DNA topoisomerase II (TOP2) is a well-known anticancer target. Its inhibitors are among the most effective anticancer drugs currently in clinical use. TOP2-targeting agents fall into two major classes of "Topo poisons" and "Topo inhibitors" based on their mechanisms of action. Mammalian cells possess two genetically distinct TOP2 isoforms, TOP2α and TOP2β, that are differentially regulated and play different roles in living cells. Compared to TOP2β, TOP2α may be an efficacious and safe chemotherapeutic target for cancer treatment. This review discusses the advantage of targeting TOP2α over TOP2β and action of various agents on TOP2α.
Catecholamines, such as dopamine and L-dihydroxyphenylalanine (L-DOPA), are associated with different physiological functions and diseases. In our recent studies, a novel water-soluble boronic acid compound 3c was identified as a selective fluorescent sensor for L-DOPA. This compound not only has the ability to interact with dopamine and catechol, but also has no fluorescence intensity change for L-DOPA precursors in vivo, such as L-tyrosine.
Steroidal glycoalkaloids (SGAs) are a family of nitrogenous secondary metabolites produced in solanaceous plants. In our present study, γ-solamargine and its aglycone solasodine from Solanum nigrum were found to inhibit hyphae formation of Fusarium oxysporum. As phytoalexins, the formation of SGAs was significantly increased in the plants when infected with the spore of F. oxysporum. In order to understand this inducible defense mechanism, the rate-limiting enzyme squalene synthase in the biosynthesis process of SGAs was investigated well. A full-length cDNA encoding squalene synthase was isolated from S. nigrum (the squalene synthase in S. nigrum was designated as SnSS). The full-length cDNA of SnSS was 1,765 bp and contained a 1,236 bp open reading frame (ORF) encoding a polypeptide of 411 amino acids. Bioinformatic analysis revealed that the deduced SnSS protein had a high similarity with other plant squalene synthases. Real-time RT-PCR analysis showed that SnSS was expressed constitutively in all tested tissues, with the highest expression in stems. After treatment with the spore of F. oxysporum, the mRNA level of SnSS was significantly increased in the infected plants in accordance with the change of SGAs.
The aim of the present study was to enhance the cholinesterase inhibitory activity of Zingiber cassumunar (ZC) oil using a microemulsion (ME) technique. Pseudoternary phase diagrams of the oil, water, and surfactant/co-surfactant mixture were constructed using a water titration method. Effects of co-surfactant, surfactant/co-surfactant ratio, ionic strength, and pH were examined by means of the microemulsion region which existed in the phase diagrams. The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were tested by Ellman's colorimetric assay. It was found that ZC oil possesses inhibitory activity against not only AChE but also BChE. Formulation of ZC oil as ME revealed that alkyl chain length and number of hydroxyl groups of co-surfactant exhibited a remarkable effect on the pseudoternary phase diagram. Longer alkyl chains and more hydroxyl groups gave smaller regions of MEs. Ionic strength also affected the ME region. However, the phase behavior was hardly influenced by pH. The suitable ZC oil ME was composed of Triton X-114 in combination with propylene glycol. The anticholinesterase activity of this ME was much higher than that of native ZC oil. It exhibited twenty times and twenty five times higher inhibitory activity against AChE and BChE, respectively. ZC oil loaded ME is an attractive formulation for further characterization and an in vivo study in an animal model with Alzheimer's disease.
A self-contained Wearable Electronic Disposable Drug Delivery (WEDD®) patch was used to demonstrate that diclofenac levels delivered by iontophoresis are greater than estimated minimal effective concentrations in local subcutaneous tissue and are also greater than either passive transdermal or intravenous delivery using hairless rats. In vitro iontophoretic delivery was evaluated to optimize donor cell formulation using Franz diffusion cells and 1000 NMWL Millipore ultrafiltration membrane. In vivo animal studies were done using patches powered with a 4-volt system, consisting of a 1-volt Zn anode and Ag/AgCl cathode with built in 3-volt lithium battery. Blood and microdialysis samples were collected at different time points after patch application. Current levels increased to 1.0 mA at 30 min, then fell to a steady state of ~ 0.4 mA. Both WEDD® and passive patches produced measurable levels of diclofenac in the subcutaneous tissue below the application site (Cmax ± SE = 113.3 ± 61.7 ng/mL and 36.3 ± 15.9 ng/mL, respectively). The dose delivered in six hours was calculated to be 0.226 ± 0.072 mg and 0.430 ± 0.048 mg in passive and iontophoretic delivery, respectively. Diclofenac was not detected in the subcutaneous tissue after intravenous administration of 1.5 mg/kg diclofenac solution. The trend indicates that WEDD® can be used to successfully deliver diclofenac to subcutaneous tissue to concentrations higher when compared to either passive delivery or intravenous dosing of 1.5 mg/kg.
Changes in the hardness, dissolution, and the disintegration time of brand name and generic preparations (6 preparations) of famotidine orally disintegrating tablets were investigated. Tablets had been stored in a thermo-hygrostat-controlled environment set to simulate the home conditions of patients up to 8 weeks after unit-dose packaging. Among the tablets in unit-dose packaging prepared immediately after blister packs (BP) were opened, one generic had decreased hardness to less than 2.0 kg after 1 week, 55.1% of its initial hardness value, and a shorter disintegration time of about 1/5 of its initial disintegration time. Generics met the standard for dissolution 8 weeks after unit-dose packaging. The decrease in hardness after unit-dose packaging is presumed to be associated with additives, and particularly the types and amounts of binding agents, but evidence of this association was lacking. The hardness noted in drug interview forms (IFs) and the state of sales of bulk tablet packages must be determined to facilitate the selection of generics that remain hard even after unit-dose packaging.
Based on an elementary osmotic pump, controlled release systems of diclofenac sodium (DS) were designed to deliver the drug in a zero-order release pattern. Osmotic pump tablets containing 100 mg DS were prepared and coated with either semipermeable (SPM) or microporous (PM) membranes. The tablet coats were composed of hydrophobic triacetin (TA) or hydrophilic polyethylene glycol 400 (PEG 400) incorporated in cellulose acetate (CA) solution, for SPM and PM, respectively. Variable tablet core compositions such as swelling polymers (PEO and HPMC) and osmotic agents (lactose, NaCl, and KCl) were studied. An optimized, sensitive and well controlled in vitro release design, based on the flow-through cell (FTC), was utilized to discriminate between preparations. The results revealed that the presence of PEG 400 in the coating membrane accelerated the drug release rate, while TA suppressed the release rate of DS. In the case of SPM, the amount of DS released was inversely proportional to the membrane thickness, where 5% (w/w) weight gain gave a higher DS release rate than 10% (w/w). Results of different tablet core compositions revealed that the release rate of DS decreased as PEO molecular weight increased. HPMC K15M showed the lowest DS release rate. The presence of lactose, KCl, or NaCl pronouncedly affected DS release rate depending on polymer type in the core. Scanning electron microscopy (SEM) confirmed formation of pores in the membrane that accounts for faster DS release rate. These results revealed that DS could be formulated as an osmotic pump system with a prolonged, zero-order release pattern.
We report a case of 74-year-old man presenting with a rupture of a thoracic aortic false aneurysm after undergoing conventional total arch replacement for aortic arch aneurysm (62 mm) and endovascular stent placement for descending aortic aneurysm (70 mm). His chief complaints at the present admission were fever and sensation of dyspnea and we put him on a course of antibiotics for stent graft infection. However he died of massive hemoptysis. From a standpoint of autopsy findings, a thoracic aortic false aneurysm formed at the just proximal landing zone owing to type Ia endoleak, and simultaneously stent graft infection lead to make fistula formation between the false aneurysm and the lung. We examined ourselves that stent graft infection and aortopulmonary fistula caused by an infected thoracic aortic false aneurysm rupturing into the lung should be promptly treated such as complete removal of the stent and another revascularization in a reasonable period of time except if there are complications such as comorbid1ities or withholding of consent. We experienced and reported one rare case associated with a rupture of thoracic aortic false aneurysm caused by stent graft infection and the fistulization between the lung and the stent graft.
I thank and commend the authors Xiaojing Huang et al. of the article titled "Research progress in the radioprotective effect of superoxide dismutase" for having brought a comprehensive review of the molecular, cellular, tissue, and organ level mechanism of radioprotection by superoxide dismutase (SOD) (1). ...
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