beta-Lapachone has drawn increasing attention as an anti-inflammatory and anti-cancer drug. However, its oral bioavailability has not been yet assessed, which might be useful to develop efficient dosage forms possibly required for non-clinical and clinical studies and future market. The aim of the present study was thus to investigate pharmacokinetic properties of beta-lapachone as well as its first-pass metabolism in the liver, and small and large intestines after oral administration to measure the absolute bioavailability in rats. A sensitive HPLC method was developed to evaluate levels of beta-lapachone in plasma and organ homogenates. The drug degradation profiles were examined in plasma to assess the stability of the drug and in liver and intestinal homogenates to evaluate first-pass metabolism. Pharmacokinetic profiles were obtained after oral and intravenous administration of beta-lapachone at doses of 40 mg/kg and 1.5 mg/kg, respectively. The measured oral bioavailability of beta-lapachone was 15.5%. The considerable degradation of beta-lapachone was seen in the organ homogenates but the drug was quite stable in plasma. In conclusion, we suggest that the fairly low oral bioavailability of beta-lapachone may be resulted from the first-pass metabolic degradation of beta-lapachone in the liver, small and large intestinal tracts and its low aqueous solubility.
Administration, Intravenous ; Administration, Oral ; Animals ; Biological Availability* ; Chromatography, High Pressure Liquid ; Dosage Forms ; Intestines ; Liver ; Metabolism* ; Pharmacokinetics ; Plasma ; Rats* ; Solubility

With focused ultrasound (FUS) and microbubbles, BBB can be transiently disrupted with a localized and non-invasive approach. BBB disruption induced by FUS has made progressions to move forward on delivery of therapeutic agents into a brain in a specific area of brain for better treatment of neurological diseases. In addition to be used as an improvement of drug delivery, BBB disruption has been found to induce biological effects such as a clearance of protein aggregation which cause Alzheimer's disease, regulation of proteins which facilitate drug uptake, and modulation of neuronal function and neurogenesis. In this review, we discuss overview about the principles of BBB opening with FUS and milestones in these biological effects of FUS-induced BBB disruption.
Alzheimer Disease ; Brain ; Microbubbles ; Neurogenesis ; Neurons ; Ultrasonography*

Background: Hematopoietic stem/progenitor cells (HSPCs) have the property to return to the bone marrow, which is believed to be critical in situations such as HSPC transplantation. This property plays an important role in the stemness, viability, and proliferation of HSPCs, also. However, most in vitro models so far have not sufficiently simulated the complicate environment. Here, we proposed a three-dimensional experimental platform for the quantitative study of the migration of HSPCs. Methods: After encapsulating osteoblasts (OBs) in alginate beads, we quantified the migration of HSPCs into the beads due to the physical environment using digital image processing. Intermittent hydrostatic pressure (IHP) was used to mimic the mechanical environment of human bone marrow without using any biochemical factors. The expression of stromal cell-derived factor 1 (SDF-1) under IHP was measured. Results: The results showed that the presence of OBs in the hydrogel scaffold initiate the movement of HSPCs. Furthermore, the IHP promotes the migration of HSPCs, even without the addition of any biochemical factors, and the results were confirmed by measuring SDF-1 levels. Conclusion We believe this suggested three-dimensional experimental platform consisting of a simulated in vivo physical environment and encapsulated OBs should contribute to in vitro migration studies used to investigate the effects of other external factors.

Background: Hematopoietic stem/progenitor cells (HSPCs) have the property to return to the bone marrow, which is believed to be critical in situations such as HSPC transplantation. This property plays an important role in the stemness, viability, and proliferation of HSPCs, also. However, most in vitro models so far have not sufficiently simulated the complicate environment. Here, we proposed a three-dimensional experimental platform for the quantitative study of the migration of HSPCs. Methods: After encapsulating osteoblasts (OBs) in alginate beads, we quantified the migration of HSPCs into the beads due to the physical environment using digital image processing. Intermittent hydrostatic pressure (IHP) was used to mimic the mechanical environment of human bone marrow without using any biochemical factors. The expression of stromal cell-derived factor 1 (SDF-1) under IHP was measured. Results: The results showed that the presence of OBs in the hydrogel scaffold initiate the movement of HSPCs. Furthermore, the IHP promotes the migration of HSPCs, even without the addition of any biochemical factors, and the results were confirmed by measuring SDF-1 levels. Conclusion We believe this suggested three-dimensional experimental platform consisting of a simulated in vivo physical environment and encapsulated OBs should contribute to in vitro migration studies used to investigate the effects of other external factors.

BACKGROUND/OBJECTIVES: Citrus and its peels have been used in Asian folk medicine due to abundant flavonoids and usage of citrus peels, which are byproducts from juice and/or jam processing, may be a good strategy. Therefore, the aim of this study was to examine antioxidant and anti-inflammatory effects of bioconversion of Jeju Hallabong tangor (Citrus kiyomi × ponkan; CKP) peels with cytolase (CKP-C) in RAW 264.7 cells. MATERIALS/METHODS: Glycosides of CKP were converted into aglycosides with cytolase treatment. RAW 264.7 cells were pre-treated with 0, 100, or 200 µg/ml of citrus peel extracts for 4 h, followed by stimulation with 1 µg/ml lipopolysaccharide (LPS) for 8 h. Cell viability, DPPH radical scavenging activity, nitric oxide (NO), and prostagladin E2 (PGE2) production were examined. Real time-PCR and western immunoblotting assay were performed for detection of mRNA and/or protein expression of pro-inflammatory mediators and cytokines, respectively. RESULTS: HPLC analysis showed that treatment of CKP with cytolase resulted in decreased flavanone rutinoside forms (narirutin and hesperidin) and increased flavanone aglycoside forms (naringenin and hesperetin). DPPH scavenging activities were observed in a dose-dependent manner for all of the citrus peel extracts and CKP-C was more potent than intact CKP. All of the citrus peel extracts decreased NO production by inducible nitric oxide synthase (iNOS) activity and PGE2 production by COX-2. Higher dose of CKP and all CKP-C groups significantly decreased mRNA and protein expression of LPS-stimulated iNOS. Only 200 µg/ml of CKP-C markedly decreased mRNA and protein expression of cyclooxygenase-2 in LPS-stimulated RAW 264.7 cells. Both 100 and 200 µg/ml of CKP-C notably inhibited mRNA levels of interleukin-1β (IL-1β) and IL-6, whereas 200 µg/ml CKP-C significantly inhibited mRNA levels of TNF-α. CONCLUSIONS: This result suggests that bioconversion of citrus peels with cytolase may enrich aglycoside flavanones of citrus peels and provide more potent functional food materials for prevention of chronic diseases attributable to oxidation and inflammation by increasing radical scavenging activity and suppressing pro-inflammatory mediators and cytokines.
Asian Continental Ancestry Group ; Blotting, Western ; Cell Survival ; Chromatography, High Pressure Liquid ; Chronic Disease ; Citrus ; Cyclooxygenase 2 ; Cytokines ; Dinoprostone ; Flavanones ; Flavonoids ; Functional Food ; Glycosides ; Humans ; Inflammation ; Interleukin-6 ; Medicine, Traditional ; Nitric Oxide ; Nitric Oxide Synthase Type II ; RNA, Messenger

The purpose of this study was to examine the effect of stabilization of retinyl palmitate (RP) on its skin permeation and distribution profiles. Skin permeation and distribution study were performed using Franz diffusion cells along with rat dorsal skin, and the effect of drug concentration and the addition of pectin on skin deposition profiles of RP was observed. The skin distribution of RP increased in a concentration dependent manner and the formulations containing 0.5 and 1 mg of pectin demonstrated significantly increased RP distributions in the epidermis. Furthermore, it was found that skin distribution of RP could be further improved by combined use of pectin and ascorbyl palmitate (AP), due largely to their anti-oxidative effect. These results clearly demonstrate that the skin deposition properties of RP can be improved by stabilizing RP with pectin. Therefore, it is strongly suggested that pectin could be used in the pharmaceutical and cosmetic formulations as an efficient stabilizing agent and as skin penetration modulator.
Animals ; Diffusion ; Epidermis ; Rats ; Skin*

The purpose of this study was to examine the effect of stabilization of retinyl palmitate (RP) on its skin permeation and distribution profiles. Skin permeation and distribution study were performed using Franz diffusion cells along with rat dorsal skin, and the effect of drug concentration and the addition of pectin on skin deposition profiles of RP was observed. The skin distribution of RP increased in a concentration dependent manner and the formulations containing 0.5 and 1 mg of pectin demonstrated significantly increased RP distributions in the epidermis. Furthermore, it was found that skin distribution of RP could be further improved by combined use of pectin and ascorbyl palmitate (AP), due largely to their anti-oxidative effect. These results clearly demonstrate that the skin deposition properties of RP can be improved by stabilizing RP with pectin. Therefore, it is strongly suggested that pectin could be used in the pharmaceutical and cosmetic formulations as an efficient stabilizing agent and as skin penetration modulator.
Animals ; Diffusion ; Epidermis ; Rats ; Skin*

The purpose of this study was to examine the anti-oxidative activity of pectin and other polysaccharides in order to develop a cosmeceutical base having anti-oxidative effects towards retinyl palmitate (RP). The anti-oxidative stabilizing effects of pectin and other polysaccharides on RP were evaluated by DPPH assay and then the stabilizing effect of pectin on RP was examined as a function of time. Among the polysaccharides we examined, pectin exhibited a considerably higher anti-oxidative activity, with an approximately 5-fold greater DPPH radical scavenging effect compared to other polysaccharides. The DPPH radical scavenging effect of pectin increased gradually with increasing concentrations of pectin. At two different RP concentrations, 0.01 and 0.1% in ethanol, addition of pectin improved the stability of RP in a concentration dependent manner. The stabilizing effect of pectin on RP was more effective for the lower concentration of RP (0.01%, v/v). Further, degradation of RP was reduced following the addition of pectin as measured over 8 hours. From the results obtained, it can be suggested that pectin may be a promising ingredient for cosmeceutical bases designed to stabilize RP or other pharmacological agents subject to degradation by oxidation.
Ethanol ; Pectins ; Polysaccharides ; Vitamin A

DWP208 is a sodium succinate form of ZYM-201 which is a triterpenoid glycoside isolated from Sanguisorba officinalis, a medicinal plant prescribed for various diseases, such as duodenal ulcers and bleeding in East Asian counties. We demonstrated that this compound is able to normalize the altered lipid metabolism induced by hyperglycemia and a high fat diet. In this study, we determined whether hyperlipidemic conditions induced with chronically treated alcohol can also be restored by DWP208. Similar to our previous results, orally administered DWP208 (1 to 10 mg/kg) also ameliorated the hyperlipidemia that was induced by alcohol. This compound reversed the alcohol-induced hyperlipidemia including (i) up-regulated hyperlipidemic parameters such as low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), atherosclerotic index (AI), triglyceride, and total cholesterol, and (ii) down-regulated hyperlipidemic parameters such as absolute body weight, superoxide dismutase (SOD) activity, and high-density lipoprotein (HDL) in serum and liver. According to our data, the ameliorative activity of DWP208 is due to its indirect anti-oxidative activity as a result of which lipid peroxide and hydroxyl radical levels were reduced and the activity of SOD was enhanced. Therefore, our data strongly suggest that DWP208 can be used as a remedy against alcohol-induced hyperlipidemia.
Asian Continental Ancestry Group ; Body Weight ; Cholesterol ; Diet, High-Fat ; Duodenal Ulcer ; Hemorrhage ; Humans ; Hydroxyl Radical ; Hyperglycemia ; Hyperlipidemias* ; Lipid Metabolism ; Lipoproteins ; Liver ; Plants, Medicinal ; Sanguisorba ; Sodium* ; Succinic Acid* ; Superoxide Dismutase ; Triglycerides

Retinyl palmitate (RP)-loaded pectinate micro- and nano-particles (PMP and PNP) were designed for stabilization of RP that is widely used as an anti-wrinkle agent in anti-aging cosmeceuticals. PMP/PNP were prepared with an ionotropic gelation method, and anti-oxidative activity of the particles was measured with a DPPH assay. The stability of RP in the particles along with pectin gel and ethanolic solution was then evaluated. In vitro release and skin permeation studies were performed using Franz diffusion cells. Distribution of RP in each skin tissue (stratum corneum, epidermis, and dermis) was also determined. PMP and PNP could be prepared with mean particle size diameters of 593~843 mum (PMP) and 530 nm (i.e., 0.53 mum, PNP). Anti-oxidative activity of PNP was greater than PMP due largely to larger surface area available for PNP. The stability of RP in PMP and PNP was similar but much greater than RP in pectin bulk gels and ethanolic solution. PMP and PNP showed the abilities to constantly release RP and it could be permeated across the model artificial membrane and rat whole skin. RP was serially deposited throughout the skin layers. This study implies RP loaded PMP and PNP are expected to be advantageous for improved anti-wrinkle effects.
Animals ; Diffusion ; Epidermis ; Ethanol ; Gels ; Membranes, Artificial ; Nanoparticles ; Particle Size ; Rats ; Skin*