A number of metals have been shown to be involved in the etiology of animal and human neoplasms. The molecular mechanisms have not yet been determined, but the observed plethora of genetic effects observed following treatment of mammalian cells with metals clearly indicates the possibility that metals can exert their effects at least partially at the level of DNA metabolism. Several studies have suggested that metal treatment may inhibit normal DNA repair processes in procaryotic and eucaryotic cells but a systematic study of this question has not previously been conducted. The present study surveyed the ability of 15 metal salts to interfere with repair of X-ray or UV-induced DNA damage in HeLa cells. Hg+(+), As++(+), Cu+(+), Ni+(+), Co+(+), and Cd+(+) were shown to inhibit the excision of pyrimidine dimers from DNA and to do so in a dose-dependent fashion. Inhibition of repair by only Ni+(+) and Co+(+) resulted in the accumulation of long-lived DNA strand breaks suggestive of a block in the gap-filling stage of repair. Ability to inhibit repair was not correlated with cytotoxicity. X-ray repair was sensitive to Hg+(+), Ni+(+), As++(+), Ga+(+), Zn+(+), and Mo(VI). All inhibitory metals inhibited closure of single strand DNA breaks. Ga+(+) appeared, in addition, to inhibit a later step involving chromatin reconstitution. These findings support the notion that interference of DNA repair processes may be a consequence of exposure of mammalian cells to certain metals. This may be a factor in the etiology of metal-associated carcinogenesis.
Human leukocyte complement receptor type three (CR3) was shown to be lectin-like and to resemble bovine serum conglutinin (K) in that it bound to both iC3b and unopsonized yeast (Saccharomyces cerevisiae), and was inhibited by EDTA or N-acetyl-D-glucosamine (NADG). CR3 and K also bound to zymosan (Z), a yeast cell wall extract that contains primarily polysaccharide and no detectable protein. However, structural differences and the absence of K on bovine phagocytes indicated that CR3 was not the human homologue of bovine K. Phagocytic and respiratory responses to unopsonized Z were CR3 dependent because they were inhibited by monoclonal antibodies specific for the alpha-chain of CR3 and did not occur with phagocytes from patients with a genetic deficiency of CR3. The binding of CR3 to Z did not require opsonization of the Z with neutrophil-secreted C3, as Z binding and responses were not inhibited by Fab anti-C3. In addition, CR3-dependent binding of yeast occurred with neutrophils from which protein secretion was blocked by fixation with paraformaldehyde. Rabbit erythrocytes (RaE) also bound weakly to neutrophil CR3 and triggered ingestion. Anti-CR3 not only blocked the binding and ingestion of RaE but also blocked selectively the ingestion of RaEC3b without affecting the strong binding mediated by CR1. Even though sheep E and sheep EC3b were not ingested by neutrophils, a weak binding of CR3 to sheep E was suggested by the finding of 20 to 40% inhibition of sheep EAIgG ingestion by anti-CR3. Such inhibition was only observed in buffers that allowed activity of the CR3 binding site and not in buffers containing either EDTA or NADG. An apparently contradictory finding was that the weak CR3-dependent binding of Z triggered neutrophil ingestion and a superoxide burst, whereas the avid CR3-dependent binding of sheep EC3bi did not induce significant ingestion or a respiratory burst. Blocking studies with monoclonal antibodies specific for different epitopes of the alpha-chain of CR3 suggested that this might result from the presence of two distinct binding sites in CR3: one site for fixed iC3b that did not trigger functions, and a second function-triggering site for Z that did not bind to fixed iC3b.
We have recently demonstrated that HeLa cells that had been depleted of polyamines by treatment with inhibitors of polyamine biosynthesis were deficient in their ability to repair X-ray-induced DNA strand breaks. Since it had previously been demonstrated that hyperthermic shock also inhibited strand break repair following X irradiation and that hyperthermia resulted in a leakage of polyamines from cells, it seemed of interest to examine whether the inhibition of repair by hyperthermia was related to this loss of cellular polyamines. In the present paper it is demonstrated that both polyamine depletion and hyperthermia inhibit strand closure, and that a combined treatment further reduces the rate of repair. In cells not depleted of polyamines, repair is restored to normal levels if hyperthermia treatment is followed by a 4-h incubation at 37 degrees C before X irradiation. In polyamine-depleted cells, this 37 degrees C incubation does not result in a return of repair ability. Polyamine supplementation was not effective in reversing hyperthermia-dependent repair inhibition, and, in fact, restoration of repair in control cells following hyperthermic shock corresponded to a time at which polyamines show a maximum decrease in those cells. These results suggest that the inhibition of repair and the increased radiosensitivity observed in hyperthermically treated cells is not related to polyamine depletion. However, data further suggest that polyamine-depleted cells may have other alterations, perhaps in chromatin, which render them more sensitive to thermal inhibition of repair.
Metabolic studies using radioiodine labelled third component of complement (C3) and the glycine-rich / 3 glycoprotein (GBG), a major component of the C3b-feedback pathway, were undertaken in normal subjects, in thirty-three patients with in vivo evidence of complement activation and in nine patients with various renal diseases without evidence of complement activation. In seven normal subjects GBG was found to be a rapidly metabolized protein with catabolic rates ranging from 1.7% to 2.2% of the plasma pool per hour, and synthesis rates from 0.14 to 0.21 mg kg-' h-'. In patients with reduced plasma C3, both increased C3 fractional catabolic rates and reduced C3 synthesis rates were observed, and in some patients there was also evidence of extravascular sequestration of the protein. GBG catabolism was usually increased when there was evidence of C3 activation, presumably reflecting activation of the C3b-feedback; but GBG turnover was normal in some patients with accelerated C3 catabolism and profound hypocomplementaemia suggesting that reduced C3 synthesis had limited activation of the C3b-feedback. Since normal C3 synthesis rates were reported in the patient congenitally deficient in the C3b inactivator (KAF), we suggest that this reduction in C3 synthesis is secondary to the generation of C3 breakdown products by the action of KAF on C3b. ENDOTOXINAEMIA IN ACUTE RENAL FAILURE, OBSTRUCTIVE JAUNDICE AND IN RENAL TRANSPLANT RECIPIENTS E. NIGEL WARDLE Royal Victoria Infirmary, Newcastle upon o n eUsing gelation of limulus lysate positive reactions for endotoxin have been detected in 68% patients with septic shock, 65% patients at the onset of acute renal failure and 65% patients with renal transplants with infection but not at rejection. Positive tests also occurred in 75% patients with obstructive jaundice at the day of operation and 15% at other times.Since infection is associated with the onset of the majority of cases of acute renal failure in man, this evidence of endotoxinaemia together with other evidence for disseminated intravascular coagulation, suggests that the Shwartzman reaction is the common cause of acute renal failure. The finding is also relevant to the hepatorenal syndrome.The limulus test gave positive reactions with cholic acid and also staphylococcal a-haemolysin. The reliability of the test will be discussed.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.