OBJECTIVE: To explore the impact on cerebral protection of Trichostatin A (TSA) preconditioning in rats with middle cerebral artery occlusion (MCAO); the relationship between cerebral protection of TSA and interleukin-1 beta (IL-1β); and the impact of age on the mechanism of cerebral protection of TSA. METHODS: The modified suture method was used to create stable a MCAO model. A total of 96 male SD rats were assigned randomly to four groups: a control group, a dimethyl sulfoxide (DMSO) preconditioned group, a low-dose (0.03 mg/kg) TSA-preconditioned group, and a high-dose (0.1 mg/kg) TSA-preconditioned group. Each group included four sub-groups for reperfusion for 6, 12, 24 and 48 hours, respectively, 6 rats per sub-group. An additional, eighteen healthy, male Sprague Dawley (SD) rats that received TSA preconditioning (0.1 mg/kg) were divided into three groups based on their age: young, mid-age, and old, One-way analysis of variance was used to compare the differences between groups, and the Spearman rank correlation was used to examine relationships between IL-1β concentrations in blood and cerebrospinal fluid and cerebral infarction volume. RESULTS: The cerebral infarction volume of rats in the high-dose TSA group was less than that of the other 3 groups (P<0.05). The IL-1β in blood and the cerebrospinal fluid of rats in the highdose TSA group was lower than that in control and DMSO groups (P<0.05); for the low-dose TSA group IL-1β levels were statistically the same as in controls. The Spearman rank coefficients were 0.841 and 0.618 for cerebral infarction volume correlate to blood IL-1β and to cerebrospinal fluid IL-1β, respectively (P<0.05). No statistical differences were found in cerebral infarction volume and IL-1β levels in blood or cerebrospinal fluid (P>0.05). CONCLUSION High-dose TSA preconditioning reduces cerebral infarction volume and decreases IL- 1β levels in blood and cerebrospinal fluid; age does not affect these parameters.
Animals ; Histone Deacetylase Inhibitors ; therapeutic use ; Hydroxamic Acids ; therapeutic use ; Infarction, Middle Cerebral Artery ; physiopathology ; Interleukin-1beta ; metabolism ; Ischemic Preconditioning ; methods ; Male ; Rats ; Reperfusion Injury ; prevention & control

More than 95% of the thyroid carcinomas are well differentiated types showing favorable prognosis. However, only a few therapeutic options are available to treat the patients with undifferentiated thyroid carcinomas, especially with refractory thyroid carcinomas that are not amenable to surgery or radioiodine ablation. We investigated the anticancer effects of 20 chemotherapy and hormonal therapy drugs on 8 thyroid carcinoma cell lines. In vitro chemosensitivity was tested using the adenosine-triphosphate-based chemotherapy response assay (ATP-CRA). The tumor inhibition rate (TIR; or cell death rate) or half maximal inhibitory concentration (IC50) was analyzed to interpret the results. Of the 12 chemotherapy drugs, etoposide (178.9 index value in follicular carcinoma cell line) and vincristine (211.7 in Hurthle cell carcinoma cell line) were the most active drugs showing the highest chemosensitivity, and of the 8 additional drugs, trichostatin A (0.03 microg/mL IC50 in follicular carcinoma cell line) showed favorable outcome having the anticancer effect. In our study, the result of etoposide and vincristine show evidence as active anticancer drugs in thyroid carcinoma cell lines and trichostatin A seems be the next promising drug. These drugs may become an innovative therapy for refractory thyroid carcinomas in near future.
Adenosine Triphosphate/chemistry/pharmacology/therapeutic use ; Antineoplastic Agents/chemistry/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Cell Line, Tumor ; Etoposide/chemistry/pharmacology/therapeutic use ; Humans ; Hydroxamic Acids/chemistry/pharmacology/therapeutic use ; Thyroid Neoplasms/drug therapy ; Vincristine/chemistry/pharmacology/therapeutic use

Aminopyridines ; therapeutic use ; Antineoplastic Agents ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Benzamides ; therapeutic use ; Clinical Trials as Topic ; Depsipeptides ; therapeutic use ; Histone Deacetylase Inhibitors ; therapeutic use ; Histone Deacetylases ; metabolism ; Humans ; Hydroxamic Acids ; therapeutic use ; Indoles ; therapeutic use ; Neoplasms ; drug therapy ; enzymology ; Sulfonamides ; therapeutic use

Objective: To investigate the gene expression characteristics of peripheral blood mononuclear cells from patients with high altitude pulmonary hypertension (HAPH) in Naxi residents living in Lijiang, Yunnan, and to explore the underlying pathogenesis and value for potential drug selection. Methods: This is a case-control study. Six patients with HPAH (HPAH group) and 4 normal subjects (control group) were selected from the Naxi residents who originally lived in Lijiang, Yunnan Province. The general clinical data of the two groups were collected, and the related indexes of pulmonary artery pressure were collected. Peripheral blood mononuclear cells of the subjects were collected for RNA sequencing. The differences on gene expression, regulatory network of transcription factors and drug similarity between the two groups were compared. The results were compared with the public data of idiopathic pulmonary arterial hypertension (IPAH). Biological processes and signal pathways were analyzed and compared between HPAH and IPAH patients. Results: The age of 6 patients with HAPH was (68.1±8.3) years old, and there were 2 males (2/6). The age of 4 subjects in the control group was (62.3±10.9) years old, and there were 2 males (2/4). Tricuspid regurgitation velocity, tricuspid pressure gradient and pulmonary systolic pressure in HAPH group were significantly higher than those in control group (all P<0.05). The results of RNA sequencing showed that compared with the control group, 174 genes were significantly upregulated and 169 genes were downregulated in peripheral blood mononuclear cells of HAPH group. These differentially expressed genes were associated with 220 biological processes, 52 molecular functions and 23 cell components. A total of 21 biological processes and 2 signal pathways differed between HPAH and IPAH groups, most of which were related to inflammation and immune response. ZNF384, SP1 and STAT3 were selected as highly correlated transcription factors by transcription factor prediction analysis. Trichostatin A and vorinostat were screened out as potential drugs for the treatment of HAPH by drug similarity analysis. Conclusions: There are significant differences in gene expression in peripheral blood monocytes between HAPH patients and normal population, and inflammation and immune dysfunction are the main pathogenic factors. Trichostatin A and Vorinostat are potential drugs for the treatment of HAPH.
Aged ; Altitude ; Altitude Sickness/genetics* ; Case-Control Studies ; China ; Familial Primary Pulmonary Hypertension/genetics* ; Humans ; Hydroxamic Acids/therapeutic use* ; Hypertension, Pulmonary/genetics* ; Inflammation ; Leukocytes, Mononuclear/pathology* ; Male ; Middle Aged ; Transcription Factors ; Transcriptome/genetics* ; Vorinostat/therapeutic use*

Antineoplastic Agents ; therapeutic use ; Enhancer of Zeste Homolog 2 Protein ; Epigenesis, Genetic ; Histone Deacetylase Inhibitors ; therapeutic use ; Humans ; Hydroxamic Acids ; therapeutic use ; Indoles ; therapeutic use ; Lymphoma ; classification ; drug therapy ; genetics ; metabolism ; MicroRNAs ; metabolism ; Phenotype ; Polycomb Repressive Complex 2 ; metabolism ; Polycomb-Group Proteins ; metabolism

There is still a need for better protection against or mitigation of the effects of ionizing radiation following conventional radiotherapy or accidental exposure. The objective of our current study was to investigate the possible roles of matrix metalloproteinase inhibitor, ilomastat, in the protection of mice from total body radiation (TBI), and the underlying protective mechanisms. Ilomastat treatment increased the survival of mice after TBI. Ilomastat pretreatment promoted recovery of hematological and immunological cells in mice after 6 Gy γ-ray TBI. Our findings suggest the potential of ilomastat to protect against or mitigate the effects of radiation.
Acute Radiation Syndrome ; blood ; immunology ; prevention & control ; Animals ; Blood Cells ; drug effects ; radiation effects ; Dose-Response Relationship, Drug ; Gamma Rays ; adverse effects ; Hydroxamic Acids ; therapeutic use ; Indoles ; therapeutic use ; Matrix Metalloproteinase Inhibitors ; therapeutic use ; Mice ; Radiation Injuries, Experimental ; blood ; immunology ; prevention & control ; Radiation-Protective Agents ; therapeutic use ; Spleen ; drug effects ; immunology ; radiation effects ; Survival Analysis ; Whole-Body Irradiation

SUV39H1 is a histone 3 lysine 9 (H3K9)-specific methyltransferase that is important for heterochromatin formation and the regulation of gene expression. Chaetocin specifically inhibits SUV39H1, resulted in H3K9 methylation reduction as well as reactivation of silenced genes in cancer cells. Histone deacetylase (HDAC) inhibitors inhibit deacetylases and accumulate high levels of acetylation lead to cell cycle arrest and apoptosis. In this study, we demonstrated that treatment with chaetocin enhanced apoptosis in human leukemia HL60, KG1, Kasumi, K562, and THP1 cells. In addition, chaetocin induced the expression of cyclin-dependent kinase inhibitor 2B (p15), E-cadherin (CDH1) and frizzled family receptor 9 (FZD9) through depletion of SUV39H1 and reduced H3K9 methylation in their promoters. Co-treatment with chaetocin and HDAC inhibitor trichostatin A (TSA) dramatically increased apoptosis and produced greater activation of genes. Furthermore, this combined treatment significantly increased loss of SUV39H1 and reduced histone H3K9 trimethylation responses accompanied by increased acetylation. Importantly, co-treatment with chaetocin and TSA produced potent antileukemic effects in leukemia cells derived from patients. These in vitro findings suggest that combination therapy with SUV39H1 and HDAC inhibitors may be of potential value in the treatment of leukemia.
Acetylation/drug effects ; Adolescent ; Adult ; Aged ; Apoptosis/*drug effects ; Cadherins/metabolism ; Cell Line, Tumor ; Cyclin-Dependent Kinase Inhibitor p15/metabolism ; DNA Methylation/drug effects ; Enzyme Inhibitors/therapeutic use/*toxicity ; Frizzled Receptors/metabolism ; Gene Expression Regulation/drug effects ; HL-60 Cells ; Histone Deacetylase Inhibitors/therapeutic use/*toxicity ; Histone-Lysine N-Methyltransferase/*antagonists & inhibitors/metabolism ; Histones/genetics/metabolism ; Humans ; Hydroxamic Acids/therapeutic use/*toxicity ; K562 Cells ; Leukemia/drug therapy/metabolism/pathology ; Leukemia, Myeloid, Acute/genetics/metabolism/pathology ; Male ; Middle Aged ; Piperazines/therapeutic use/toxicity ; Promoter Regions, Genetic ; Young Adult