Genetic Analysis with Man-Mouse Somatic Cell Hybrids: Linkage between Human Lactate Dehydrogenase B and Peptidase B Genes
TL;DR: Evidence of an active linkage between the human genes that control lactate dehydrogenase B and peptidase B is presented, but it is concluded that there is no link between the genes for lactate dehydration A and lactatehydrogenase A.
Abstract: Evidence of an active linkage between the human genes that control lactate dehydrogenase B and peptidase B is presented. It is also concluded that there is no link between the genes for lactate dehydrogenase A and lactate dehydrogenase B.
Citations
More filters
TL;DR: The object of this paper is that of pointing out the most important lines in the current state of knowledge in this field, evaluating the methodological applications and their advantages/disadvantages with respect to traditional surveying methods.
704 citations
TL;DR: It is shown for the first time that insulin and c-peptide concentration in the brain are correlated and decrease with aging, as do brain insulin receptor densities, which favor the hypothesis that insulin dependent functions may be of pathogenetic relevance in sporadic Alzheimer's disease.
Abstract: The search for the causes of neurodegenerative disorders is a major theme in brain research. Acquired disturbances of several aspects of cellular metabolism appear pathologically important in sporadic Alzheimer's disease (SDAT). Among these brain glucose utilisation is reduced in the early stages of the disease and the regulatory enzymes important for glucose metabolism are reduced. In the brain, insulin, insulin-like growth factors and their receptors regulate glucose metabolism and promote neuronal growth. To detect changes in the functional activity of the brain insulin neuromodulatory system of SDAT patients, we determined the concentrations of insulin and c-peptide as well as insulin receptor binding and IGF-I receptor binding in several regions of postmortem brain cortex during aging and Alzheimer's disease. Additionally, we performed immunohistochemical staining with antibodies against insulin in neocortical brain areas in SDAT and controls. We show for the first time that insulin and c-peptide concentration in the brain are correlated and decrease with aging, as do brain insulin receptor densities. Weak insulin-immunoreactivity could be demonstrated histochemically in pyramidal neurons of controls, whereas in SDAT a stronger insulin-immunoreactivity was found. On a biochemical level, insulin and c-peptide levels were reduced compared to middle-aged controls, but were unchanged compared to age-matched controls. Brain insulin receptor densities in SDAT were decreased compared to middle-aged controls, but increased in comparison to age-matched controls. IGF-I receptor densities were unchanged in aging and in SDAT. Tyrosine kinase activity, a signal transduction mechanism common to both receptor systems, was reduced in SDAT in comparison to middle-aged and age-matched control groups. These data are consistent with a neurotrophic role of insulin in the human brain and a disturbance of insulin signal transduction in SDAT brain and favor the hypothesis that insulin dependent functions may be of pathogenetic relevance in sporadic SDAT.
697 citations
TL;DR: It is proposed that three theories of aging, the glucocorticoid theory, the membrane theory, and the free radical theory, constitute three facets of age with one underlying trigger: an increase in the endogenous concentration of interleukin-1β in hippocampus.
Abstract: Several cytokines and their receptors are identified in brain; one of these is the proinflammatory cytokine interleukin-1β that is synthesized and released from neurons and glia in response to stress or insult. Among the actions of interleukin-1β is its ability to inhibit long-term potentiation in the hippocampus in vitro, an action that mimics one of the consequences of stress and age. It has been shown that the concentration of interleukin-1β in brain tissue is increased in neurodegenerative conditions, and recent evidence from our laboratory has indicated an increase in the concentration of interleukin-1β in the hippocampus of aged rats. These observations led us to consider that the underlying common cause of impaired long-term potentiation in aged and stressed rats might be increased endogenous interleukin-1β concentration in hippocampus. The data presented here indicate that there was an inverse relationship between concentration of interleukin-1β in the dentate gyrus and long-term potentiation in perforant path→granule cell synapses in aged rats, stressed rats, and rats pretreated with interleukin-1β. The evidence suggested that the cytokine induces formation of reactive oxygen species that triggers lipid peroxidation in vivo, as well as in vitro, and that these changes lead to depletion of membrane arachidonic acid that correlates with impaired long-term potentiation. We propose that three theories of aging, the glucocorticoid theory, the membrane theory, and the free radical theory, constitute three facets of age with one underlying trigger: an increase in the endogenous concentration of interleukin-1β in hippocampus.
413 citations
TL;DR: It is demonstrated that inhibition of GSK3β by serine‐9 phosphorylation or directly by lithium increases CREB activation, and lithium enhances,CREB activation.
Abstract: The regulatory influences of glycogen synthase kinase-3 beta (GSK3 beta) and lithium on the activity of cyclic AMP response element binding protein (CREB) were examined in human neuroblastoma SH-SY5Y cells. Activation of Akt (protein kinase B) with serum-increased phospho-serine-9-GSK3 beta (the inactive form of the enzyme), inhibited GSK3 beta activity, and increased CREB DNA binding activity. Inhibition of GSK3 beta by another paradigm, treatment with the selective inhibitor lithium, also increased CREB DNA binding activity. The inhibitory regulation of CREB DNA binding activity by GSK3 beta also was evident in differentiated SH-SY5Y cells, indicating that this regulatory interaction is maintained in non-proliferating cells. These results demonstrate that inhibition of GSK3 beta by serine-9 phosphorylation or directly by lithium increases CREB activation. Conversely, overexpression of active GSK3 beta to 3.5-fold the normal levels completely blocked increases in CREB DNA binding activity induced by epidermal growth factor, insulin-like growth factor-1, forskolin, and cyclic AMP. The inhibitory effects due to overexpressed GSK3 beta were reversed by treatment with lithium and with another GSK 3beta inhibitor, sodium valproate. Overall, these results demonstrate that GSK3 beta inhibits, and lithium enhances, CREB activation.
411 citations
TL;DR: This study suggests that the anticarcinogenic effect of dietary ETs could be mainly due to their hydrolysis product, EA, which induced apoptosis via mitochondrial pathway in colon cancer Caco-2 cells but not in normal colon cells.
Abstract: Polyphenol-rich dietary foodstuffs have attracted attention due to their cancer chemopreventive and chemotherapeutic properties. Ellagitannins (ETs) belong to the so-called hydrolysable tannins found in strawberries, raspberries, walnuts, pomegranate, oak-aged red wine, etc. Both ETs and their hydrolysis product, ellagic acid (EA), have been reported to induce apoptosis in tumour cells. Ellagitannins are not absorbed in vivo but reach the colon and release EA that is metabolised by the human microflora. Our aim was to investigate the effect of a dietary ET [pomegranate punicalagin (PUNI)] and EA on human colon cancer Caco-2 and colon normal CCD-112CoN cells. Both PUNI and EA provoked the same effects on Caco-2 cells: down-regulation of cyclins A and B1 and upregulation of cyclin E, cell-cycle arrest in S phase, induction of apoptosis via intrinsic pathway (FAS-independent, caspase 8-independent) through bcl-XL down-regulation with mitochondrial release of cytochrome c into the cytosol, activation of initiator caspase 9 and effector caspase 3. Neither EA nor PUNI induced apoptosis in normal colon CCD-112CoN cells (no chromatin condensation and no activation of caspases 3 and 9 were detected). In the case of Caco-2 cells, no specific effect can be attributed to PUNI since it was hydrolysed in the medium to yield EA, which entered into the cells and was metabolised to produce dimethyl-EA derivatives. Our study suggests that the anticarcinogenic effect of dietary ETs could be mainly due to their hydrolysis product, EA, which induced apoptosis via mitochondrial pathway in colon cancer Caco-2 cells but not in normal colon cells.
409 citations
References
More filters
572 citations
TL;DR: The behaviour of the ADA isozyme pattern on storage or after treatment with thiol reagents suggests the occurrence of reactive sulphydryl groups in the enzyme molecules.
Abstract: Summary
1
A new and specific method for the study of adenosine deaminase isozymes is described.
2
Examination of red-cell lysates has revealed three genetically determined electrophoretically different ADA phenotypes: ADA 1, ADA 2–1 and ADA 2.
3
Family studies indicate that these phenotypes are determined by two alleles, ADA1 and ADA2 at an autosomal locus.
4
Preliminary population data suggest that ADA2 has a frequency of about 0.06 in European, 0.04 in Negroes and 0.11 in Asiatic Indians.
5
The behaviour of the ADA isozyme pattern on storage or after treatment with thiol reagents suggests the occurrence of reactive sulphydryl groups in the enzyme molecules.
465 citations
TL;DR: A new method for characterizing peptidases in terms of electrophoretic behaviour in starch gel and of substrate specificity is described and genetically determined variants of two enzymes appear to be involved.
Abstract: A new method for characterizing peptidases in terms of electrophoretic behaviour in starch gel and of substrate specificity is described. A survey of red cells from a large number of people has revealed genetically determined variants of two of these enzymes. Separate loci appear to be involved.
268 citations
TL;DR: Somatic hybridization between mouse cells and human leucocytes confirms the X-linkage of 8-azaguanine resistance in man and suggests that human lactate dehydrogenase A and B genes are not linked.
Abstract: Somatic hybridization between mouse cells and human leucocytes confirms the X-linkage of 8-azaguanine resistance in man and suggests that human lactate dehydrogenase A and B genes are not linked.
237 citations
TL;DR: The elctrophoretic pattern of phosphohexose isomerase has been examine in the blood of 3397 unrelated individuals from several different populations groups and it is shown that the pattern is similar to that of E.1.
Abstract: SUMMARY
1. The elctrophoretic pattern of phosphohexose isomerase has been examine in the blood of 3397 unrelated individuals from several different populations groups.
2. Eight variant phenotypes were identinfied and these were designated PHI 2-1, 3-1, 4-1, 5-11 6-1, 7-1, 8-1, 9-1. All of these were rare in the populations studied except the variant designated PHI 3-1, which was observed with a frequency of about 1% in a mixed population of Asiatic Indians.
3. Studies of selected families indicated that the variants occured in individuals who are heterozygous for one or another of a series of rare alleles at an autosomal locus.
4. Studies on the family of a patient that the patient was heterozygous for two different rare alleles at the PHI locus, each associated with reduced PHI activity. The patinet's mother showed the PHI 9-1 phenotype and his father showed a new phenotype designated PHI 10-1. The patient's phenotype has been designeated PHI 9-10.
5. The enzyme appears to be a dimer and in heterozygotes isozymes of hybrid submit compostion as well as isozymes of like subunit compostion are apparently formed.
227 citations