactant phospholipid composition. Pathogenic variants disrupt ABCA3 function through altered protein trafficking (type 1) or by impaired phospholipid transport (type 2) into lamellar bodies. Here we tested ABCA3 gene complementation using a human pulmonary epithelial cell line (A549) with a genomically silenced ABCA3 locus (ABCA3 KO). From this line, additional cell lines that stably express individual ABCA3 variant cDNA constructs from a single genomic locus were tested: L101P (type 1), E292V (type 2), E690K (type 2), or wild-type ABCA3. Lentiviral-mediated ABCA3 delivery to each cell line partially rescued localization to LAMP3+ vesicles, lamellar body-like structure morphology, and cell proliferation. A functional assay measuring NF-κB signaling suggested that ABCA3 complementation ameliorated aberrant inflammatory signaling in E292V or E690K (type 2) mutant lines, but not in L101P (type 1) or knockout lines. These studies highlight the therapeutic potential of gene addition as well as differences between ABCA3 pathogenic variants that may influence genetic therapy outcomes.

ABCA3 deficiency↗
PubMedDate not supplied

Cross-linking between thymine and indolyl radical: possible mechanisms for cross-linking of DNA and tryptophan-containing peptides.

As experimentally observed in gamma-irradiated aqueous solutions of tryptophan-containing peptides in the presence of DNA, a fast electron (or hydrogen atom) transfer from the DNA restores an intact tryptophan residue at the expense of the DNA integrity. Alternatively, addition of the deprotonated electron-deficient indolyl radical to the DNA, followed by subsequent rearrangement, may lead toward DNA/tryptophan-containing peptide cross-linking. Herein, possible reaction mechanisms for thymine-indolyl radical cross-linking are proposed. The consistent use of the contact spin density distribution is the key virtue of this work. The Becke 3, Lee, Yang, and Parr (B3LYP) density functional theory (DFT) method is employed to investigate the feasibility of the proposed cross-linking mechanisms. A possible complete reaction mechanism consists of a combination of the C(5)-hydroxylated thymine and indolyl radicals forming the initial cross-linked product, a hydrogen transfer within the initial cross-linked product by use of a bridging water molecule, and a dehydration step. The overall thermodynamics of the free energy profiles at 0 and 298 K are similar and display differences of magnitude for the hydrogen-transfer reaction. Temperature may be a key factor influencing the overall mechanism. The skeletal structures and contact spin densities on the heavy atoms of the tryptophan side chain and indolyl radicals are essentially equal. Hence, it is believed that a direct combination of the C(5)-hydroxylated thymine and tryptophan radicals should form the initial cross-linked product, as far as addition of the tryptophan radical to the DNA is concerned.

Cross-Linking Reagents↗
PubMed1977

Variable phenotypic expression of an X-linked recessive lymphoproliferative syndrome.

Investigation of a family with cancer in boys revealed that at least 20 males had the X-linked recessive lymphoproliferative syndrome. A variety of phenotypes occurred: aproliferative phenotypes consisted of aplastic anemia, agranulocytosis or acquired hypogammaglobulinemia; and proliferative phenotypes of B cells included disorders associated with the Epstein-Barr virus, American Burkitt's lymphoma, immunoblastic sarcoma of B cells, fatal infectious mononucleosis or plasmacytoma. The lymphoproliferative disorders observed in males could have resulted from an immunodeficiency to Epstein-Barr virus. The variable phenotypic expression could have resulted from individual differences in the viral dose, duration of exposure and age at which the boys were exposed to the virus. Aproliferative phenotypes such as acquired hypogammaglobulinemia could have ensued from excessive suppressor-cell activity on B cells, whereas proliferative phenotypes such as Burkitt's lymphoma or fatal infectious mononucleosis could have resulted from infection by Epstein-Barr virus and failure to stop proliferation of B cells.

Adolescent↗
PubMed2000

Low [Mg(2+)](o) induces contraction of cerebral arteries: roles of tyrosine and mitogen-activated protein kinases.

The present study was designed to investigate the mechanism of action of low extracellular magnesium ion concentration ([Mg(2+)](o)) on isolated canine basilar arteries and single cerebral vascular smooth muscle cells from these arteries. Low-[Mg(2+)](o) medium (0-0.6 mM) produces endothelium-independent contractions in isolated canine basilar arteries in a concentration-dependent manner; the lower the concentration of [Mg(2+)](o), the stronger the contractions. The low-[Mg(2+)](o) medium-induced contractions are significantly attenuated by pretreatment of the arteries with low concentrations of either SB-203580, U-0126, PD-98059, genistein, or an Src homology 2 (SH2) domain inhibitor peptide. IC(50) levels obtained for these five antagonists are consistent with reported inhibitor constant (K(i)) values for these tyrosine kinase and mitogen-activated protein kinase (MAPK) antagonists. Low-[Mg(2+)](o) medium (0-0.6 mM) produces transient intracellular calcium ion concentration ([Ca(2+)](i)) peaks followed by a slow, sustained, and elevated plateau of [Ca(2+)](i) in primary single smooth muscle cells from canine basilar arteries. Low-[Mg(2+)](o) medium induces rapid and stable increases in [Ca(2+)](i); these increases are inhibited markedly in the presence of either SB-203580, U-0126, PD-98059, genistein or a SH2 domain inhibitor peptide. Several specific antagonists of known endogenously formed vasoconstrictors do not inhibit or attenuate either the low-[Mg(2+)](o)-induced contractions or the elevation of [Ca(2+)](i). The present study suggests that activation of several cellular signaling pathways, such as protein tyrosine kinases (including the Src family) and MAPK, appears to play important roles in low-[Mg(2+)](o)-induced contractions and the elevation of [Ca(2+)](i) in smooth muscle cells from canine basilar arteries.

Animals↗
PubMed2005

Phenotype and genotype analysis in Chinese patients with Gitelman's syndrome.

Inactivation mutations of the luminal thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubules or the basolateral chloride channel (CLCNKB) in the distal nephron are the most common genetic mutations in Gitelman's syndrome (GS) or Bartter's syndrome (BS). We conducted clinical and molecular studies in Chinese patients with GS or BS. Twenty patients with chronic hypokalemia (15 males and five females, age 25 +/- 7 yr) from 15 unrelated Chinese families were investigated. All had renal K+ wasting, metabolic alkalosis, and normotension. The urinary calcium excretion rate was used to distinguish between BS or GS on clinical grounds. Clinical symptoms and biochemical studies were recorded. Molecular analysis included PCR single-strand confirmational polymorphism, direct sequencing of both the NCC and CLCNKB genes, and restriction fragment length polymorphism. Sixteen patients had a clinical diagnosis of GS with hypocalciuria and four BS without hypocalciuria. Four of these 20 patients did not have hypomagnesemia. The males had severe hypokalemia [1.9 +/- 0.4 mEq/liter (mmol/liter)] with paralytic episodes, whereas females had moderate hypokalemia [2.6 +/- 0.2 mEq/liter (mmol/liter)] and less severe symptoms. There were no mutations detected in CLCNKB. Twelve NCC mutations, including six novel mutations and nine recurrent ones, were identified. Allele frequency of the detected NCC mutations was 3% in 100 healthy subjects. Some GS patients with NCC mutations may have normocalciuria and/or normomagnesemia. Gender differences may account for phenotype variability. Screening of these identified NCC mutations remains the gold standard for the diagnosis of GS.

Adolescent↗
PubMed2004

Presenilin-1 deficiency impairs glutamate-evoked intracellular calcium responses in neurons.

Presenilin 1 (PS1) plays a critical role in cleaving amyloid precursor protein (APP) to produce amyloid-beta (Abeta), the primary proteinaceous component of the senile plaques associated with Alzheimer's disease. In addition to mediating the cleavage of APP and a number of other proteins, a growing body of evidence suggests that PS1 also regulates intracellular endoplasmic reticulum calcium levels. Such findings suggest that PS1 activity may modulate neuronal excitability, as well. To address this issue we examined cytosolic intracellular calcium responses in PS1-deficient neurons stimulated by the excitatory amino acid neurotransmitter, glutamate. We found that glutamate-induced intracellular calcium levels were markedly reduced in neurons lacking PS1 (-/-) compared with heterozygous (+/-) and wild-type (+/+) neurons. To prove that PS1 was sufficient to mediate normal glutamate-induced calcium responses, we used a Semliki-forest virus (SFV) vector to express wild-type PS1 in PS1 knock-out neurons. We found that heterologous PS1 expression restored glutamate-evoked calcium responses in PS1-deficient neurons to levels matching non-infected wild-type cells. PS1-deficient neurons infected with SFV directing expression of beta-galactosidase failed to rescue the wild-type phenotype. These results support the idea that normal PS1 activity regulates neuronal responses to neurotransmitter stimulation.

Alzheimer Disease↗
PubMed2004

Notch activation induces apoptosis in neural progenitor cells through a p53-dependent pathway.

Notch signaling is involved in a variety of cell-fate decisions during development. Here we investigate the role of Notch signaling in apoptotic cell death of neural progenitors through the generation and analysis of cell type-specific conditional transgenic and knockout mice. We show that conditional expression of a constitutively active form of Notch1 in early neural progenitor cells, but not postmitotic neurons, selectively induces extensive apoptosis, resulting in a markedly reduced progenitor population. Conversely, attenuation of Notch signaling in Notch1 conditional knockout or Presenilin-1-/- mice results in reduced apoptosis of early neural progenitor cells. Furthermore, Notch activation in neural progenitor cells leads to elevated levels of nuclear p53 and transcriptional upregulation of the target genes Bax and Noxa, and the promotion of apoptotic cell death by Notch activation is completely suppressed by p53 deficiency. Together, these complementary gain-of-function and loss-of-function studies reveal a previously unappreciated role of Notch signaling in the regulation of apoptotic cell death during early mammalian neural development.

Animals↗
PubMed2003

Light stimulates IFNgamma-mediated intercellular adhesion molecule-1 upregulation of cancer cells.

Intercellular adhesion molecule-1 (ICAM-1) works as one of the ligands for activating the killing activity of natural killer (NK) cells and cancer specific cytotoxic T lymphocytes (CTL). Expression of ICAM-1 enhances lymphocyte adhesion to the cancer cells in vivo. Cancer cell lines express significantly lower level of ICAM-1 than that of normal epithelium or benign cells. Overexpression of LIGHT (LIGHT: homologous to lymphotoxins, indicating inducible expression, and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator [HVEM/TR2]) in MDA-MB-231 human breast cancer cells was observed to suppress tumor growth in vivo. In order to elucidate the mechanisms how LIGHT overexpression could trigger tumor suppression, the expression level of a panel of cell surface makers CD54, CD56, CD95, and CD119 was investigated in a group of cancer cells. Flow cytometry analysis results demonstrate that LIGHT gene expression in cancer cells can greatly increase ICAM-1 expression level, IFNgamma alone can stimulate cancer cells to express ICAM-1, which can be highly augmented by LIGHT in a dose-dependent manner. This upregulation of ICAM-1 expression is not only at ICAM-1 protein trafficking level on cell surface as demonstrated by flow cytometry analysis, but also at ICAM-1 total protein level as confirmed by Western blot. There is no difference of expression level among these cancer cell lines for the other three cell surface markers: CD56, CD95 (Fas), and CD119. It was confirmed that LIGHT enhancement upregulation of ICAM-1 expression is at least STAT1 and JAK1 dependent by using STAT1-deficient U3A and JAK1-deficient E2A4 cells. These findings suggest that LIGHT-induced inhibition of tumor growth is highly correlated with its upregulation of ICAM-1 expression.

Animals↗
PubMed2000

Attenuation of pulmonary neuroendocrine differentiation in mice lacking Clara cell secretory protein.

During development and injury, pulmonary neuroendocrine (NE) cells may transiently express Clara cell 10 kD protein (CC10), a major product of the nonciliated progenitor cells for normal and neoplastic airway epithelia suggesting a close relationship between the cells. To assess the role of CC10 during NE differentiation, we studied CC10-deficient mouse lungs by immunohistochemistry and digital imaging. The knockout model revealed a lack of the disrupted gene product in the lung. Because NE cells, which occur as solitary cells or in neuroepithelial bodies (NEBS), comprise less than 1% of airway epithelia, we counted foci positive for each of the three NE markers--synaptophysin, calcitonin gene-related peptide (CGRP), and protein gene product (PGP) 9.5--and developed a method to analyze numerous airways in serial sections. Digitized images of slides were segmented with Photoshop imaging software. The length of airway epithelium and total section areas were then measured using MetaMorph image analysis software. A comparable range of NE foci was observed regardless of CC10 expression patterns with all three markers, suggesting that CC10 is not critical for NE ontogenesis. However, discrimination according to size revealed that wild-type lungs harbored 30% to 40% greater synaptophysin- and CGRP-containing NEBs relative to CC10 deficient lungs. We posit that an attenuation of pulmonary NE differentiation afflicts the CC10-deficient state. Our imaging application greatly facilitates the acquisition and analysis of complex structures such as the lung and promises to be a widely applicable technique for assessments of tissue sections.

Animals↗
PubMed1993

The epidemiology of selenium deficiency in the etiological study of endemic diseases in China.

The distribution of chemical elements in rocks and soils varies widely. Selenium is one of the elements that has remarkable regional variations in distribution and bioavailability. This paper reviews the epidemiology of selenium deficiency in China in connection with the etiology of human selenium-responsive diseases, the well-defined Keshan disease (KD) and the less-well-defined Kashin-Beck disease (KBD).

Bone Diseases↗
PubMed1984

Xeroderma pigmentosum fibroblasts are more sensitive to asbestos fibers than are normal human fibroblasts.

Xeroderma pigmentosum fibroblasts (XPF) are defective in the repair of certain DNA adducts. We show here that XPF cells are more sensitive to the toxic effects of chrysotile, amosite and crocidolite asbestos than are normal human fibroblasts (NF). XPF cells from different complementation groups have a sensitivity to chrysotile which parallels the degree of their DNA repair deficiency. In addition, the survival of normal cells after chrysotile exposure increases with time if they are kept from replicating, while the survival of XPF cells under the same circumstances does not change.

Asbestos↗
PubMed1999

Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice.

The p38 mitogen-activated protein kinase (MAPK) pathway, like the c-Jun N-terminal kinase (JNK) MAPK pathway, is activated in response to cellular stress and inflammation and is involved in many fundamental biological processes. To study the role of the p38 MAPK pathway in vivo, we have used homologous recombination in mice to inactivate the Mkk3 gene, one of the two specific MAPK kinases (MAPKKs) that activate p38 MAPK. Mkk3(-/-) mice were viable and fertile; however, they were defective in interleukin-12 (IL-12) production by macrophages and dendritic cells. Interferon-gamma production following immunization with protein antigens and in vitro differentiation of naive T cells is greatly reduced, suggesting an impaired type I cytokine immune response. The effect of the p38 MAPK pathway on IL-12 expression is at least partly transcriptional, since inhibition of this pathway blocks IL-12 p40 promoter activity in macrophage cell lines and IL-12 p40 mRNA is reduced in MKK3-deficient mice. We conclude that the p38 MAP kinase, activated through MKK3, is required for the production of inflammatory cytokines by both antigen-presenting cells and CD4(+) T cells.

Animals↗
PubMed2004

Endogenous salicylic acid protects rice plants from oxidative damage caused by aging as well as biotic and abiotic stress.

Salicylic acid (SA) is a key endogenous signal that mediates defense gene expression and disease resistance in many dicotyledonous species. In contrast to tobacco and Arabidopsis, which contain low basal levels of SA, rice has two orders of magnitude higher levels of SA and appears to be insensitive to exogenous SA treatment. To determine the role of SA in rice plants, we have generated SA-deficient transgenic rice by expressing the bacterial salicylate hydroxylase that degrades SA. Depletion of high levels of endogenous SA in transgenic rice does not measurably affect defense gene expression, but reduces the plant's capacity to detoxify reactive oxygen intermediates (ROI). SA-deficient transgenic rice contains elevated levels of superoxide and H2O2, and exhibits spontaneous lesion formation in an age- and light-dependent manner. Exogenous application of SA analog benzothiadiazole complements SA deficiency and suppresses ROI levels and lesion formation. Although an increase of conjugated catechol was detected in SA-deficient rice, catechol does not appear to significantly affect ROI levels based on the endogenous catechol data and exogenous catechol treatment. When infected with the blast fungus (Magnaporthe grisea), SA-deficient rice exhibits increased susceptibility to oxidative bursts elicited by avirulent isolates. Furthermore, SA-deficient rice is hyperresponsive to oxidative damage caused by paraquat treatment. Taken together, our results strongly suggest that SA plays an important role to modulate redox balance and protect rice plants from oxidative stress.

Catechols↗
PubMed2005

IL-6 plays a unique role in initiating c-Maf expression during early stage of CD4 T cell activation.

The transcription factor c-Maf plays a critical and selective role in IL-4 gene transcription. Little is known about the mechanism that guides c-Maf regulation during early T cell activation. We report that IL-6 but not IL-4 or other cytokines, rapidly up-regulates c-Maf transcription, as early as 3 h after TCR activation in naive CD4(+) T cells. c-Maf induction requires both IL-6- and TCR-initiated signals, and is independent of IL-4/Stat6 signals. Cyclosporin A and FK506, which target calcineurin and thereby inhibit TCR-mediated Ca(2+) signal pathways, block IL-6-mediated c-Maf expression. We show that Stat3 binds the c-maf promoter in CD4 T cells after IL-6 stimulation, and also transactivates the c-maf promoter in reporter gene assays. IL-6 induces similar c-Maf expression in protein kinase Ctheta-deficient CD4(+) T cells. Furthermore, IL-6 enhances IL-4 gene expression very early after TCR activation in both wild-type and Stat6-deficient CD4(+) T cells. Our findings suggest that IL-6 plays a unique role in initiating c-Maf expression after TCR engagement, and may subsequently regulate early IL-4 production and Th2 commitment.

Animals↗
PubMed1994

Inhibition of human HL-60 cell responses to chemotactic factors by antisense messenger RNA depletion of G proteins.

Chemotactic factors bound to receptors of the seven-transmembrane domain family signal leukocytes through associated guanine nucleotide-binding (G) proteins. Human leukocytes of the HL-60 line, which express G protein-coupled receptors for leukotriene B4 (LTB4) and N-formyl-methionyl-leucyl-phenylalanine (fMLP) after differentiation with vitamin D3 and transforming growth factor-beta, were transfected with expression plasmids containing antisense-oriented cDNAs encoding the alpha-chains of Go, Gi1, Gi2, and Gi3. Antisense mRNA for Go and Gi2 alpha-chains suppressed by over 80% the level of the respective G protein. Go-deficient HL-60 cells had depressed functional and intracellular calcium responses to LTB4 and fMLP, but no alterations in the responses of cyclic adenosine 3',5'-monophosphate (cAMP). In contrast, HL-60 cells deficient in Gi2 lost only responses of the intracellular concentration of cAMP. Antisense mRNA suppression of distinct G proteins thus may delineate some transductional requirements for cellular responses.

Cell Line↗