Benzothiazole-containing hydroxamic acids as histone deacetylase inhibitors and antitumor agents

Data from clinical studies indicate that inhibitors of Class I and Class II histone deacetylase (HDAC) enzymes show great promise for the treatment of cancer. Zolinza (SAHA, Zolinza) was recently approved by the FDA for the treatment of the cutaneous manifestations of cutaneous T-cell lymphoma. As a part of our ongoing effort to identify novel small molecules to target these important enzymes, we have prepared two series of benzothiazole-containing analogues of SAHA. It was found that several compounds with 6C-bridge linking benzothiazole moiety and hydroxamic functional groups showed good inhibition against HDAC3 and 4 at as low as 1 μg/ml and exhibited potent cytotoxicity against five cancer cell lines with average IC₅₀ values of as low as 0.81 μg/ml, almost equipotent to SAHA.     

Characterization of Renibacterium salmoninarum with reduced susceptibility to macrolide antibiotics by a standardized antibiotic susceptibility test

Three cohorts of juvenile and subadult Chinook salmon Oncorhynchus tshawytscha received multiple treatments with macrolide antibiotics for bacterial kidney disease (BKD) during rearing in a captive broodstock program. A total of 77 mortalities among the cohorts were screened for Renibacterium salmoninarum, the etiologic agent of BKD, by agar culture from kidney, and isolates from 7 fish were suitable for growth testing in the presence of macrolide antibiotics. The minimum inhibitory concentration (MIC) of erythromycin and azithromycin was determined by a modification of the standardized broth assay using defined medium. The American Type Culture Collection (ATCC) type strain 33209 exhibited a MIC of 0.008 microg m(-1) to either erythromycin or azithromycin. Isolates from 3 fish displayed MICs identical to the MICs for the ATCC type strain 33209. In contrast, isolates from 4 fish exhibited higher MICs, ranging between 0.125 and 0.250 microg ml(-1) for erythromycin and between 0.016 and 0.031 microg ml(-1) for azithromycin. Sequence analysis of the mutational hotspots for macrolide resistance in the 23S rDNA gene and the open reading frames of ribosomal proteins L4 and L22 found identical sequences among all isolates, indicating that the phenotype was not due to mutations associated with the drug-binding site of 23S rRNA. These results are the first report of R. salmoninarum with reduced susceptibility to macrolide antibiotics isolated from fish receiving multiple antibiotic treatments.     

Effect of Portacaval Anastomosis on Electrically Stimulated Release of Glutamate from Rat Hippocampal Slices

To evaluate the effects of chronic liver failure on release of the excitatory transmitter glutamate, electrically stimulated Ca2(+)-dependent and Ca2(+)-independent release of glutamate in the absence or presence of NH4+ was studied in superfused slices of hippocampus from portacaval-shunted or sham-operated rats 4 weeks after surgery. Spontaneous and stimulation-evoked release of glutamate was higher in shunted rats in the presence of normal or low Ca2+ concentrations, and this release was depressed by 5 mM ammonium chloride. These findings suggest that portacaval shunting results in increased levels of extracellular glutamate in brain, probably due to a decreased reuptake of glutamate into perineuronal astrocytes, shown in previous studies to undergo neuropathological changes following portacaval shunting. Changes in the inactivation of transmitter glutamate could be responsible, at least in part, for the neurological dysfunction resulting from sustained hyperammonemia and portal-systemic shunting resulting from chronic liver failure.     

Enucleation and development of cluster headache: a retrospective study

Background  

Cluster headache (CH) is a neurovascular, primary headache disorder. There are, however, several case reports about patients whose CH started shortly after a structural brain disease or trauma. Motivated by a patient who developed CH 3 weeks after the removal of an eye and by similar case reports, we tested the hypothesis that the removal of an eye is a risk factor for CH.     

D-Glyceraldehyde causes production of intracellular peroxide in pancreatic islets, oxidative stress, and defective beta cell function via non-mitochondrial pathways

D-Glyceraldehyde (D-GLYC) is usually considered to be a stimulator of insulin secretion but theoretically can also form reactive oxygen species (ROS), which can inhibit beta cell function. We examined the time- and concentration-dependent effects of D-GLYC on insulin secretion, insulin content, and formation of ROS. We observed that a 2-h exposure to 0.05-2 mM D-GLYC potentiated glucose-stimulated insulin secretion (GSIS) in isolated Wistar rat islets but that higher concentrations inhibited GSIS. A 24-h exposure to 2 mm D-GLYC inhibited GSIS, decreased insulin content, and increased intracellular peroxide levels (2.14 +/- 0.31-fold increase, n = 4, p < 0.05). N-Acetylcysteine (10 mM) prevented the increase in intracellular peroxides and the adverse effects of d-GLYC on GSIS. In the presence of 11.1 but not 3.0 mm glucose, koningic acid (10 microM), a specific glyceraldehyde-3-phosphate dehydrogenase inhibitor, increased intracellular peroxide levels (1.88 +/- 0.30-fold increase, n = 9, p < 0.01) and inhibited GSIS (control GSIS = p < 0.001; koningic acid GSIS, not significant). To determine whether oxidative phosphorylation was the source of ROS formation, we cultured rat islets with mitochondrial inhibitors. Neither rotenone or myxothiazol prevented D-GLYC-induced increases in islet ROS. Adenoviral overexpression of manganese superoxide dismutase also failed to prevent the effect of D-GLYC to increase ROS levels. These observations indicate that exposure to excess D-GLYC increases reactive oxygen species in the islet via non-mitochondrial pathways and suggest the hypothesis that the oxidative stress associated with elevated D-GLYC levels could be a mechanism for glucose toxicity in beta cells exposed chronically to high glucose concentrations.     

The insight of in vitro and in silico studies on cholinesterase inhibitors from the roots of Cimicifuga dahurica (Turcz.) Maxim.

Cholinesterases (ChEs) are enzymes that break down neurotransmitters associated with cognitive function and memory. We isolated cinnamic acids (1 and 2), indolinones (3 and 4), and cycloartane triterpenoid derivatives (5–19) from the roots of Cimicifuga dahurica (Turcz.) Maxim. by chromatography. These compounds were evaluated for their inhibitory activity toward ChEs. Compound 1 was determined to have an IC₅₀ value of 16.7?±?1.9?μM, and to act as a competitive inhibitor of acetylcholinesterase (AChE). Compounds 3, 4 and 14 were found to be noncompetitive with IC₅₀ values of 13.8?±?1.5 and 6.5?±?2.5?μM, and competitive with an IC₅₀ value of 22.6?±?0.4?μM, respectively, against butyrylcholinesterase (BuChE). Our molecular simulation suggested each key amino acid, Tyr337 of AChE and Asn228 of BuChE, which were corresponded with potential inhibitors 1, and 3 and 4, respectively. Compounds 1 and 4 were revealed to be promising compounds for inhibition of AChEs and BuChEs, respectively.     

A new fluorescent chemosensor for Hg2+ in aqueous solution

We prepared an aminothiourea‐derived Schiff base (DA) as a fluorescent chemosensor for Hg²⁺ ions. Addition of 1 equiv of Hg²⁺ ions to the aqueous solution of DA gave rise to an obvious fluorescence enhancement and the subsequent addition of more Hg²⁺ induced gradual fluorescence quenching. Other competing ions, including Pb²⁺, Cd²⁺, Cr³⁺, Zn²⁺, Fe²⁺, Co³⁺, Ni²⁺, Ca²⁺, Mg²⁺, K⁺ and Na⁺, did not induce any distinct fluorescence changes, indicating that DA can selectively detect Hg²⁺ ions in aqueous solution. Copyright © 2012 John Wiley & Sons, Ltd.     

Effect of Health Expenses on Household Capabilities and Resource Allocation in a Rural Commune in Vietnam

Background

Significant health expenses can force households to reduce consumption of items required for daily living and long-term well-being, depriving them of the capability to lead economically stable and healthy lives. Previous studies of out-of-pocket (OOP) and other health expenses have typically characterized them as “catastrophic” in terms of a threshold level or percentage of household income. We aim to re-conceptualize the impact of health expenses on household “flourishing” in terms of “basic capabilities.”

Methods and Findings

We conducted a 2008 survey covering 697 households, on consumption patterns and health treatments for the previous 12 months. We compare consumption patterns between households with and without inpatient treatment, and between households with different levels of outpatient treatment, for the entire study sample as well as among different income quartiles. We find that compared to households without inpatient treatment and with lower levels of outpatient treatment, households with inpatient treatment and higher levels of outpatient treatment reduced investments in basic capabilities, as evidenced by decreased consumption of food, education and production means. The lowest income quartile showed the most significant decrease. No quartile with inpatient or high-level outpatient treatment was immune to reductions.

Conclusions

The effects of health expenses on consumption patterns might well create or exacerbate poverty and poor health, particularly for low income households. We define health expenditures as catastrophic by their reductions of basic capabilities. Health policy should reform the OOP system that causes this economic and social burden.