Kidney-Targeted Epoxyeicosatrienoic Acid Analog, EET-F01, Reduces Inflammation, Oxidative Stress, and Cisplatin-Induced Nephrotoxicity

Although epoxyeicosatrienoic acid (EET) analogs have performed well in several acute and chronic kidney disease models, targeted delivery of EET analogs to the kidney can be reasonably expected to reduce the level of drug needed to achieve a therapeutic effect and obviate possible side effects. For EET analog kidney-targeted delivery, we conjugated a stable EET analog to folic acid via a PEG-diamine linker. Next, we compared the kidney targeted EET analog, EET-F01, to a well-studied EET analog, EET-A. EET-A or EET-F01 was infused i.v. and plasma and kidney tissue collected. EET-A was detected in the plasma but was undetectable in the kidney. On the other hand, EET-F01 was detected in the plasma and kidney. Experiments were conducted to compare the efficacy of EET-F01 and EET-A for decreasing cisplatin nephrotoxicity. Cisplatin was administered to WKY rats treated with vehicle, EET-A (10 mg/kg i.p.) or EET-F01 (20 mg/kg or 2 mg/kg i.p.). Cisplatin increased kidney injury markers, viz., blood urea nitrogen (BUN), N-acetyl-β-(D)-glucosaminidase (NAG), kidney injury molecule-1 (KIM-1), and thiobarbituric acid reactive substances (TBARS). EET-F01 was as effective as EET-A in decreasing BUN, NAG, KIM-1, TBARS, and renal histological injury caused by cisplatin. Despite its almost 2×-greater molecular weight compared with EET-A, EET-F01 was comparably effective in decreasing renal injury at a 10-fold w/w lower dose. EET-F01 decreased cisplatin nephrotoxicity by reducing oxidative stress and inflammation. These data demonstrate that EET-F01 targets the kidney, allows for a lower effective dose, and combats cisplatin nephrotoxicity. In conclusion, we have developed a kidney targeted EET analog, EET-F01, that demonstrates excellent potential as a therapeutic for kidney diseases.

A chimeric, multivalent assembly of galectin-1 and galectin-3 with enhanced extracellular activity

Assembly of a fusion of galectin-1 and galectin-3 with higher carbohydrate binding affinity and a significantly lower effective dose than galectin-1.

GSK461364A, a Polo-Like Kinase-1 Inhibitor Encapsulated in Polymeric Nanoparticles for the Treatment of Glioblastoma Multiforme (GBM)

Glioblastoma Multiforme (GBM) is a common primary brain cancer with a poor prognosis and a median survival of less than 14 months. Current modes of treatment are associated with deleterious side effects that reduce the life span of the patients. Nanomedicine enables site-specific delivery of active pharmaceutical ingredients and facilitates entrapment inside the tumor. Polo-like kinase 1 (PLK-1) inhibitors have shown promising results in tumor cells. GSK461364A (GSK) is one such targeted inhibitor with reported toxicity issues in phase 1 clinical trials. We have demonstrated in our study that the action of GSK is time dependent across all concentrations. There is a distinct 15−20% decrease in cell viability via apoptosis in U87-MG cells dosed with GSK at low concentrations (within the nanomolar and lower micromolar range) compared to higher concentrations of the drug. Additionally, we have confirmed that PLGA-PEG nanoparticles (NPs) containing GSK have shown significant reduction in cell viability of tumor cells compared to their free equivalents. Thus, this polymeric nanoconstruct encapsulating GSK can be effective even at low concentrations and could improve the effectiveness of the drug while reducing side effects at the lower effective dose. This is the first study to report a PLK-1 inhibitor (GSK) encapsulated in a nanocarrier for cancer applications.

Abstract 111: A Kidney Targeted Epoxyeicosatrienoic Acid Analog, EET-F01, Reduces Cisplatin-induced Nephrotoxicity

Epoxyeicosatrienoic acid (EET) analogs have exceptional therapeutic potential to combat cardiovascular and kidney diseases. EET analogs combat damage in acute and chronic kidney disease models. Biological actions attributed to EET analogs such as vasodilation, anti-inflammation, anti-apoptosis, and anti-fibrosis are ideally suited to treat kidney diseases. Although EET analogs have performed well in several in vivo models, targeted delivery of EET analogs to the kidney can be reasonably expected to reduce the level of drug needed to achieve a therapeutic effect in the kidney and obviate possible side effects. For EET analog kidney-targeted delivery, we conjugated an EET analog to folic acid because there is a high concentration of folate receptors in renal tissue. The EET analog was conjugated to folic acid via a PEG-diamine linker. Next, we compared the kidney targeted EET analog, EET-F01, to a well-studied EET analog, EET-A. EET-A or EET-F01 was infused i.v. (10mg/kg/hr) for 6 hours via the rat jugular vein. Plasma and kidney tissue were collected and EET-A or EET-F01 measured by LC-MS-MS. EET-A plasma level was 1.6 ng/mL, but EET-A was undetectable in the kidney. On the other hand, EET-F01 was 6.5 ng/mL in plasma and 26.7 ng/mL in kidney tissue. These data demonstrate that EET-F01 targets the kidney. Experiments were conducted to compare EET-F01 and EET-A to decrease cisplatin-induced nephrotoxicity. A single injection of cisplatin (7 mg/kg ip) was administered to WKY rats treated with vehicle, EET-A (10 mg/kg ip) or EET-F01 (20 mg/kg or 2 mg/kg ip) for five days. Cisplatin increased BUN (125 ± 11 mg/dL) and NAG (12 ± 4 IU/L) compared to control (36 ± 9 mg/dL and 4 ± 1 IU/L). EET-F01 was as effective as EET-A in decreasing BUN, NAG, and renal histological injury five days following cisplatin administration. Despite it almost 2x-greater molecular weight compared with EET-A, EET-F01 was effective in lowering BUN and NAG at 20 mg/kg/d and at a 10-fold lower dose of 2 mg/kg/d. These data clearly demonstrate that EET-F01 targets the kidney and allows for a lower effective dose. In conclusion, we have developed a kidney targeted EET analog, EET-F01, that demonstrates excellent potential as a therapeutic for kidney diseases.

The Shielding Materials from EM Radiation for Aircraft Fuselage

In the last few decades, when travel makes one modest, people prefer air travel instead of car. As such, aircrews and flight passengers are prone to electromagnetic (EM) radiation exposure overtime during flight. Various researches were conducted by the Federal Aviation Agency (FAA) and European Union (EU) in order to understand its details. This paper offers reviews of EM radiation effect to human body in altitude of commercial jet and materials that may provide a convince protection for fuselage structure of aircraft. It was found that Polyethylene (PE) is a convincing material that may absorb EM radiation. NASA has found that lower effective dose toward galactic cosmic rays (GCR) was obtained in PE at 0.1 cSv/day compared to aluminum at 0.125 cSv/day at the same thickness which was 20 g/cm2.

Cone-Beam Computed Tomography and Radiographs in Dentistry: Aspects Related to Radiation Dose

Introduction. The aim of this study was to discuss the radiation doses associated with plain radiographs, cone-beam computed tomography (CBCT), and conventional computed tomography (CT) in dentistry, with a special focus on orthodontics.Methods. A systematic search for articles was realized by MEDLINE from 1997–March 2011.Results. Twenty-seven articles met the established criteria. The data of these papers were grouped in a table and discussed.Conclusions. Increases in kV, mA, exposure time, and field of view (FOV) increase the radiation dose. The dose for CT is greater than other modalities. When the full-mouth series (FMX) is performed with round collimation, the orthodontic radiographs transmit higher dose than most of the large FOV CBCT, but it can be reduced if used rectangular collimation, showing lower effective dose than large FOV CBCT. Despite the image quality, the CBCT does not replace the FMX. In addition to the radiation dose, image quality and diagnostic needs should be strongly taken into account.

Coronary artery reactivity in deoxycorticosterone acetate hypertensive rats

Helical strips of coronary arteries from normotensive and deoxycorticosterone acetate (DOCA) hypertensive rats were studied in vitro for their responsiveness to a variety of vasoactive agents. After application of passive force (50-400 mg), arteries developed spontaneous tonic contractions. These tonic contractions were not different between the two groups, and the contractions were not altered by inhibitors of neurogenic, prostaglandin, peptidergic, or purine activity. Coronary arteries from DOCA rats were more sensitive (lower effective dose, 50%) to the contractile effects of norepinephrine, serotonin, and potassium chloride relative to those from normotensive rats. Following contraction induced by serotonin, coronary arteries from DOCA rats relaxed less to isoproterenol and adenosine compared with those from control rats. Relaxation of arteries from DOCA rats in response to prostacyclin, nitroprusside, and acetylcholine did not differ from that in coronary arteries from normotensive rats. These observations demonstrate increased vascular sensitivity to constrictor agents and altered relaxation responses to adenosine and isoproterenol in the coronary vasculature of DOCA hypertensive rats.