trichostatin-a and Body-Weight

Many aspects of physiological functions are controlled by the hypothalamus, a brain region that connects the neuroendocrine system to whole-body metabolism. Growth hormone (GH) and the GH receptor (GHR) are expressed in hypothalamic regions known to participate in the regulation of feeding and whole-body energy homeostasis. Sirtuin 1 (SIRT1) is the most conserved mamma-lian nicotinamide adenine dinucleotide (NAD

Topics: Agouti-Related Protein; Animals; Body Weight; Fasting; Female; Hydroxamic Acids; Hypothalamus; Male; Mice, Transgenic; Neurons; Receptors, Somatotropin; Signal Transduction; Sirtuin 1

Obesity is becoming a major global health issue and is mainly induced by the accumulation of adipose tissues mediated by adipogenesis, which is reported to be regulated by peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT enhancer-binding protein α (C/EBPα). Trichostatin A (TSA) is a novel histone deacetylase inhibitor (HDACI) that was recently reported to exert multiple pharmacological functions. The present study will investigate the inhibitory effect of TSA on adipogenesis, as well as the underlying mechanism.. TSA inhibited adipogenesis in 3T3-L1 preadipocytes by activating the AMPK pathway.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adipose Tissue; Animals; Anti-Obesity Agents; Body Weight; Diet, High-Fat; Fatty Acid-Binding Proteins; Glycerol; Histone Deacetylase Inhibitors; Hydroxamic Acids; Leptin; Lipolysis; Male; Mice; Mice, Obese; Obesity; Triglycerides

Trichostatin A (TSA) has been shown to mitigate whole body γ-radiation-induced morbidity and mortality. The current study aimed at studying the effects of TSA post-irradiation treatment on gut-microbiota, especially the translocation of the microbes from the intestine to other organs in C57 Bl/6 mice model.. On 1st, 3rd 5th 7th 9th 12th and 14th days after various treatments bacteria were isolated from the intestine and nearby organs (mesenteric lymph node, spleen and liver) for further analysis. The jejunum part of all animals was processed for histological analysis.. The group radiation + drug showed reduced susceptibility to radiation injury as well as microbiota related anomalies compared to the irradiated alone group. This was described by increased microflora in different parts of the GI tract in the radiation + drug group compared to the irradiated group and reduced histopathological damages in the jejunum. Also, a reduced percentage of translocated bacteria were found in different organs of radiation + drug group animals.. TSA treatment post-irradiation could effectively control bacterial translocation as well as GI injury in mice.

Topics: Animals; Bacterial Load; Body Weight; Gastrointestinal Microbiome; Histone Deacetylase Inhibitors; Hydroxamic Acids; Male; Mice; Mice, Inbred C57BL; Organ Specificity; Time Factors

Gelsolin (GSN), a multifunctional protein, binds to amyloid beta-protein (Aβ), inhibits its fibrillization, solubilizes preformed Aβ fibrils, and helps in its clearance from the brain. Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, induces the protein expression of gelsolin. In the present study, we investigated how TSA-treatment of APPswe/PS1δE9 transgenic (Tg) mice of Alzheimer's disease (AD) will affect the plasma levels of gelsolin and Aβ.. TSA (5mg/kg body weight on alternate days for two months) was intraperitoneally injected to AD Tg mice. Gelsolin was measured by Western blotting and Aβ was measured by enzyme-linked immunosorbent assay.. TSA-treatment significantly increased the levels of plasma gelsolin by 1.79-fold as compared with vehicle-treated control mice (p<0.01). The levels of Aβ 1-40 and Aβ 1-42 in the plasma were also higher in TSA-treated mice in comparison with vehicle-treated mice. The treatment of transgenic AD mice with TSA did not affect the body weight in both male and female groups as compared to vehicle-treated animals. A positive correlation was observed between the plasma levels of gelsolin and Aβ 1-40 (r=0.594, p=0.042) or Aβ 1-42 (r=0.616, p=0.033) in AD Tg mice.. These results suggest that TSA increases the levels of plasma gelsolin and Aβ in AD Tg mice, which may have implications in gelsolin-mediated clearance of Aβ.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blotting, Western; Body Weight; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Gelsolin; Gene Expression Regulation; Hydroxamic Acids; Infusions, Parenteral; Male; Mice; Mice, Transgenic; Peptide Fragments; Protein Synthesis Inhibitors

It is well known that benzene is a hematotoxic carcinogen. PTEN promoter methylation is a representative example of transcriptional silencing of tumor suppressor genes. However, the effect of PTEN methylation on benzene-induced hematotoxicity has not yet been elucidated. In this study, the animal model of benzene hematotoxicity was successfully established. WBC significantly decreased in experimental groups (P < 0.01). Compared with the control group, the weight of rats increased slowly and even declined with increasing doses of benzene in the benzene-treated groups. An increase in the level of PTEN methylation was observed in the low dose group, and PTEN methylation level increased significantly in a dose-dependent manner. However, it was interesting that PTEN mRNA expression increased in the low dose group, but declined with increasing doses of benzene. The decrease of tumor suppressor function caused by PTEN methylation may be an important mechanism of benzene hematotoxicity. Furthermore, lymphoblast cell line F32 was incubated by benzene and then treated with 5-aza and TSA, alone or in combination. A dramatic decrease in the PTEN mRNA expression and a significant increase of PTEN methylation level in benzene-treated cells were also shown. PTEN mRNA expression was up regulated and PTEN methylation level was reduced by the epigenetic inhibitors, 5-aza and TSA. In conclusion, PTEN methylation is involved in benzene-induced hematotoxicity through suppressing PTEN mRNA expression.

Topics: Animals; Azacitidine; Benzene; Body Weight; Carcinogens; Cell Line, Tumor; Chemical and Drug Induced Liver Injury; DNA Methylation; Down-Regulation; Epigenesis, Genetic; Genes, Tumor Suppressor; Hydroxamic Acids; Leukocytes; Male; Promoter Regions, Genetic; PTEN Phosphohydrolase; Rats; Rats, Sprague-Dawley; RNA, Messenger; Up-Regulation

Adulthood hypertension can be programmed by corticosteroid exposure in early life. Oxidative stress, epigenetic regulation by histone deacetylases (HDACs), and alterations of renin-angiotensin system (RAS) are involved in the developmental programming of hypertension. We examined whether melatonin prevented neonatal dexamethasone (DEX)-induced programmed hypertension and how melatonin prevented these processes. We also examined whether HDAC inhibition by trichostatin A (TSA, a HDAC inhibitor) had similar effects. Male offspring were assigned to 5 groups (n=6/group): control, DEX, melatonin, DEX+melatonin, and DEX+TSA. Male rat pups were injected i.p. with DEX on day 1 (0.5mg/kg BW), day 2 (0.3mg/kg BW), and day 3 (0.1mg/kg BW) after birth. Melatonin was administered in drinking water at the dose of 0.01% during the lactation period. The DEX+TSA group received DEX and 0.5mg/kg TSA subcutaneous injection once daily for 1 week. All rats were killed at 16 weeks of age. Neonatal DEX exposure induced hypertension in male offspring at 16 weeks of age, which melatonin prevented. Neonatal DEX exposure decreased gene expression related to apoptosis, nephrogenesis, RAS, and sodium transporters. Yet DEX treatment increased protein levels of HDAC-1, -2, and -3 in the kidney. Melatonin therapy preserved the decreases of gene expression and decreased HDACs. Similarly, HDAC inhibition prevented DEX-induced programmed hypertension. In conclusion, melatonin therapy exerts a long-term protection against neonatal DEX-induced programmed hypertension. Its beneficial effects include alterations of RAS components and inhibition of class I HDACs. Given that the similar protective effects of melatonin and TSA, melatonin might inhibit HDACs to epigenetic regulation of hypertension-related genes to prevent programmed hypertension.

Topics: Animals; Animals, Newborn; Blood Pressure; Body Weight; Dexamethasone; Gene Expression Regulation; Histone Deacetylase Inhibitors; Histone Deacetylases; Hydroxamic Acids; Hypertension; Kidney; Male; Melatonin; Organ Size; Oxidative Stress; Rats, Sprague-Dawley; Renin-Angiotensin System

We examined the comprehensive epigenetic status, including histone H3 and H4 acetylation, DNA methylation and level of mRNA transcripts of bovine somatic cell nuclear transfer (SCNT) embryos treated with trichostatin A (TSA), along with their full-term developmental efficacy. Treatment with 50 nM TSA enhanced early developmental competence; increased acetylation of two histones, H3K9K14 and H4K8, at the blastocyst stage; and maintained the DNA methylation status of the satelliteI sequence in bovine SCNT embryos. The difference in IGFBP-3 transcript levels between in vivo and SCNT embryos disappeared in SCNT embryos after treatment with 50 nM TSA. Pregnancy, full-term developmental competence and body weight at birth of offspring did not differ between SCNT embryos treated with 50 nM TSA and untreated embryos. These results suggest that treatment with TSA improves preimplantation development and changes the epigenetic status but does not promote the full-term development competence in bovine SCNT embryos.

Topics: Animals; Blastocyst; Body Weight; Cattle; Cloning, Organism; DNA Methylation; Dose-Response Relationship, Drug; Epigenesis, Genetic; Female; Fertilization in Vitro; Histone Deacetylase Inhibitors; Histones; Hydroxamic Acids; Nuclear Transfer Techniques; Oocytes; Pregnancy

Early treatment with the histone deacetylase inhibitor, trichostatin A, plus nutritional support extended median survival of spinal muscular atrophy mice by 170%. Treated mice continued to gain weight, maintained stable motor function, and retained intact neuromuscular junctions long after trichostatin A was discontinued. In many cases, ultimate decline of mice appeared to result from vascular necrosis, raising the possibility that vascular dysfunction is part of the clinical spectrum of severe spinal muscular atrophy. Early spinal muscular atrophy disease detection and treatment initiation combined with aggressive ancillary care may be integral to the optimization of histone deacetylase inhibitor treatment in human patients.

Topics: Age Factors; Animals; Animals, Newborn; Body Weight; Disease Models, Animal; Disease Progression; Enzyme Inhibitors; Hydroxamic Acids; Mice; Mice, Transgenic; Motor Activity; Muscular Atrophy, Spinal; Necrosis; Nutritional Support; Survival Analysis; Survival of Motor Neuron 1 Protein

A series of N-hydroxy-3-phenyl-2-propenamides were prepared as novel inhibitors of human histone deacetylase (HDAC). These compounds were potent enzyme inhibitors, having IC(50)s < 400 nM in a partially purified enzyme assay. However, potency in cell growth inhibition assays ranged over 2 orders of magnitude in two human carcinoma cell lines. Selected compounds having cellular IC(50) < 750 nM were tested for maximum tolerated dose (MTD) and for efficacy in the HCT116 human colon tumor xenograft assay. Four compounds having an MTD > or = 100 mg/kg were selected for dose-response studies in the HCT116 xenograft model. One compound, 9 (NVP-LAQ824), had significant dose-related activity in the HCT116 colon and A549 lung tumor models, high MTD, and low gross toxicity. On the basis, in part, of these properties, 9 has entered human clinical trials in 2002.

Topics: Acetyltransferases; Acrylamides; Animals; Antineoplastic Agents; Body Weight; Cell Division; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Female; Histone Acetyltransferases; Humans; Hydroxamic Acids; Indicators and Reagents; Mice; Mice, Nude; Molecular Conformation; Neoplasm Transplantation; Saccharomyces cerevisiae Proteins