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At least 559 records · Page 31Linked to original sources
PubMed1991

Evidence for the induction of fatty acid desaturation in proliferating hepatic endoplasmic reticulum in response to treatment with polychlorinated biphenyls. Are fatty acid desaturases cytochrome P-450-dependent monooxygenases?

1. Polychlorinated biphenyls (PCBs) are abundant and persistent pollutants in the ecosystem which accumulate in biological systems. 2. We have shown previously (Borlakoglu et al., 1990; Eur. J. Biochem. 118, 327-332) that 120 hr after treating pigeons and rats with 1.5 mmol Aroclor 1254/kg body weight, hepatic microsomal membranes showed significant increases in the proportion of arachidonate (20:4,5, 8,11,14), in the concentration of cytochrome P-450 and in the activities of a wide range of cytochrome P-450-dependent enzymes involved in the metabolism of drugs and other xenobiotics. 3. After treating pigeons and rats in vivo with Aroclor 1254, linoleate desaturases activity increased significantly 3.35-, 4.35-, 5.83- and 8.61-fold 24, 48, 68 and 120 hr for pigeons and 2- and 7-fold for rats respectively 48 and 120 hr post treatment. The total activity of linoleate desaturases in the whole liver of pigeons and rats increased 40- and 10-fold respectively. 4. There were excellent correlations between the concentrations of cytochrome b5 and cytochrome P-450 and the activity of pigeon linoleate desaturases. Extrapolation of the concentration of cytochrome P-450 to zero is coincident with zero linoleate desaturase activity. 5. Evidence is presented to suggest the novel concept that linoleate desaturation is dependent upon the catalytic cycle of these monooxygenases.

Animals↗
PubMed1991

In vitro metabolism of [14C]4-chlorobiphenyl and [14C]2,2',5,5'-tetrachlorobiphenyl by hepatic microsomes from rats and pigeons. Evidence against an obligatory arene oxide in aromatic hydroxylation reactions.

1. The catalytic activities of cytochromes P-450IA1 and P-450IIB1 in control and Aroclor 1254 treated rats and pigeons (1 mmol/kg) were assessed using [14C]4-chloro- and [14C]2,2',5,5'-tetrachlorobiphenyl as substrates. Treatment of rats resulted in increases of the total amount of chloroform-extractable metabolites of [14C]4-chlorobiphenyl from 37.2 (control) to 199.4 and 221.6 nmol/hr per mg microsomal protein at 48 and 120 hr post treatment. The portion of [14C]4-chloro-3',4'-dihydroxybiphenyl (M4) and of a second unidentified dihydroxylated metabolite (M3) increased during these incubations from 13.7% for controls to 53.5% at 48 hr and 69.12% at 120 hr post treatment. 2. [14C]4-chloro-3'-hydroxybiphenyl (M1) and [14C]4-chloro-4'-hydroxybiphenyl (M2) were the major metabolites formed by pigeon hepatic microsomes; however, the amounts formed were 38.7- and 29.3-fold less, respectively, than in untreated rats. Treatment of pigeons with Aroclor 1254 increased the metabolite formation from 1.0 (control) to 13.6 and 22.4 nmol/hr per mg microsomal protein at 48 hr and 120 hr post treatment respectively; however, only small amounts of metabolites M3 (0.5 nmol/hr per mg protein) and M4 (2.0 nmol/hr per mg protein) were detected. 3. Treatment of rats with Aroclor 1254 resulted in an approximately two-fold increase in the rate of metabolism of [14C]2,2',5,5'-tetrachlorobiphenyl, and the ratio of 3- to 4-hydroxylation increased from 0.45 (control) to 0.6 and 0.8 at 48 hr and 120 hr post treatment respectively. The rate of metabolism of [14C]2,2',5,5'-tetrachlorobiphenyl by control and Aroclor 1254 treated pigeons was up to 23-fold lower than in rats and there was no evidence for the formation of the diol metabolite M3. However, as with rats, the ratio of meta- to para-carbon atom hydroxylation increased from 0.58 (controls) to 0.72 at 120 hr post treatment. 4. From the evidence presented, it is suggested that cytochromes P-450IA1 and P-450IIB1 may not metabolize PCB-congeneric substrates via an obligatory arene oxide intermediate.

Animals↗
PubMed1992

Phenotypic responses of mouse mammary tumours and normal mammary epithelium cultured in collagen gels: correlation with tumour type and progression.

Mammary tumours in female BR6/Icrf mice and the corresponding contralateral normal mammary glands were disaggregated with collagenase and the epithelial structures released ('organoids') separated from other cellular components by filtration. The organoids were established in primary culture in a collagen matrix and the outgrowths obtained were studied by light microscopy and time-lapse cinemicroscopy. The pattern of three-dimensional outgrowths produced was found to be specific to the original tissue. Organoids from normal tissue formed a characteristic outgrowth designated Pattern A. Normal tissue from pregnant mice formed an additional characteristic outgrowth (Pattern A') which has not been described previously. Pregnancy-dependent tumours produced a distinctive phenotypic outgrowth designated Pattern D, whereas pregnancy-independent tumours gave a different distinctive Pattern B as well as a unique specific outgrowth designated Pattern C. Outgrowths of Pattern D from a pregnancy-dependent tumour were removed from culture and implanted into a syngeneic female mouse. Tumours arising in the host were found to be pregnancy-independent and showed phenotypic outgrowths in subsequent culture of pregnancy-independent Patterns B and C. The results show that the type of outgrowths in these cultures correlates with the biology of the tissue in vivo and that changes in tumour progression in vivo are accompanied by alterations in phenotypic outgrowths in culture.

Animals↗
PubMed1992

Effects of insulin, hydrocortisone and prolactin on cell morphology, growth and survival of mammary organoids from mid-pregnant mice cultured on collagen gels.

Mammary epithelial organoids consisting of groups of lobular-alveolar acini were prepared from mid-pregnant mice and cultured for 24, 48, 96 and 192 hr on attached collagen gels in the presence of combinations of insulin, hydrocortisone and prolactin. The organoids rapidly attached to the gels and with all the combinations of hormones used colonies of cells spread out as a monolayer from the organoids within 48 hr. Although colony formation continued for up to 192 hr in culture, the maintenance of parental organoid structure after 96 and 192 hr was strongly favoured when hydrocortisone was present in the culture medium. The presence of hydrocortisone produced a dose-dependent increase in the amount of organoid DNA associated with the collagen substratum but decreased the rate of DNA synthesis by the organoids, as measured by the incorporation of labelled thymidine into DNA, in a dose-dependent manner under these conditions. The results suggest that the presence of hydrocortisone minimised the loss of cells from the collagen matrix in these cultures.

Animals↗
PubMed1990

Effects of molecular substitution patterns on the cytochrome P-450-dependent metabolism of 2,2',3,5,5',6- and 2,2',3,4,4',6-hexachlorobiphenyl by rat liver microsomal monooxygenases.

The metabolism by rat hepatic microsomal cytochrome P-450-dependent monooxygenases of several model substrates that are specific for individual isoforms of cytochrome P-450 and the metabolism by these monooxygenases of two structurally related isomers of hexachlorobiphenyl was studied. The most striking result was that 2,2',3,5,5',6-hexachlorobiphenyl was metabolised in vitro at the rate of 4.5 pmol/mg microsomal protein per min, whereas the other isomer 2,2',3,4,4',6-hexachlorobiphenyl was not metabolised at detectable rates. This finding provides strong evidence for a regioselective oxidative attack by cytochrome P-450-dependent monooxygenase with preferential insertion of oxygen at meta-para unsubstituted carbon atoms. Investigations into the mechanism of this oxidative attack suggest that the ortho hydrogen atom at carbon atom C-6' of 2,2',3,4,4',6-hexachlorobiphenyl was associated with a lower charge (0.075 e) compared with the meta or para hydrogen atoms at carbon atom C-3' and C-4' of 2,2',3,5,5',6-hexachlorobiphenyl (0.086 e). In addition, measurement of the main C-C bond length using MOPAC calculations and X-ray crystalographic data suggests significant differences in the bond-length distance, with the main bond lengths of 1.390, 1.385 and 1.374 A, respectively, for bridgehead to ortho (C1-C2), for ortho to meta (C2-C3), and for meta to para bonds. These results provide evidence that the preferential meta-para oxidative attack is linked to a shorter carbon-carbon bond length and a more positive charge distribution of the corresponding hydrogen atoms.

Animals↗
PubMed1991

Induction of hepatic cytochrome P-450IA1 in pigeons treated in vivo with Aroclor 1254, a commercial mixture of polychlorinated biphenyls (PCBs).

1. Treatment with a commercial mixture of polychlorinated biphenyls (PCBs) resulted in highly significant increases in pigeon hepatic microsomal proteins (100-fold), cytochrome P-450 (11-fold), cytochrome b5 (7-fold), NADPH-cytochrome c-(P450) reductase (7-fold), ethoxycoumarin-O-deethylation (9-fold), aldrin epoxidase (22-fold), ethoxyresorufin-O-deethylation (48-fold), N-demethylation of dimethylnitrosamine (28-fold) but not of lauric acid 12-hydroxylation. 2. SDS-PAGE analysis of pigeon hepatic microsomal proteins induced by Aroclor 1254 suggested highly significant increases in the density of staining in bands of estimated Mr 51-52 kD, 54-54.5 kD, 57-58 kD, 59-60 kD and of 77.5-78.5 kD. 3. The induction of cytochrome P-450IA1 was confirmed by Western immunoblotting using the monoclonal antibodies MAB 1-12-3 and MAB 1-8-4. 4. There was agreement between the 8-fold increase in cytochrome P-450IA1 increased staining of microsomal proteins, as judged by SDS-PAGE, and the 24-fold increase in the amount of protein that reacted with the monoclonal antibodies MAB 1-12-3 and MAB 1-8-4, as judged by Western immunoblotting. 5. It is concluded that treatment with a commercial PCB mixture resulted in the induction of several isoforms of pigeon hepatic cytochrome P-450 in a fashion that is likely to be similar to that reported for mammals.

Animals↗
PubMed1991

Metabolism of [14C]4-chlorobiphenyl by hepatic microsomes isolated from razorbills, pigeons and rats.

1. Analysis of individual PCB-isomers and congeners in extracts of adipose tissue from N = 12 razorbills suggested that 4-chlorobiphenyl was subjected to metabolism. 2. In vitro metabolism studies using [14C]-4-chlorobiphenyl as substrate showed that razorbills metabolise this substrate to [14C]4-chloro-4'-hydroxybiphenyl at an average rate of 20 pmol/mg microsomal protein/min. For comparison, the metabolism of [14C]-4-chlorobiphenyl by pigeons and rats was also studied, and average rates in the formation of [14C]-4-chloro-4'-hydroxybiphenyl of 12 pmol/mg microsomal protein min and 342 pmol/mg microsomal protein min were estimated. 3. A comparison of the hepatic drug metabolising enzyme system of razorbills and pigeons showed similar concentrations of cytochrome P-450, cytochrome b5 and comparable catalytic activities of cytochrome P-450-dependent monooxygenase, when assessed for HHDN epoxidase, PROD, EROD and the Phase II enzymes glutathiones-S-transferase, but were significantly lower, when compared with rats. The results obtained suggest fundamental differences in the catalytic activities of cytochrome P-450-dependent monooxygenase between avian and mammalian species. 4. The present study, however, provides evidence that fish-eating seabirds have the ability to metabolically dispose of certain PCB isomers and congeners, which are amongst the most ubiquitously distributed pollutants in the ecosystem.

Adipose Tissue↗
PubMed2006

BRCA1 and TP53 mutation spectrum of breast carcinoma in an ethnic population of Kashmir, an emerging high-risk area.

Breast cancer shows geographical variation in its incidence, even within areas of ethnic homogeneity. Kashmir valley (India), over past few years, witnesses an increase in incidence and occurrence of familial, early onset, and male breast cancer in its unexplored ethnic population. Here, we make a preliminary attempt to estimate the nature and frequency of BRCA1 and TP53 gene mutations of breast cancer patients from Kashmir. PCR-SSCP analysis followed by direct sequencing revealed the presence of only two germline intronic variations (c.199+67T>C and c.5396+187T>C) in BRCA1 gene in only 5.26% (2/38) patients while as 44% (11/25) of sporadic breast cancer patients harboured significant amount of somatic mutations in TP53 (p=0.0074; OR=0.053). The 17 mutations found in TP53 in 11 patients, comprised of 13 substitutions [11 single-base (9 transitions+2 transversions), 1 double-base and 1 complex] and four insertions. The 11 substitutions represent missense mutations, leading to aminoacid substitution while as rest two were silent mutations. The four insertions represented three frame-shifts and one non-sense mutation. The mutation effect data was found to be significant (p=0.0002). Significant amount of mutations were found in exon 6 (p=0.04; OR=0.273) and a combination of exons 6 and 7 (p=0.0145; OR=14.22) of TP53. Comparison of mutation profile with other ethnic populations and regions reflected both differences and similarities indicating co-exposure to a unique set of risk factors. The differences could be due to exposure to particular environmental carcinogens; different lifestyle, reproductive pattern; dietary or cultural practices of Kashmiri women that need further investigations. The infrequent presence of germline BRCA1 mutations in our study agree with the idea that a great proportion of moderate risk breast cancer population could be due to the susceptibility genes distinct from BRCA1. However, high frequency of somatic TP53 gene mutations implicates TP53 as a predominant factor for breast carcinogenesis in moderate risk ethnic Kashmiri population. The study also suggests TP53 as a potential molecular marker and prognostic tool, at least in a subset of sporadic breast tumors.

Adult↗
PubMed2025

Comprehensive genotypic, phenotypic, and biochemical characterization of GOT2 deficiency: A progressive neurodevelopmental disorder with epilepsy and abnormal movements.

PURPOSE: Glutamic-oxaloacetic transaminase (GOT), also known as aspartate aminotransferase, catalyzes the reversible transamination of oxaloacetate and glutamate to aspartate and α-ketoglutarate. Two isoforms, cytosolic (GOT1) and mitochondrial (GOT2), are integral to the malate-aspartate shuttle, a key regulator of intracellular redox homeostasis. Recently, 5 patients with biallelic variants in GOT2 were described, presenting with developmental and epileptic encephalopathy. METHODS: We report 11 additional patients with homozygous GOT2 variants, along with additional data from 4 previously reported patients. Through genetic, clinical, and biochemical analyses, we further characterize the phenotypic spectrum of GOT2 deficiency. RESULTS: Most patients exhibited progressive neurodevelopmental delay, severe to profound intellectual disability, infantile epilepsy, progressive microcephaly, and hypotonia evolving into spasticity with axial hypotonia. Dysmorphic features included narrow foreheads, broad nasal tips, and tall or pointed chins. Neuroimaging revealed 2 severity groups based on cerebral volume loss and myelination defects. Thinning of the corpus callosum and white matter abnormalities were common. Biochemical profiling identified low aspartate and high glycerol-3-phosphate in dried blood spots as potential screening markers. Patient fibroblast cells showed reduced serine and glycine biosynthesis, rescuable by pyruvate supplementation. CONCLUSION: These findings expand the phenotypic spectrum of GOT2 deficiency, establish it as a cause of developmental epileptic encephalopathy, and propose novel biomarkers for diagnosis and treatment.

Humans↗
PubMed2005

A tiered risk-based approach for predicting diffuse and point source phosphorus losses in agricultural areas.

Implementation of the European Union Water Framework Directive requires an assessment of the pressures from human activity, which, combined with information on the sensitivity of the receiving waterbody to the pressures, will identify those water bodies at risk of failing to meet the Directive's environmental objectives. Part of the process of undertaking the risk assessment for lakes is an assessment of diffuse agricultural phosphorus (P) pressures. Three approaches of increasing sophistication were developed for this purpose: a basic 'risk screening' approach (tier 1) applicable to all lakes in Great Britain (GB) and based on export coefficients for different land cover classes and animal types; the Pressure Delivery Risk Screening Matrix approach (tier 2) that differentiated between pressures in surface water and groundwater river basins; and the Phosphorus Indicators Tool (PIT), a simple model of locational risk and P delivery potential (tier 3). Application of the three approaches to a range of lake catchments in England demonstrated that a tiered risk assessment approach was appropriate which was tailored to the quality of the available data. A step-wise procedure was developed whereby if the tier 1 and 2 approaches showed a catchment to be at high risk of failing to meet the Directive's environmental objectives with regard to P, it was justifiable to undertake a more detailed assessment using the tier 3 approach. The tier 1 approach was applied to all lakes in GB greater than 1 ha in size on the assumption that the boundary between the good/moderate status classes under the Water Framework Directive guidelines represented a doubling of the total P (TP) reference conditions. The initial outputs suggested that 51% of lakes in GB are predicted to not meet the TP targets identified for high or good status and must, therefore, be considered at risk. There were regional differences in numbers of lakes at risk. Scotland appeared to have the fewest sites at risk (18%); England the most (88%), with Wales having an intermediate percentage (56%). A comparison of P pressures on freshwaters using the tier 2 approach with other pressures on waterbodies (e.g. nitrate, sediment) in GB is shown as risk maps on the Environment Agency website at: . The tier 3 approach was applied to data-rich catchments and identified at the 1 km(2) areas of relatively high risk of P delivery to water.

Agriculture↗
PubMed2026

Genome-wide insights into the evolutionary and demographic history of the red alga Mazzaella laminarioides: Evidence for speciation with ancient migration along the southeast Pacific coast.

The mechanisms driving lineage divergence in red algae remain unexplored, despite the group's remarkable diversity and ancient evolutionary history. The red alga Mazzaella laminarioides, a Chilean intertidal species complex composed of three parapatric cryptic lineages (North, Center, South), offers a valuable system to evaluate these processes, as its life history combines severe dispersal limitation with a haploid-diploid cycle that may influence the emergence of reproductive barriers. We reconstructed its evolutionary history using whole-genome sequencing and nuclear genome assembly of representative individuals from each lineage. Phylogenomic analyses based on 1,507 single-copy orthologs recovered three deeply divergent lineages with limited nuclear discordance consistent with incomplete lineage sorting. For both splits, demographic modelling was most consistent with an Ancient Migration scenario, although support over strict isolation was moderate, suggesting that divergence may have begun with low asymmetric ancestral gene flow followed by subsequent loss of connectivity, demographic bottlenecks, and later population expansion. Coding sequence analyses revealed lineage-specific dN/dS heterogeneity; only one South-lineage locus passed FDR correction (metaxin-1, mitochondrial protein import), with two further South-lineage candidates in chlorophyll and heme biosynthesis falling below the FDR threshold. Together, these signals suggest that divergent selective pressures on energy acquisition may have contributed to divergence at the southern end of the distribution. These results add to the small but growing body of whole-genome data for red algae and, alongside recent macroalgal studies, suggest that ancestral connectivity could be a recurrent feature of lineage divergence even in marine organisms with extremely restricted dispersal.

Rhodophyta↗