Multifunctional drug delivery system using starch-alginate beads for controlled release

Utilizing starch-containing alginate beads, a novel drug delivery system (DDS) was developed. With the starch inside, the composite bead could be dried in its original bead shape and handled in the dried state. By employing alginate multi-coating strategy on the starch-alginate beads, detained or controlled release was efficiently achieved and successfully demonstrated for a model peptide drug, L-phenylalanine. The initial latent time and release rate of the drug inside the beads were able to be controlled simply by varying the number of multi-coatings. While the latent time for the initial release was negligible for non-coated starch-alginate beads, the latent times of beads coated one, two, and four times increased to 15, 30, and 70 min, respectively. Furthermore, the alginate component of the composite beads could adsorb and remove heavy metals such as lead from the body. These multifunctional beads combined with the novel coating process will greatly benefit alginate gel-based DDS.     

Wnt-C59 inhibits proinflammatory cytokine expression by reducing the interaction between β-catenin and NF-κB in LPS-stimulated epithelial and macrophage cells

Dysregulation of the Wnt pathway causes various diseases including cancer, Parkinson’s disease, Alzheimer’s disease, schizophrenia, osteoporosis, obesity and chronic kidney diseases. The modulation of dysregulated Wnt pathway is absolutely necessary. In the present study, we evaluated the anti-inflammatory effect and the mechanism of action of Wnt-C59, a Wnt signaling inhibitor, in lipopolysaccharide (LPS)-stimulated epithelial cells and macrophage cells. Wnt-C59 showed a dose-dependent anti-inflammatory effect by suppressing the expression of proinflammatory cytokines including IL6, CCL2, IL1A, IL1B, and TNF in LPS-stimulated cells. The dysregulation of the Wnt/β-catenin pathway in LPS stimulated cells was suppressed by Wnt-C59 treatment. The level of β-catenin, the executor protein of Wnt/β-catenin pathway, was elevated by LPS and suppressed by Wnt-C59. Overexpression of β-catenin rescued the suppressive effect of Wnt-C59 on proinflammatory cytokine expression and nuclear factor-kappa B (NF-κB) activity. We found that the interaction between β-catenin and NF-κB, measured by co-immunoprecipitation assay, was elevated by LPS and suppressed by Wnt-C59 treatment. Both NF-κB activity for its target DNA binding and the reporter activity of NF-κB-responsive promoter showed identical patterns with the interaction between β-catenin and NF-κB. Altogether, our findings suggest that the anti-inflammatory effect of Wnt-C59 is mediated by the reduction of the cellular level of β-catenin and the interaction between β-catenin and NF-κB, which results in the suppressions of the NF-κB activity and proinflammatory cytokine expression.     

Advances in Targeted Drug Delivery Approaches for the Central Nervous System Tumors: The Inspiration of Nanobiotechnology

At present, brain tumor is among the most challenging diseases to treat and the therapy is limited by the lack of effective methods to deliver anticancer agents across the blood-brain barrier (BBB). BBB is a selective barrier that separates the circulating blood from the brain extracellular fluid. In its neuroprotective function, BBB prevents the entry of toxins, as well as most of anticancer agents and is the main impediment for brain targeted drug delivery approaches. Nanotechnology-based delivery systems provide an attractive strategy to cross the BBB and reach the central nervous system (CNS). The incorporation of anticancer agents in various nanovehicles facilitates their delivery across the BBB. Moreover, a more powerful tool in brain tumor therapy has relied surface modifications of nanovehicles with specific ligands that can promote their passage through the BBB and favor the accumulation of the drug in CNS tumors. This review describes the physiological and anatomical features of the brain tumor and the BBB, and summarizes the recent advanced approaches to deliver anticancer drugs into brain tumor using nanobiotechnology-based drug carrier systems. The role of specific ligands in the design of functionalized nanovehicles for targeted delivery to brain tumor is reviewed. The current trends and future approaches in the CNS delivery of therapeutic molecules to tumors are also discussed.     

Gender Differences in Hypertension Control Among Older Korean Adults: Korean Social Life,Health, and Aging Project

Objectives:

Controlling blood pressure is a key step in reducing cardiovascular mortality in older adults. Gender differences in patients’ attitudes after disease diagnosis and their management of the disease have been identified. However, it is unclear whether gender differences exist in hypertension management among older adults. We hypothesized that gender differences would exist among factors associated with hypertension diagnosis and control among community-dwelling, older adults.

Methods:

This cross-sectional study analyzed data from 653 Koreans aged ≥60 years who participated in the Korean Social Life, Health, and Aging Project. Multiple logistic regression was used to compare several variables between undiagnosed and diagnosed hypertension, and between uncontrolled and controlled hypertension.

Results:

Diabetes was more prevalent in men and women who had uncontrolled hypertension than those with controlled hypertension or undiagnosed hypertension. High body mass index was significantly associated with uncontrolled hypertension only in men. Multiple logistic regression analysis indicated that in women, awareness of one’s blood pressure level (odds ratio [OR], 2.86; p=0.003) and the number of blood pressure checkups over the previous year (OR, 1.06; p=0.011) might influence the likelihood of being diagnosed with hypertension. More highly educated women were more likely to have controlled hypertension than non-educated women (OR, 5.23; p=0.013).

Conclusions:

This study suggests that gender differences exist among factors associated with hypertension diagnosis and control in the study population of community-dwelling, older adults. Education-based health promotion strategies for hypertension control might be more effective in elderly women than in elderly men. Gender-specific approaches may be required to effectively control hypertension among older adults.     

Inhibition of skin inflammation and atopic dermatitis by topical application of a novel ceramide derivative, K112PC-5, in mice

PC-9S (N-Ethanol-2-mirystyl-3-oxo-stearamide) is a synthetic ceramide and has been known to be effective in atopic and psoriatic patients. K112PC-5 (2-Acetyl-N-(1,3-dihydroxyisopropyl)-tetradecanamide) is a novel ceramide derivative of PC-9S. In the present study, we examined the effect of K112PC-5 on macrophage and T lymphocyte function in primary macrophages and splenocytes, respectively, as well as the effect of topical application of K112PC-5 on skin inflammation and atopic dermatitis (AD) in mouse models. K112PC-5 inhibited lipopolysaccharide-induced nitrite generation in mouse peritoneal macrophages in a dose-dependent manner. However, K112PC-5 did not affect concanavalin A-induced proliferation, interleukin (IL)-2 secretion and IL-4 secretion in mouse splenocytes. In addition, K112PC-5 significantly suppressed the increase in phorbol ester-induced ear thickness in BALB/c mice. Further study demonstrated that topical application of K112PC-5 also inhibited AD induced by extracts of dust mites, Dermatophagoides pteronyssinus and Dermatophagoides farinae, in NC/Nga mice. Taken together, these results showed that K112PC-5 exerted an anti-inflammatory effect both in vitro and in vivo and proved to be beneficial in an animal model of AD. Our results suggest that K112PC-5 might be beneficial as a topical agent for the treatment of AD.     

Effect of previous cerebrovascular accident on outcome after hip fracture

OBJECTIVE: To evaluate the effect of previous cerebrovascular accident on outcome after hip fracture. STUDY DESIGN: Prospective, consecutive. PATIENTS: From July 1987 to March 1997, 862 community-dwelling patients sixty-five years of age or older who had sustained an operatively treated femoral neck or intertrochanteric fracture were prospectively followed. INTERVENTION: All patients had operative fracture treatment. MAIN OUTCOME MEASUREMENTS: Postoperative complications, in-hospital mortality, hospital length of stay, hospital discharge status, one-year mortality and place of residence, and return to preinjury ambulatory level, basic and instrumental activities of daily living status. RESULTS: Sixty-three patients (7.3 percent) had a history of cerebrovascular accident; the fracture was on the hemiplegic side in forty-six (86.8 percent) of the fifty-three patients with hemiplegia. Patients who had a history of cerebrovascular accident were more likely to be male and have an American Society of Anesthesiologists (ASA) rating of III or IV. They were also more likely to have three or more comorbidities, be a home ambulator, and be dependent on basic and instrumental activities of daily living before hip fracture. Hospital length of stay was significantly higher for patients who had a history of cerebrovascular accident. There were no differences in the incidence of hospital mortality or one-year mortality between patients who did and did not have a history of cerebrovascular accident before hip fracture. In addition, at one-year follow-up, when controlling for prefracture level of function, there were no differences in the rate of functional recovery between the two groups of patients. CONCLUSIONS: The functional recovery of elderly hip fracture patients who had a prior cerebrovascular accident was similar to that of patients who had no history of a prior cerebrovascular accident.     

Topical application of a novel ceramide derivative, K6PC-9, inhibits dust mite extract-induced atopic dermatitis-like skin lesions in NC/Nga mice

Atopic dermatitis (AD) is a chronic inflammatory skin disease. K6PC-9 (N-Ethanol-2-hexyl-3-oxo-decanamide) is a novel synthetic ceramide derivative of PC-9S (N-Ethanol-2-mirystyl-3-oxo-stearamide), which was known to be effective in atopic and psoriatic patients. To investigate the immunomodulatory activity of K6PC-9, we examined the effect of K6PC-9 on T lymphocyte and macrophage function and the effect of topical application of K6PC-9 on skin inflammation and AD-like skin lesions in mouse models. K6PC-9 had no effect on concanavalin A-induced proliferation, interleukin (IL)-2 secretion and IL-4 secretion in mouse splenocytes. In contrast, lipopolysaccharide-induced nitrite generation was potently suppressed by K6PC-9 in mouse peritoneal macrophages. In mouse model of skin inflammation, K6PC-9 inhibited phorbol ester-induced increase in ear thickness and expression of tumor necrosis factor-alpha in the ear of BALB/c mice. Topical application of K6PC-9 also suppressed mite extract-induced AD-like skin lesions in NC/Nga mice. Increase in ear thickness was significantly inhibited by K6PC-9 in this model. K6PC-9 also blocked the infiltration of mast cells and neutrophils into the ear. Further study demonstrated that the mRNA expression of tumor necrosis factor-alpha and adhesion molecules, such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, was also suppressed by K6PC-9 in the ear of mite extract-treated NC/Nga mice. Taken together, the results presented in this report show that K6PC-9 has an anti-inflammatory potential and exerts beneficial effects in an animal model of AD, indicating that K6PC-9 might be used as a topical agent for the treatment of AD.     

A computational model of cytosolic and mitochondrial [ca] in paced rat ventricular myocytes

We carried out a series of experiment demonstrating the role of mitochondria in the cytosolic and mitochondrial Ca(2+) transients and compared the results with those from computer simulation. In rat ventricular myocytes, increasing the rate of stimulation (1~3 Hz) made both the diastolic and systolic [Ca(2+)] bigger in mitochondria as well as in cytosol. As L-type Ca(2+) channel has key influence on the amplitude of Ca(2+)-induced Ca(2+) release, the relation between stimulus frequency and the amplitude of Ca(2+) transients was examined under the low density (1/10 of control) of L-type Ca(2+) channel in model simulation, where the relation was reversed. In experiment, block of Ca(2+) uniporter on mitochondrial inner membrane significantly reduced the amplitude of mitochondrial Ca(2+) transients, while it failed to affect the cytosolic Ca(2+) transients. In computer simulation, the amplitude of cytosolic Ca(2+) transients was not affected by removal of Ca(2+) uniporter. The application of carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) known as a protonophore on mitochondrial membrane to rat ventricular myocytes gradually increased the diastolic [Ca(2+)] in cytosol and eventually abolished the Ca(2+) transients, which was similarly reproduced in computer simulation. The model study suggests that the relative contribution of L-type Ca(2+) channel to total transsarcolemmal Ca(2+) flux could determine whether the cytosolic Ca(2+) transients become bigger or smaller with higher stimulus frequency. The present study also suggests that cytosolic Ca(2+) affects mitochondrial Ca(2+) in a beat-to-beat manner, however, removal of Ca(2+) influx mechanism into mitochondria does not affect the amplitude of cytosolic Ca(2+) transients.     

Oral immunogenicity of potato-derived HBsAg middle protein in BALB/c mice

The antibodies to preS2 synthetic peptides have been probed to neutralize hepatitis B virus (HBV), and also the addition of preS2 sequence could enhance the antibody response compared with a conventional vaccine in the non- and low responders. Previously, we generated transgenic potatoes expressing middle protein, which contains additional 55 amino acid preS2 region at the N-terminus of the S protein, of HBV to determine the feasibility of developing a plant-delivered HBV vaccine. In this study, we monitored the immune response after induction of immunoglobulin by boosting and assessed the efficacy of the mucosal immune response with regard to generate IgA antibodies. The HBsAg middle protein expressed in our transgenic potatoes was well immunized at low antigenic quantities in mice and the induced anti-S or anti-preS2 antibodies were sustained for the whole period without decrease. Orally delivery of plant-derived HBsAg middle protein to mice resulted in fecal anti-S or anti-preS2 as well as serum IgG. In addition, we used antibodies induced from the immunized mice with the potato-derived rHBsAg in competition assay as competitors to confirm the binding ability of preS2 antibodies to surface antigen of hepatitis virus. Anti-preS2 antibodies induced from immunized mice with transgenic potatoes effectively competed with anti-preS2 murine antibody H8 as expected. From these results, the inclusion of preS2 antigen to HBV plant vaccine may provide additional protective immunity in the HBV prevention.     

Determination of terbutaline enantiomers in human urine by capillary electrophoresis using hydroxypropyl-β-cyclodextrin as a chiral selector

A method for the determination of terbutaline enantiomers in human urine by capillary electrophoresis has been developed. Optimum resolution was achieved using 50 mM phosphate buffer, pH 2.5, containing 15 mM of hydroxypropyl-beta-cyclodextrin as a chiral selector. Urine samples were prepared by solid-phase extraction with Sep-pak silica, followed by CE. The assay was linear between 2-250 ng/mL (R = 0.9998 for (S)-(+)-terbutaline and R = 0.9999 for (R)-(-)terbutaline) and detection limit was 0.8 ng/mL. The intra-day variation ranged between 6.3 and 14.5% in relation to the measured concentration and the inter-day variation was 8.2-20.1%. It has been applied to the determination of (S)-(+)terbutaline and (R)-(-)-terbutaline in urine from healthy volunteer dosed with racemic terbutaline sulfate.