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Importance of genetic factors in the regulation of diazepam metabolism: relationship to S-mephenytoin, but not debrisoquin, hydroxylation phenotype.

Single oral 10 mg doses of diazepam and demethyldiazepam were given on different occasions to 16 healthy subjects. The subjects included fou … nzodiazepines between the phenotypes. This study shows that the metabolism of both diazepam (mainly demethylation) and demethyldiazepam (mainly hydroxylation) is related to the mephenytoin, but not to the debrisoquin, hydroxylation phenotype.

Comparative effects of rifabutin and rifampicin on hepatic microsomal enzyme activity in normal subjects.

The comparative enzyme inducing effects of rifabutin and the chemically related drug rifampicin have been investigated in 8 normal subjects. … 7 days also enhanced the metabolic elimination of antipyrine, with preferential stimulation of the demethylation pathway, and increased the excretion of 6-beta-hydroxycortisol, but the magnitude of the effects was significantly less than after rifampicin. No significant change in plasma GGT was seen. The results indicate that, contrary to the findings in anima …

Depression of murine hepatic mixed function oxidase during infection with Listeria monocytogenes.

The level of cytochrome P-450 and the oxidation of aminopyrine and benzo(a)pyrene hydroxylase were depressed in hepatic microsomes prepared … on. During the infective period the half-life of theophylline was significantly prolonged and the N-demethylation of aminopyrine as measured by the expiration of 14CO2 from radiolabeled aminopyrine was diminished. The loss of drug metabolism was not due to interferon production, fever or morphological damage to the liver. These results indicate that certain bac …

Bacterial chemotaxis: biochemistry of behavior in a single cell.

Bacterial chemotaxis is a primitive behavioral system that shows great promise for being amenable to a description of its molecular mechanism. In Gram-negatives like Escherichia coli, addition of amino acid attractant begins a series of events, starting with binding to certain intrinsic membrane proteins, the MCPs, and ending with a period of smooth swimming. Immediately, methyl-esterification of these MCPs begins and continues during this period. By contrast in the Gram-positive Bacillus subtilis, demethylation of MCPs occurs during the same period. At least two other mechanisms for mediating…

Disposition of caffeine and its metabolites in man.

The disposition of caffeine and its metabolites was studied in six healthy subjects by use of sensitive and specific assays. The primary degradation of caffeine in man was found to be N-demethylation and/or ring oxidation to theophylline, paraxanthine, theobromine and 1,3,7-trimethyluric acid. These compounds were further degraded to dimethylated uric acids, monomethylxanthines and monomethyluric acids. About 3 and 6% of the drug was converted to theophylline and theobromine, respectively. The elimination of paraxanthine after its formation did not follow linear kinetics. A large urine recover…

Hepatic mono-oxygenase activity and hepatocellular morphology in chickens treated with 3-methylcholanthrene.

Hepatic drug metabolism in the chicken was investigated. White leghorn chickens were administered 20 mg of 3-methylcholanthrene (3MC) per kg 72 and 48 hr before killing. Levels of hepatic cytochrome P-450 were increased approximately 4-fold. In vitro ethylmorphine N-demethylase (ND) activity was enhanced approximately 1.7-fold, aniline hydroxylase (AH) was increased 2.5-fold, aryl hydrocarbon hydroxylase was increased 20-fold, and NADPH-cytochrome c reductase was unchanged. The Vmax was increased for both ND and AH activities, but the KM for demethylation was depressed whereas that for hydroxy…

Selective Recruitment of a Synthetic Histone Acetyltransferase Can Boost CHO Cell Productivity.

Industrial production of biologics typically involves the integration of transgenes into host cell genomes, most often Chinese hamster ovary (CHO) cells. Epigenetic control of transgene expression is a major determinant of production titers. Although the cytomegalovirus (CMV) promoter has long been used to drive industrial transgene expression, we found that its associated histones are suboptimally acetylated in CHO cells, providing an opportunity to enhance productivity through epigenetic manipulation. Expression of monoclonal antibody mRNAs increased up to 12-fold when a CRISPR-dCas9 system

[Dysimmune manifestations associated with myelodysplastic neoplasms and chronic myelomonocytic leukaemias].

Systemic inflammatory or autoimmune diseases (SIAD) are observed in up to a quarter of patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML), with a broad clinical spectrum including asymptomatic biological abnormalities, isolated inflammatory clinical manifestations (recurrent fever, arthralgia, neutrophilic dermatoses…) or identified systemic diseases (giant cell arteritis, recurrent polychondritis…). Recent advances in molecular biology have shed new light on the pathophysiological mechanisms that link inflammatory manifestations and myeloid hemopathies, pa

Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination.

In the tumor microenvironment, senescent non-malignant cells, including cancer-associated fibroblasts (CAFs), exhibit a secretory profile under stress conditions; this senescence-associated secretory phenotype (SASP) leads to cancer progression and chemoresistance. However, the role of senescent CAFs in metastatic lesions and the molecular mechanism of inflammation-related SASP induction are not well understood. We show that pro-inflammatory cytokine-driven EZH2 downregulation maintains the SASP by demethylating H3K27me3 marks in CAFs and enhances peritoneal tumor formation of gastric cancer (

[Epigenetic abnormalities in non-Hodgkin lymphomas].

Epigenetics is the study that involves understanding of the DNA sequence-independent mechanism of transcriptional regulation. The epigenetic regulation of gene expression is exerted via the alteration of chromatin structures through covalent modifications of core histone tails and methylation of CpG dinucleotides. In general, histone acetylation and DNA methylation are associated with transcriptional activation and repression, respectively. Histone methylation offers an additional layer for transcriptional regulation. Epigenetic abnormalities underlie the development of various hematological m

Dnmt3a restrains mast cell inflammatory responses.

DNA methylation and specifically the DNA methyltransferase enzyme DNMT3A are involved in the pathogenesis of a variety of hematological diseases and in regulating the function of immune cells. Although altered DNA methylation patterns and mutations in DNMT3A correlate with mast cell proliferative disorders in humans, the role of DNA methylation in mast cell biology is not understood. By using mast cells lacking Dnmt3a, we found that this enzyme is involved in restraining mast cell responses to acute and chronic stimuli, both in vitro and in vivo. The exacerbated mast cell responses observed in

Targeting the Sonic Hedgehog-Gli1 Pathway as a Potential New Therapeutic Strategy for Myelodysplastic Syndromes.

The complex mechanistic array underlying the pathogenesis of myelodysplastic syndrome (MDS) is still unclear. Although dysregulations of different signaling pathways involved in MDS have been described, the identification of specific biomarkers and therapy targets remains an important task in order to establish novel therapeutic approaches. Here, we demonstrated that the Shh signaling pathway is active in MDS and correlated it with disease progression. Additionally, the knockdown of Gli1 significantly inhibited cell proliferation in vitro and in vivo. Gli1 silencing also induced apoptosis and

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… Given the limited therapeutic effects of demethylating agents used in MDS, some studies have focused on novel molecular targets coupled with traditional demethylation therapy, which may prompt therapeutic improvement [ 31 ]. … This further confirmed that the downregulation of Shh-Gli1 signaling could lead to DNA demethylation and consequent p15 expression recovery in MDS. …

Study of methyl transferase (G9aMT) and methylated histone (H3-K9) expressions in unexplained recurrent spontaneous abortion (URSA) and normal early pregnancy.

We investigated the expression of methyl transferase G9a and methylated histone H3-K9 in fresh human decidual/endometrial tissue of 12 normal early pregnancies and 15 unexplained recurrent spontaneous abortions (URSA). The samples were obtained through dilatation and curettage and collected as per strict inclusion-exclusion criteria. The tissue was subjected to immunohistochemical analysis (IHC), western blotting (WB) and RT-PCR analysis. The results demonstrated methyl transferase G9a to have a lower expression in abortions when compared with that in normal pregnancy (P < 0.05). The sensitivi

Nuclear receptor, coregulator signaling, and chromatin remodeling pathways suggest involvement of the epigenome in the steroid hormone response of endometrium and abnormalities in endometriosis.

Human endometrium, a steroid hormone-dependent tissue, displays complex cellular regulation mediated by nuclear receptors (NRs). The NRs interact with histone-modifying and DNA-methylating/-demethylating enzymes in the transcriptional complex. We investigated NRs, their coregulators, and associated signaling pathways in endometrium across the normal menstrual cycle and in endometriosis, an estrogen-dependent, progesterone-resistant disorder. Endometrial tissue was processed for analysis of 84 genes using NR and coregulator polymerase chain reaction (PCR) arrays. Select genes were validated by

Recent advances in diagnosis, molecular pathology and therapy of chronic myelomonocytic leukaemia.

The clinical, morphological, and genetic heterogeneity of chronic myelomonocytic leukaemia (CMML), has made it difficult to clearly assign this entity to a distinct haematological category. In 2001, the World Health Organization transferred CMML to a new category of mixed myeloproliferative/myelodysplastic disorders, which was maintained in the last revision in 2008. Considering the rare occurrence of CMML, most pharmacotherapeutic and transplant studies combined CMML with myelodysplastic syndrome cases, but some clinical trials specifically investigated the use of demethylating agents in CMML

Hyperhomocysteinemia, DNA methylation and vascular disease.

Hyperhomocysteinemia (HHcy) has been established as a potent independent risk factor for cardiovascular disease (CVD) and the underlying mechanism is largely unknown. We were the first to propose that hypomethylation is the key biochemical mechanism by which homocysteine (Hcy) inhibits endothelial cell (EC) growth. We reported that clinically relevant concentrations of Hcy (10-50 micromol/L) exerts highly selective inhibitory effects on cyclin A transcription and EC growth through a hypomethylation related mechanism, which blocks cell cycle progression and endothelium regeneration. Recently, w

Phenothiazine drug metabolites: dopamine D2 receptor, alpha 1- and alpha 2-adrenoceptor binding.

The in vitro binding affinities of levomepromazine, chlorpromazine, fluphenazine, perphenazine and methoxypromazine and their main metabolites to dopamine D2 receptors, alpha 1- and alpha 2-adrenoceptors in rat brain, were examined using [3H]spiperone, [3H]WB 4101 and [3H]yohimbine binding. All compounds had 10-500 times lower affinities to alpha 2-adrenoceptors than to dopamine D2 receptors and alpha 1-adrenoceptors. Ring-hydroxylated and N-demethylated metabolites had relative potencies for dopamine D2 receptor and alpha 1-adrenoceptor binding ranging from 20 to 70%, compared to that of the

m6 A demethylase ALKBH5 drives denervation-induced muscle atrophy by targeting HDAC4 to activate FoxO3 signalling.

BACKGROUND: Skeletal muscle atrophy is a common clinical manifestation of various neurotrauma and neurological diseases. In addition to the … < 0.001). CONCLUSIONS: Our findings elucidate on the roles and mechanisms of ALKBH5-mediated m6 A demethylation in the control of muscle mass during denervation and activation of FoxO3 signalling by targeting HDAC4. These results suggest that ALKBH5 is a potential therapeutic target for neurogenic muscle atrophy.

Hypermethylation of the death-associated protein kinase CpG island in canine B-cell lymphoid tumors.

Death-associated protein kinase (DAPK) is a 160-kD serine/threonine kinase known as a key molecule in interferon-γ (IFN-γ)-induced apoptosis … ed by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay. The influence of demethylation was examined with 5-aza-2'-deoxycytidine (5-aza-dC). The methylation status in 14 dogs with various lymphoid tumors was screened by MSP. A 1926-bp CpG island containing 280 CpG repeats was identified upstream of the translation start site of canine …

The effect of certain vitamin deficiencies on hepatic drug metabolism.

There is increasing evidence that the liver microsomal drug metabolizing system is affected by various vitamins such as ascorbic acid, riboflavin, and alpha-tocopherol. In regard to ascorbic acid deficiency there is a decrease in the quantity of hepatic microsomal electron transport components such as cytochrome P-450 and NADPH-cytochrome P-450 reductase, as well as decreases in a variety of drug enzyme reactions such as N-demethylation, O-demethylation, and steroid hydroxylation. In addition, young animals given high supplements of vitamin C have increased quantities of electron transport com…