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PubMed1996

Structural organization of the rat branched-chain 2-oxo-acid dehydrogenase kinase gene and partial characterization of the promoter-regulatory region.

The gene encoding the rat branched-chain 2-oxo-acid dehydrogenase kinase (EC 2.7.1.115) has been isolated and partially characterized. The entire gene, including the promoter-regulatory region, spans 6 kb and contains 11 exons. The 5'-untranslated region comprising 264 bp is interrupted by intron 1 which is 581 bp in size. The complete in-frame sequence of intron 7 encodes the 49 amino acid insert previously reported to be present in the larger isoform of the rat kinase (Harris, Popov, Shimomura, Zhao, Jaskiewicz, Nanaumi and Suzuki (1992) Adv. Enzyme Regul. 32, 267-284). Sequencing of the 679 bp of the 5'-flanking region showed the absence of a canonical TATA box, similar to other branched-chain 2-oxo-acid dehydrogenase-complex genes. Several candidate cis-acting elements are present. These include CAAT boxes, Sp-1-binding sites, GCN-4 sites, CCAAT enhancer binding-protein sites (C/EBP) and glucocorticoid-responsive element (GRE) sites. Also present are a pair of direct repeats of unknown function. The luciferase-reporter assay showed that promoter activity is markedly higher in normal rat kidney (NRK-52E) cells than in rat hepatoma (FTO-2B) cells, and that the 5'-flanking region between bases -449 and +264 is both necessary and sufficient for basal transcription of the kinase gene.

Alternative Splicing↗
PubMed1998

Hepatitis B virus infection in microcarrier-attached immortalized human hepatocytes cultured in molecularporous membrane bags: a model for long-term episomal replication of HBV.

Studies on the pathobiology of chronic (long-term) hepatitis B virus (HBV) infection and in vitro drug testing have been hampered by the lack of appropriate systems for culturing susceptible cells chronically infected with HBV. Most of the in vitro studies of HBV replication have been performed with HBV genome-transduced cell lines. In this system, viral production is mainly the result of chromosomal replication. In an in vitro infection system, owing to medium refreshment (which leads to the removal of infectious particles necessary for the perpetuation of infection) and to trypsinization for cell passages, it is difficult, if not impossible, to maintain chronic HBV infection, despite the use of susceptible cells. To circumvent these unfavourable factors for chronic HBV infection in vitro, we cultured microcarrier-attached immortalized human hepatocytes, infected with HBV, in molecularporous (MW 12,000-14,000) membrane (dialysis) bags for a duration of 2 months. HBV covalently-closed-circular (ccc) DNA, HBV precore/core and X mRNAs were detected in the cells cultured in this system following infection until the end of the experiment (day 58), while in classical culture conditions (monolayer), markers of HBV replication were also detected. Production of hepatitis B surface antigen (HBsAg) and HBV DNA was detected and their levels in culture medium (collected at the end of experiments from the molecularporous membrane bags) were increased 2.86- and 3.28-fold respectively. Using Southern blot analysis, HBV replicative intermediates could also be demonstrated throughout the experiments. However, integrated HBV DNA was not present. In contrast, HBV ccc DNA, HBV precore/core and X mRNAs, and replicative intermediates were not demonstrable in FTO 2B rat hepatoma cells infected in the same manner in parallel experiments. This in vitro infection system, using susceptible, immortalized human hepatocytes, therefore provides a new tool for studying the long-term effect of HBV infection, mainly involving episomal replication in hepatocytes, and for drug testing.

Blotting, Southern↗
PubMed2003

Upstream and intronic regulatory sequences interact in the activation of the glutamine synthetase promoter.

Glutamine synthetase (GS) is expressed at high levels in subsets of cells in some tissues and at low levels in all cells of other tissues, suggesting that the GS gene is surrounded by multiple regulatory elements. We searched for such elements in the 2.5-kb upstream region and in the 2.6-kb first intron of the GS gene, using FTO-2B hepatoma and C2/7 muscle cells as representatives of both cell types and transient transfection assays as our tools. In addition to the entire upstream region and entire intron, an upstream enhancer module at -2.5 kb, and 5', middle and 3' modules of the first intron were tested. The main effects of the respective modules and their combinatorial interactions were quantified using the analysis of variance (anova) technique. The upstream enhancer was strongly stimulatory, the middle intron module strongly inhibitory, and the 3'-intron module weakly stimulatory in both hepatoma and muscle cells. The 5'-intron module was strongly stimulatory in muscle cells only. The major new finding was that in both cell types, the upstream enhancer and 5'-intron module needed to be present simultaneously to fully realize their transactivational potencies. This interaction was responsible for a pronounced inhibitory effect of the 5'-intron module in the absence of the upstream enhancer in hepatoma cells, and for a strong synergistic effect of these two modules, when present simultaneously in muscle cells. The main difference between hepatoma and muscle cells therefore appeared to reside in tissue-specific differences in activity of the respective regulatory elements due to interactions rather than in the existence of tissue-specific regulatory elements.

Animals↗
PubMed1992

Microstructure of skeletal muscles of growing calves fed silage-based vs hay-based diets. I. Fibre diameters.

Samples of musculus longissimus dorsi, semimembranosus and semitendinosus were obtained post-slaughter from 2-week, 3-month and 10-month-old bull calves. The 2-week-old calves were fed milk only. All the remaining animals were fed grass silage or hay ad lib and a restricted amount of concentrate from 2 weeks of age onwards. Muscle fibres were differentiated according to Ziegan into fast-twitch glycolytic, fast-twitch oxidoglycolytic and slow-twitch oxidative fibres (FTG, FTO and STO, respectively). In all calves, marked fibre growth took place between 3 and 10 months of age. From the 2nd week to the 3rd month, growth was observed virtually only in the FTG fibres, irrespective of feeding. Feeding calves with a silage-based vs hay-based diet resulted in thicker muscle fibres for each type of fibre. Significant linear regression coefficients have shown the fibre diameters to be clearly related to live weight gain resulting from DM intake that was higher in the silage-based diet.

Animal Feed↗
PubMed1992

Microstructure of skeletal muscles of growing calves fed silage-based vs hay-based diets. II. Fibre type distribution.

As described in part I, samples of musculus longissimus dorsi, semimembranosus and semitendinosus were obtained post-slaughter from 2-week, 3-month and 10-month-old bull calves. The 2-week-old calves were fed milk only. All the remaining animals were fed grass silage or hay ad lib and a restricted amount of concentrate from 2 weeks of age onwards. Muscle fibres were differentiated according to Ziegan (1979) into fast-twitch glycolytic, fast-twitch oxidoglycolytic and slow-twitch oxidative fibres (FTG, FTO and STO, respectively). The percent distribution of individual types of fibres was estimated as related to the calves age and diet. The most numerous were always fast-twitch glycolytic fibres, the lowest values being observed in the 2-week-old calves. The effect of the diet on fibre percentage distribution in 3-month-old calves differed from that found in 10-month-old animals. This research suggests that a hay-free diet based on grass silage alters the microstructure of skeletal muscles, which thus might also affect the quality of meat.

Aging↗
PubMed1995

The far-upstream enhancer of the carbamoyl-phosphate synthetase I gene is responsible for the tissue specificity and hormone inducibility of its expression.

The role of the proximal promoter and the far-upstream enhancer in the hepatocyte-specific and hormonal regulation of the carbamoyl-phosphate synthetase I (CPS) gene was investigated in transient transfection assays using primary rat hepatocytes, hepatoma cells, and fibroblasts. These experiments revealed that the activity of the promoter is comparable in all cells tested and is, therefore, not responsible for tissue-specific expression. The 5'-untranslated region of the mRNA is a major, non-tissue specific stimulator of expression in FTO-2B hepatoma cells, acting at the post-transcriptional level. A 469-base pair DNA fragment, 6 kilobase pairs upstream of the transcription start-site in the CPS gene, confers strong hormone-dependent tissue specific expression, both in combination with the CPS promoter and a minimized viral thymidine kinase promoter. Sequences similar to a cyclic AMP-responsive element and a glucocorticosteroid-responsive element were found in the isolated enhancer. Substitutional mutations in these sites strongly affected hormone-induced expression. Analysis of the interaction between the enhancer and parts of the CPS promoter revealed that, in addition to the TATA box, the GAG box, a motif similar to the GC box near the TATA motif, is instrumental in conferring the enhancer activity.

Animals↗
PubMed2002

Self-monitoring and future time orientation in romantic relationships.

The author examined the relationship between self-monitoring and participant's gender, and future time orientation in romantic relationships (FrORR) and tested the concurrent validity of the FTORR scale in this respect. One hundred seventy-three undergraduate students from Middle East Technical University were given M. Snyder's (1974) self-monitoring scale and B. Oner's (2000b) FTORR scale. Low self-monitoring participants had a more extended future time orientation (FTO) than high self-monitoring participants in terms of romantic associations.

Analysis of Variance↗
PubMed2026

Proteomic insights into Helicobacter pylori infection in stomach cells, revealing host response and host-targeted therapeutics repurposing.

BACKGROUND: Helicobacter pylori (H. pylori) is a globally prevalent gastric pathogen strongly associated with chronic gastritis, peptic ulcers, and gastric cancer. While bacterial factors have been extensively studied, host proteomic responses and their therapeutic potential remain largely underexplored. RESEARCH DESIGN AND METHODS: Current analyses employed a systematic proteomics-based data integration and harmonization approach (retrospective qualitative cohort study) to identify important differentially regulated host proteins. Proteomic datasets were curated from in vitro studies and analyzed for functional enrichment, protein-protein interaction networks, and hub protein identification. To explore therapeutic repurposing, drug repositioning was performed using the DrugBank database. RESULTS: Data summation describing protein differential regulation in human gastric cells as a result of the infection revealed 1672 perturbed host proteins. Bioinformatics analysis revealed 11 proteins including CSK, MET, RELA, MARK2, GRB2, FTO, PLCG1, CRKL, RPS5, RPS9, and RPS27A to be ideal host targets for therapeutic repurposing. Clinically approved drugs such as Dasatinib (targeting CSK) and Crizotinib (targeting MET) emerged as promising candidates due to favorable pharmacokinetics and known bioactivity. CONCLUSIONS: Host-directed therapeutics could offer alternative strategies to conventional antibiotic therapy, addressing challenges such as resistance and infection recurrence, providing a foundation for future experimental validation and development of host-targeted interventions for infection control.

Humans↗
PubMed1993

[Effect of a beta-agonist and a beta-agonist/beta-antagonist combination on muscle growth, body composition and protein metabolism in rats].

In 3 experimental groups 9 female Wistar rats (initial live weight 150 g) were fed either the control diet, the control diet supplemented with 5 mg clenbuterol or the combination of 5 mg clenbuterol and 500 mg propranolol per kg diet over a 12-day period. The N-balance was estimated over days 6 to 10 followed by a 15N-tracer experiment for determining the influence of the feed additives on characteristics of protein metabolism on day 12. All differences in the means were concluded to be significant for P < 0.05. Live weight gain and feed efficiency were improved by clenbuterol. The animals treated with clenbuterol had 18%-24% higher muscle weights whereas the combined treatment increased the muscle weights by 10%-16% only. The good correlation between the increase of muscle weights and the total protein content indicates that clenbuterol does not change the relation between protein- and water accumulation. Histological-histochemical investigations showed that the higher muscle weights were achieved through muscle fibre hypertrophy. The number of muscle fibres remained constant. Concerning the distribution of the fibre types, clenbuterol increased the proportion of FTG-fibres (white, fast-twitch, glycolytic) on the expense of the FTO-fibres (fast-twitch, oxidative). While the number of nuclei per muscle fibre did not change, the nucleus-cytoplasm relation decreased by 24%. Compared to the animals fed the control diet, the N-balance in the clenbuterol-treated group was increased by 41%. Feeding the combination of clenbuterol and propranolol resulted in an increase of 24% only. Clenbuterol increased the N-content of the carcass by 6% and reduced the carcass fat content by 30%. In the group fed clenbuterol and propranolol, the N-content of the carcass only tended to be increased and the influence on carcass fat reduction was only 16%. The stimulated N-deposition in the carcass of clenbuterol-treated rats was obtained, since the calculated protein degradation rates were more reduced than protein synthesis rates. In-vitro investigations of the muscle protein synthesis and -protease activities support these results. The clenbuterol-induced increase in muscle protein was accompanied by an inhibition of the Ca-dependent protease activity and an increase of muscle DNA- and RNA-content. The additional application of propranolol reduced these effects of clenbuterol again. Since propranolol partly prevented the effects of clenbuterol on protein metabolism it is suggested that not only the lipolytic but also protein anabolic effects are caused by the beta-adrenergic action of clenbuterol.

Adrenergic beta-Agonists↗
PubMed1999

Insulin production by engineered muscle cells.

Type 1 diabetic patients depend dramatically on insulin replacement therapy, which involves the administration of intermediate- or long-acting insulin, together with short-acting insulin to mimic physiological insulin profiles. However, the delayed-action preparations available are not generally able to produce smooth background levels of insulin. Muscle cells were tested for long-term delivery of active human insulin as an approach to achieve a constant basal level of insulin. Thus, C2C12 mouse myoblast cells were stably transfected with a chimeric gene obtained by linking the myosin-light chain 1 (MLC1) promoter to the human proinsulin gene, containing genetically engineered furin endoprotease cleavage sites (MLC1/Insm). When differentiated, C2C12Insm myotube cells expressed high levels of insulin mRNA and protein, whereas no insulin was detected in myoblast cells. HPLC fractionation of culture medium and cell extracts from differentiated C2C12Insm cells revealed that about 90% of the proinsulin was processed to mature insulin. In addition, these cells released significant levels (about 100 microU/10(6) cells/hr) of mature insulin to the medium. The hormone was biologically active since it increased glucose consumption and utilization by the differentiated C2C12Insm cells and was able to block the expression of the endogenous phosphoenolpyruvate carboxykinase (PEPCK) gene in FTO-2B rat hepatoma cells. Furthermore, when C2C12Insm myoblast cells were transplanted into diabetic mice an increase in insulinemia and a decrease in hyperglycemia were observed. Thus, our results suggest that the use of engineered myotube cells continuously secreting a defined level of insulin might be a useful approach to improve the efficacy of insulin injection treatment.

Animals↗
PubMed1997

Glucose response elements in a gene that codes for 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase.

We have shown previously that rat hepatoma FTO-2B cells express two mRNAs, called F (fetal) and L (liver), from distinct promoters of the same gene coding for 6-phosphofructo-2-kinase (PFK-2). This enzyme catalyzes the synthesis of fructose 2,6-bisphosphate, an allosteric stimulator of glycolysis. We have now found that glucose, as well as lactate and pyruvate, increases the concentration of the F and L mRNAs. The effect of glucose was mimicked by xylitol, a precursor of xylulose 5-phosphate, and hence of intermediates of the pentose phosphate and glycolytic pathways, and was inhibited by okadaic acid, an inhibitor of protein phosphatases. Transfection experiments showed that the F promoter region is a target of the glucose effect, with glucose stimulating F promoter activity in a way probably similar to mitogens. Another region of the gene, located between the F and L promoters, also behaved as a glucose-sensitive element. This region corresponds to a cluster of DNase I-hypersensitive sites that were induced in chromatin following glucose treatment. The sequence organization of this region is very similar to the functional architecture of the glucose-sensitive insulin gene promoter. We propose a model for the concerted regulation by glucose metabolites of three pathways that lead to increased PFK-2 activity.

Animals↗
PubMed1990

Efficient packaging of a specific VL30 retroelement by psi 2 cells which produce MoMLV recombinant retroviruses.

FTO-2B rat hepatoma cells acquired mouse VL30 retrotransposon(s) when infected with Moloney murine leukemia virus (MoMLV) recombinant retroviruses produced from psi 2 cells. The VL30 provirus was integrated into the rat genome, expressed at high levels, and its transcription induced 40-fold by dexamethasone, VL30 RNA was detected in hepatoma cells even without selection for the expression of the amino-3'-glycosyl phosphotransferase (neo) gene, which was co-transferred with a MoMLV retrovirus. However, the extent of transfer of the VL30 RNA was inversely related to the titer of the MoMLV recombinant retrovirus. The restriction map analysis of the transferred VL30 provirus was identical to the mouse VL30s of the NVL subfamily which is known to be a significant fraction of the transcriptionally active VL30 subset. Additionally, the regenerating liver from an adult rat, which was infected with a defective MoMLV-derived retrovirus, expressed VL30 RNA. These results indicate that great care should be given to the transfer of unwanted passengers, like VL30, present in retroviral packaging cell lines like the psi 2 cells, which are currently being used for gene therapy.

Animals↗
PubMed1994

Expression of the neomycin-resistance (neo) gene induces alterations in gene expression and metabolism.

The amino 3'-glycosyl phosphotransferase (neo) gene is the selectable marker most widely used in stable transfection or infection protocols. Because the neo gene product has phosphotransferase activity, it might modify the phosphorylation state when introduced in mammalian cells. NIH-3T3 fibroblast cells expressing the neo gene, after either infection with retroviral vectors or transfection with plasmids, showed a 50% reduction in both fructose 2,6-bisphosphate (Fru 2,6-P2) concentration and lactate production compared with control NIH-3T3 cells, indicating that these neo-expressing cells are less glycolytic. In addition, a marked decrease in the levels of mRNA for the procollagen 1 alpha and fibronectin genes was also observed in neo-expressing NIH-3T3 cells. This decrease was concomitant with an increase in the mRNA concentration of the endogenous c-myc gene. FTO-2B rat hepatoma cells also showed modifications in gene expression when the neo gene was introduced by stable transfection or infection. In these cells an increase in both P-enolpyruvate carboxykinase (PEPCK) and tyrosine aminotransferase (TAT) mRNA was observed. These results suggest that neo gene expression may induce changes in the cells, which should be considered when neo-selected cells are used to deliver specific genes in different therapy approaches and in embryo manipulation.

3T3 Cells↗
PubMed1997

Regulated production of mature insulin by non-beta-cells.

Rat hepatoma cells were engineered to express, in a regulated manner, mature human insulin as an approach to the development of artificial beta-cells for insulin-dependent diabetes mellitus (IDDM) gene therapy. A chimeric gene obtained by linking a 2.4-kb fragment of the P-enolpyruvate carboxykinase (PEPCK) gene promoter to a human proinsulin gene (PEPCK/Insm), containing genetically engineered furin endoprotease cleavage sites, was stably transfected into FTO-2B rat hepatoma cells. The FTOInsm cells expressed high levels of insulin mRNA and protein after Northern blot or immunocytochemical analysis. High-performance liquid chromatography (HPLC) fractionation of culture medium and cell extracts revealed that about 90% of the proinsulin was processed to mature insulin. Insulin secretion was very fast, and 15 min after induction with dibutyryl cyclic AMP (Bt2cAMP) plus dexamethasone significant amounts of the hormone were released. Moreover, during the first hour, the rise in insulin concentration in the medium was 10-fold that detected in nontreated FTOInsm cells. Insulin produced by FTOInsm cells was biologically active because it blocked endogenous PEPCK gene expression and induced glucose uptake and lactate production. Thus, our results showed that genetically engineered FTOInsm hepatoma cells synthesized, processed, and secreted active insulin. The implantation of encapsulated engineered FTOInsm cells might provide a safe and practical therapeutic approach for IDDM treatment.

Animals↗
PubMed1991

Glucocorticoid- and estrogen-responsive elements in the 5'-flanking region of the rat angiotensinogen gene.

We investigated the 5'-flanking region of the rat angiotensinogen gene to define the DNA elements conferring inducibility by glucocorticoids and estrogens. Two putative glucocorticoid-responsive elements (GREs) based on sequence comparison were identified. Here we report the functional importance of these sequences. We constructed several deletion mutants of the 5'-region in front of the bacterial reporter gene for chloramphenicol acetyltransferase (CAT). The angiotensinogen-CAT-reporter plasmids (pRagCAT) were transiently transfected into the rat hepatoma cells FTO 2B and Fe 33. All pRagCAT constructs in which the 5'-region contained at least one of the two GRE consensus sequences were stimulated by dexamethasone. On the other hand, deletion mutants containing no GRE sequences were not inducible with dexamethasone. In additional experiments, the transcriptional functions of the two putative GREs were assessed by cloning synthetic oligonucleotides encompassing the GRE sequences directly in front of the heterologous herpes simplex virus thymidine-kinase promoter. Our results showed that each synthetic GRE was capable of stimulating the heterologous TK promoter after administration of dexamethasone and that both GREs together act synergistically. We also investigated the transcriptional control of angiotensinogen by estrogen. Although no estrogen-responsive element consensus sequences were detectable by sequence comparison, we did identify sequences between -60 to -92 which conferred estrogen inducibility to the rat angiotensinogen gene. In this region, a so-called half-palindromic estrogen-responsive element is localized at nucleotides -87 to -91.

Amino Acid Sequence↗
PubMed1991

Inducibility of the DNA repair gene encoding O6-methylguanine-DNA methyltransferase in mammalian cells by DNA-damaging treatments.

The inducibility of the mammalian O6-methylguanine-DNA methyltransferase (MGMT) gene encoding the MGMT protein (EC 2.1.1.63) responsible for removal of the procarcinogenic and promutagenic lesion O6-alkylguanine from DNA was examined by an analysis of transcription of the MGMT gene following exposure of repair-competent (Mex+) and repair-deficient (Mex-) cells to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). While human and rodent Mex- cells (CHO-9, V79, HeLa MR) showed no detectable MGMT mRNA despite the presence of the gene in their genome, the amount of it in several Mex+ lines (NIH 3T3, HeLa S3, HepG2) paralleled their MGMT activity. However, none of these cell lines showed an increase in the MGMT mRNA level after treatment with various concentrations of MNNG. In contrast, MNNG-treated rat hepatoma cells, H4IIE and FTO-2B, both Mex+, had three- to fivefold more MGMT mRNA than the corresponding untreated controls as measured 12 to 72 h after alkylation. N-Methyl-N-nitrosourea, methyl methanesulfonate, N-hydroxyethyl-N-chloroethylnitrosourea, UV light, and X rays caused a similar accumulation of MGMT mRNA in rat hepatoma cells. Studies with inhibitors of RNA and protein synthesis indicate that the induced increase in the amount of MGMT mRNA was due to enhanced transcription of the gene. Furthermore, they revealed the turnover of the MGMT mRNA to be relatively low (half-life, greater than 7 h). Mutagen-induced increase of transcription of MGMT mRNA in H4IIE cells was accompanied by elevation of MGMT repair activity and resulted in reduction of mutation frequency after a challenge dose of MNNG. Although induction of MGMT mRNA transcription has been observed in two rodent hepatoma cell lines so far, this appears to be the first demonstration of inducibility of a mammalian gene encoding a clearly define DNA repair function. The transcription activation of the MGMT gene protects cells from the mutagenic effects of methylating agents.

Alkylation↗
PubMed2026

Multi-omics uncovers the pleiotropic genetic mechanisms linking MASLD and cardiometabolic syndromes.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular-kidney-metabolic (CKM) syndrome are interrelated conditions with shared pathophysiological features; however, the genetic architecture underlying their relationship has not been fully elucidated. Deciphering this shared genetic basis holds promise for advancing mechanistic insights and therapeutic discovery. METHODS: We performed an integrated genome-wide cross-trait analysis using GWAS summary statistics for MASLD and 38 CKM traits. Our analysis estimated genetic correlations, inferred causal relationships, and identified pleiotropic variants. Candidate causal genes and druggable targets were subsequently prioritized through integrating multi-omics data. RESULTS: MASLD exhibited significant genetic correlations with 16 CKM traits, especially metabolic and cardiovascular conditions. Bidirectional causal relationships were observed between MASLD and T2D, adiposity, and lipid traits. We discovered 116 pleiotropic loci, including 65 shared causal variants such as rs429358 near APOE, which exerted influence across multiple traits. Gene-based analyses prioritized 152 unique candidate pleiotropic genes, enriched in lipid and cholesterol metabolism, and highly expressed in the liver, adipose, and immune-related cell types, such as macrophages and endothelial cells. Multi-omics integration validated 131 genes using eQTL and pQTL data from multiple tissues and cohorts. Notably, FTO and APOE emerged as central pleiotropic hubs, and druggability evaluation highlighted APOE, LPL, PPARG, and GPBAR1 as established therapeutic targets for metabolic diseases. CONCLUSION: This study provides a comprehensive map of the shared genetic architecture between MASLD and CKM syndrome, reveals novel causal genes and repurposable drug targets, and offers insights into precision medicine approaches for cardiometabolic and liver diseases.

Humans↗