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21.
Hydrogen peroxide inhibits gap junctional intercellular communication in glutathione sufficient but not glutathione deficient cells 总被引:7,自引:5,他引:7
Cell to cell communication via gap junctions is essential in the
maintenance of the homeostatic balance of multicellular organisms. Aberrant
intercellular gap junctional communication (GJIC) has been implicated in
tumor promotion, neuropathy and teratogenesis. Oxidative stress has also
been implicated in similar pathologies such as cancer. We report a
potential link between oxidative stress and GJIC. Hydrogen peroxide, a
known tumor promoter, inhibited GJIC in WB-F344 rat liver epithelial cells
with an I50 value of 200 microM. Inhibition of GJIC by H2O2 was reversible
as indicated by the complete recovery of GJIC with the removal of H2O2 via
a change of fresh media. Free radical scavengers, such as t-butyl alcohol,
propylgallate, and Trolox, did not prevent the inhibition of GJIC by H2O2,
which indicated that the effects of H2O2 on GJIC was probably not a
consequence of aqueous free radical damage. The depletion of intracellular
GSH reversed the inhibitory effect of H2O2 on GJIC. The treatment of
glutathione- sufficient cells with H2O2 resulted in the
hyperphosphorylation of connexin43, which is the basic subunit of the
hexameric gap junction protein, as determined by Western blot analysis.
TPA, a well-known tumor promoter, also inhibits GJIC via
hyperphosphorylation of GJIC, which is a result of protein kinase-C
activation. However, H2O2 also induced hyperphosphorylation in
GSH-deficient cells that had normal rates of GJIC. Therefore, the mechanism
of GJIC inhibition must be different from the TPA-pathway and involves GSH.
相似文献
22.
Dietary polyamines promote the growth of azoxymethane-induced aberrant crypt foci in rat colon 总被引:1,自引:1,他引:1
We have examined whether dietary polyamines influence the formation and
initial growth of azoxymethane (AOM)-induced aberrant crypt foci (ACF) in
rat colon. Effects of a combination of dietary polyamines at three dose
levels (putrescine: 50, 280, 740 nmol/g; spermidine: 10, 261, 763 nmol/g;
spermine: 1, 31, 91 nmol/g) in the polyamine-poor AIN-76A diet were studied
in animals in two different experimental situations: animals treated with
AOM alone and animals treated with AOM + difluoromethylornithine (DFMO), a
specific inhibitor of endogenous polyamine synthesis. In both experimental
situations, dietary polyamines enhanced the growth of ACF, expressed as the
number of large ACF (foci with three or more aberrant crypts, ACF > or =
3), whereas the formation of ACF, expressed as the number of ACF, was
apparently not altered. In animals treated with AOM alone, maximal growth
enhancing effect on ACF was nearly obtained with the median level of
dietary polyamine. In rats fed a low polyamine diet, basic AIN-76A, DFMO
reduced the growth of AOM-induced ACF by 83%. This inhibitory effect of
DFMO was counteracted by dietary polyamines in a dose- dependent manner,
and it was abolished at the highest level of polyamines. In conclusion, it
was demonstrated that dietary polyamines are able to enhance the growth of
AOM-induced ACF. Further, dietary polyamines reversed the DFMO-caused
inhibition of ACF growth, probably by compensating for the DFMO-reduced
endogenous polyamine synthesis.
相似文献
23.
Hansen LA; Malarkey DE; Wilkinson JE; Rosenberg M; Woychik RE; Tennant RW 《Carcinogenesis》1998,19(10):1837-1845
We previously reported that papillomas can arise from the follicular
epithelium of v-Ha-ras transgenic TGxAC mice. Since the viable-yellow
mutation (A(vy)) of the mouse agouti gene which regulates coat color
pigmentation by acting within the micro-environment of the hair follicle
has been shown to function as a tumor promoter in the liver, we
hypothesized that it may also play a role in TGxAC skin tumorigenesis.
Endogenous agouti protein product was detected in the outer root sheath of
anagen hair follicles following plucking of the hair shaft, but not in the
interfollicular epithelium, in TGxAC mice on an FVB/N genetic background.
It was also detected in papillomas from these mice produced by
12-O-tetradecanoylphorbol-13-acetate (TPA) treatment or plucking.
Expression of the A(vy) allele in the v-Ha-ras transgenic TGxAC mouse line
results in an approximately 2-fold increase in papilloma development
compared with controls which did not carry the A(vy) allele following
twice-weekly treatment with 1.25, 2.5 or 5.0 microg TPA. In addition,
TPA-treated, papilloma-bearing F1 mice which carried the A(vy) allele, but
not F1 mice which did not carry the A(vy) allele, exhibited a syndrome of
humoral hypercalcemia mediated by parathyroid hormone-related protein
(PTHrP) that led to weight loss, hypercalcemia and hypophosphatemia. Thus,
we conclude that the A(vy) allele can influence the development of skin
tumors and PTHrP-mediated humoral hypercalcemia in v-Ha-ras transgenic
TGxAC mice.
相似文献
24.
25.
The efficacy and outcome of bone marrow transplantation therapy following lethal irradiation were examined in syngeneic mice that had a hereditary macrocytic anemia (an/an) or were genotypically normal (+/+). Successful RBC and WBC replacement, based on blood cell parameters and donor genetic markers, were observed in all combinations of transplant therapy. Nevertheless, the an/an mice died prematurely several months after treatment, whether they received +/+ or an/an marrow cells. In contrast, the +/+ recipients of either +/+ or an/an marrow cells survived for at least 1 year after transplantation. Premature death of the an/an mice was associated with lymphopenia, anemia, kidney lesions, and severe pathogen-free pneumonitis. On the basis of our results, we hypothesize that the premature deaths of an/an mice are caused by a kind of chronic irradiation damage to which an/an mice are especially susceptible. 相似文献
26.
The widespread assumption that cytoplasts generated from human polymorphonuclear leukocytes (PMNs) are vesicles consisting solely of cytoplasm surrounded by plasma membrane and devoid of granule activity remains to be tested. PMN cytoplasts were prepared by centrifugation of intact cells on a Ficoll step gradient in the presence of cytochalasin B. Two granule membrane markers, Mol, a fluorometrically detectable antigen, and cytochrome b, both of which have been shown to translocate to the plasma membrane during granule release, were compared for their activity in cytoplasts and intact PMNs. We found that the amount of Mol detected on the plasma membrane of intact PMNs, as compared with other membrane markers (such as antigens LFA-1 and beta 2m), increased 1.6- fold upon exposure of PMNs to Ficoll plus cytochalasin B prior to centrifugation. Another twofold increase in Mol expression occurred upon cytoplast preparation. Release of the granule enzymes, vitamin B12- binding protein, and lysozyme were also followed and correlated well (r = .78 and .92) with the amount of Mol antigen present on the cell surface. Cytochrome b was also found to be higher (1.4-fold) on plasma membranes isolated from cytoplasts than on plasma membranes isolated from intact control cells. These results indicate that some fusion of granule membranes and plasma membranes occurred during treatment of PMNs with Ficoll plus cytochalasin b and during cytoplast preparation. 相似文献
27.
Talmadge JE; Schneider M; Keller J; Ruscetti F; Longo D; Pennington R; Bowersox O; Tribble H 《Blood》1989,73(6):1458-1467
In a series of studies designed to extend our understanding of interleukin-2 (IL-2) and to study the effect of biologic response modifiers on bone marrow, we observed that administering recombinant human (rH) IL-2 to normal mice resulted in an increase in the frequency of colony-forming units-culture (CFU-C) in bone marrow. In addition, rH IL-2 was able to accelerate host recovery from cyclophosphamide (CTX)- or radiation-induced bone marrow depression and peripheral blood leukopenia. Not only can rH IL-2 accelerate, in a dose-dependent manner, the return of bone marrow, peripheral blood cellularity, and CFU-C frequency to normal levels following cytoreduction by CTX or irradiation, but it also significantly increases CFU-C frequency to greater than normal levels. Furthermore, rH IL-2 can significantly prolong survival of animals receiving a lethal dose of irradiation or CTX. Thus, multiple mechanisms are responsible for the synergistic therapeutic activity associated with rH IL-2 and CTX. rH IL-2 does not act only as an immunomodulatory agent in the presence or absence of suppressor T cells, but also accelerates host recovery from cytoreductive agents, resulting in decreased leukopenia and perhaps resistances to secondary infection. Thus, rH IL-2 plus chemotherapy may increase therapeutic activity against neoplastic disease, not only by adding immune stimulation to the direct antitumor effect of the drug but also by allowing delivery of higher, more effective doses of chemotherapy. 相似文献
28.
We have further characterized the biological activities, mechanism of action, and target cell populations of recombinant human and murine thrombopoietin (rhTPO and rmTPO) in in vitro human and murine model systems. Alone, hTPO or mTPO stimulated the maturation of immature murine megakaryoblasts as measured in a single cell assay. The combination of hTPO or mTPO and interleukin-6 (IL-6) resulted in a further increase in megakaryocyte differentiation in this system. Murine TPO stimulated mouse megakaryocyte progenitor development. Human megakaryocyte progenitor development was potentiated by hTPO alone and further augmented in the presence of the early-acting cytokines (IL-3) or kit ligand/stem cell factor (KL/SCF). To further define the mechanism of action of TPO, neutralization studies were performed with antisera to IL-3, granulocyte-macrophage colony-stimulating factor (GM- CSF), IL-1 beta, and IL-11. No diminution in TPO activity was observed in the presence of these antisera. Moreover, because adhesive interactions are known to modulate hematopoiesis, we studied whether hTPO might alter such interactions between human bone marrow (BM) megakaryocytes and human BM stromal fibroblasts. No changes were observed in either megakaryocyte expression of the surface molecules lymphocyte function-associated antigen-1, very late activation antigen- 4, or intercellular adhesion molecule-1 or the adhesion of megakaryocytes to stromal fibroblasts after treatment with the growth factor. Furthermore, no induction of secretion of the cytokines IL-1 alpha, IL-1 beta, GM-CSF, IL-6, granulocyte-CSF, tumor necrosis factor- alpha, transforming growth factor-beta 1, or transforming growth factor- beta 2 by primary human BM megakaryocytes was noted after treatment of the cells with hTPO. To address whether TPO affects very primitive hematopoietic progenitors, we studied the residual cells from the BMs of mice treated with high doses of 5-fluorouracil. Although no effect of mTPO alone was noted on the viability or replication of such primitive murine progenitor populations, the triple combination of IL-3 + KL/SCF + TPO stimulated growth of megakaryocyte progenitors. These results indicate that TPO is a highly lineage-specific growth factor whose primary biological effects are likely to be direct modulation of the growth and maturation of committed megakaryocyte precursors and immature megakaryoblasts. 相似文献
29.
SG Lindquist M Duno M Batbayli A Puschmann H Braendgaard S Mardosiene K Svenstrup LH Pinborg K Vestergaard LE Hjermind J Stokholm BB Andersen P Johannsen JE Nielsen 《Clinical genetics》2013,83(3):279-283
Recently, a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 was reported as the cause of chromosome 9p21‐linked frontotemporal dementia‐amyotrophic lateral sclerosis (FTD‐ALS). We here report the prevalence of the expansion in a hospital‐based cohort and associated clinical features indicating a wider clinical spectrum of C9ORF72 disease than previously described. We studied 280 patients previously screened for mutations in genes involved in early onset autosomal dominant inherited dementia disorders. A repeat‐primed polymerase chain reaction amplification assay was used to identify pathogenic GGGGCC expansions. As a potential modifier, confirmed cases were further investigated for abnormal CAG expansions in ATXN2. A pathogenic GGGGCC expansion was identified in a total of 14 probands. Three of these presented with atypical clinical features and were previously diagnosed with clinical olivopontocerebellar degeneration (OPCD), atypical Parkinsonian syndrome (APS) and a corticobasal syndrome (CBS). Further, the pathogenic expansion was identified in six FTD patients, four patients with FTD‐ALS and one ALS patient. All confirmed cases had normal ATXN2 repeat sizes. Our study widens the clinical spectrum of C9ORF72related disease and confirms the hexanucleotide expansion as a prevalent cause of FTD‐ALS disorders. There was no indication of a modifying effect of the ATXN2 gene. 相似文献
30.
Rossatto ER da Silva LB Pereira GS Bonan CD Battastini AM Ribeiro JP Sarkis JJ 《Platelets》2003,14(1):47-52
ATP diphosphohydrolase is an enzyme described in platelets and may be related to the control of ADP-dependent platelet aggregation. Platelet aggregation in atherosclerotic coronary arteries, and the release of platelet-derived factors, play an important role in coronary artery disease syndromes. In this study, we determined the activity of ATP diphosphohydrolase in platelets from patients with chronic and acute coronary artery disease syndromes and healthy persons. The following groups were studied: healthy persons (group I), patients with chronic heart disease (group II) and acute heart disease (group III). Results did not demonstrate differences between the groups studied. The control group demonstrated a lower range of enzyme activity. The patients from groups II and III had ingested drugs with actions upon the cardiovascular system and the effect, in vitro, of these drugs upon the ATP diphosphohydrolase activity in human platelets was also investigated. The in vitro experiments demonstrated that 2.0 mM acetylsalicylic acid inhibited ATP hydrolysis by human platelets by approximately 55%. Significant correlation was observed between ADP hydrolysis and glucose blood levels in the control group and between ATP hydrolysis and triglycerides in the group II. These results contribute to our understanding of a possible relationship between ATP diphosphohydrolase and thrombogenesis. 相似文献