Hesperetin, an abundant bioactive component of citrus fruits, is poorly water-soluble, resulting in low oral bioavailability. We developed new formulations to improve the water solubility, antioxidant activity, and oral absorption of hesperetin. Two nano-based formulations were developed, namely hesperetin-TPGS (D-α-tocopheryl polyethylene glycol 1000 succinate) micelles and hesperetin-phosphatidylcholine (PC) complexes. These two formulations were prepared by a simple technique called solvent dispersion, using US Food and Drug Administration (FDA)-approved excipients for drugs. Differential scanning calorimetry (DSC) and dynamic light scattering (DLS) were used to characterize the formulations' physical properties. Cytotoxicity analysis, cellular antioxidant activity assay, and a pharmacokinetic study were performed to evaluate the biological properties of these two formulations. The final weight ratios of both hesperetin to TPGS and hesperetin to PC were 1:12 based on their water solubility, which increased to 21.5- and 20.7-fold, respectively. The hesperetin-TPGS micelles had a small particle size of 26.19 nm, whereas the hesperetin-PC complexes exhibited a larger particle size of 219.15 nm. In addition, the cellular antioxidant activity assay indicated that both hesperetin-TPGS micelles and hesperetin-PC complexes increased the antioxidant activity of hesperetin to 4.2- and 3.9-fold, respectively. Importantly, the in vivo oral absorption study on rats indicated that the micelles and complexes significantly increased the peak plasma concentration (C_max) from 2.64 μg/mL to 20.67 and 33.09 μg/mL and also increased the area under the concentration-time curve of hesperetin after oral administration to 16.2- and 18.0-fold, respectively. The micelles and complexes increased the solubility and remarkably improved the in vitro antioxidant activity and in vivo oral absorption of hesperetin, indicating these formulations' potential applications in drugs and healthcare products.
Administration, Oral ; Animals ; Antioxidants/chemistry* ; Biological Availability ; Calorimetry, Differential Scanning ; Dogs ; Dose-Response Relationship, Drug ; Drug Carriers ; Female ; Hep G2 Cells ; Hesperidin/chemistry* ; Humans ; Light ; Madin Darby Canine Kidney Cells ; Micelles ; Phosphatidylcholines/chemistry* ; Polyethylene Glycols/chemistry* ; Rats ; Rats, Sprague-Dawley ; Scattering, Radiation ; Solubility ; Solvents ; Vitamin E/chemistry* ; Water/chemistry* ; alpha-Tocopherol/chemistry*

In 2016 and 2017, there were earthquakes greater than 5.0 in magnitude on the Korean Peninsula, which has previously been considered an earthquake-free zone. Patients with chronic kidney disease are particularly vulnerable to earthquakes, as the term “renal disaster” suggests. In the event of a major earthquake, patients on hemodialysis face the risk of losing maintenance dialysis due to infrastructure disruption. In this review, we share the experience of an earthquake in Pohang that posed a serious risk to patients on hemodialysis. We review the disaster response system in Japan and propose a disaster preparedness plan with respect to hemodialysis. Korean nephrologists and staff in dialysis facilities should be trained in emergency response to mitigate risk from natural disasters. Dialysis staff should be familiar with the action plan for natural disaster events that disrupt hemodialysis, such as outages and water treatment system failures caused by earthquakes. Patients on hemodialysis also need to be educated about disaster preparedness. In the event of a disaster situation that results in dialysis failure, patients need to know what to do. At the local and national government level, long-term preparations should be made to handle renal disaster and patient safety logistics. Moreover, Korean nephrologists should also be prepared to manage cardiovascular disease and diabetes in disaster situations. Further evaluation and management of social and national disaster preparedness of hemodialysis units to earthquakes in Korea are needed.
Cardiovascular Diseases ; Dialysis ; Disasters ; Earthquakes ; Emergencies ; Federal Government ; Gyeongsangbuk-do ; Humans ; Japan ; Korea ; Organization and Administration ; Patient Safety ; Renal Dialysis ; Renal Insufficiency, Chronic ; Water Purification

BACKGROUND/OBJECTIVES: Endoplasmic reticulum (ER) stress is positively associated with atherosclerosis via elevating macrophage cell death and plaque formation, in which oxidative stress plays a pivotal role. Antioxidative, lipid-lowering, and anti-atherogenic effects of kimchi, a Korean fermented vegetable, have been established, wherein capsaicin, ascorbic acid, quercetin, 3-(4'-hydroxyl-3',5'-dimethoxyphenyl)propionic acid, and lactic acids were identified. In this study, mechanisms of action of kimchi methanol extracts (KME) on fatty streak formation via suppression of ER stress and apoptosis in aorta were examined in low-density lipoprotein receptor knockout mice. MATERIALS AND METHODS: Mice fed a high cholesterol diet with an oral administration of KME (KME group, 200 mg·kg-bw⁻¹·day⁻¹) or distilled water (control group) for 8 weeks (n = 20 for group). Plasma lipid and oxidative stress levels were evaluated. Protein expression was measured by western blot assay. Fatty streak lesion size and the degree of apoptosis were examined in the aorta. RESULTS: Compared to the control group, in the KME group, plasma lipids levels were decreased and oxidative stress was alleviated (P < 0.05). Protein expression levels of nuclear factor (erythroid-derived 2)-like 2-mediated antioxidants in aorta were increased whereas those for ER stress markers, glucose regulated protein 78, phospho-protein kinase RNA-like ER kinase, phospho-eukaryotic initiation factor 2 subunit α, X-box binding protein 1, and C/EBP homologous protein were decreased in the KME group (P < 0.05). Moreover, apoptosis was suppressed via downregulation of phospho-c-Jun N-terminal kinase, bcl-2-associated X protein, caspases-9, and -3 with a concomitant upregulation of anti-apoptotic protein, B-cell lymphoma 2 (P < 0.05). Fatty streak lesion size was reduced and the degree of apoptosis was less severe in the KME group (P < 0.05). CONCLUSIONS: In conclusion, antioxidant activity of KME might prevent fatty streak formation through, in part, inhibition of ER stress and apoptosis in aortic sinus where macrophages are harbored.
Administration, Oral ; Animals ; Antioxidants ; Aorta* ; Apoptosis* ; Ascorbic Acid ; Atherosclerosis ; bcl-2-Associated X Protein ; Blotting, Western ; Capsaicin ; Carrier Proteins ; Cell Death ; Cholesterol ; Diet ; Down-Regulation ; Endoplasmic Reticulum Stress* ; Endoplasmic Reticulum* ; Glucose ; Hypercholesterolemia ; Lactic Acid ; Lipoproteins* ; Lymphoma, B-Cell ; Macrophages ; Methanol ; Mice ; Mice, Knockout* ; Oxidative Stress ; Phosphotransferases ; Plasma ; Prokaryotic Initiation Factor-2 ; Quercetin ; Receptors, Lipoprotein* ; Sinus of Valsalva ; Up-Regulation ; Vegetables ; Water

BACKGROUND/OBJECTIVES: Constipation is a condition that can result from intestinal deformation. Because humans have an upright posture, the effects of gravity can cause this shape deformation. Oligosaccharides are common prebiotics and their effects on bowel health are well known. However, studies of the physiological functionality of a product that contains both lactulose and galactooligosaccharides are insufficient. We investigated the constipation reduction effect of a dual-type oligosaccharide, Dual-Oligo, in loperamide-treated rats. MATERIALS/METHODS: Dual-Oligo consists of galactooligosaccharides (15.80%) and lactulose (51.67%). Animals were randomly divided into four groups, the normal group (normal), control group (control), low concentration of Dual-Oligo (LDO) group, and high concentration of Dual-Oligo (HDO) group. After 7 days of oral administration, fecal pellet amount, fecal weight, water content of fecal were measured. Blood chemistry, short-chain fatty acid (SCFA), gastrointestinal transit ratio and length and intestinal mucosa were analyzed. RESULTS: Dual-Oligo increased the fecal weight, and water content of feces in rats with loperamide-induced constipation. Gastrointestinal transit ratio and length and area of intestinal mucosa significantly increased after treatment with Dual-Oligo in loperamide-induced rats. A high concentration of Dual-Oligo tended to produce more acetic acid than that observed for the control group, and Dual-Oligo affected the production of total SCFA. Bifidobacteria concentration of cecal contents in the high-concentration oligosaccharide (HDO) and low-concentration oligosaccharide (LDO) groups was similar to the result of the normal group. CONCLUSIONS: These results showed that Dual-Oligo is a functional material that is derived from a natural food product and is effective in ameliorating constipation.
Acetic Acid ; Administration, Oral ; Alcian Blue ; Animals ; Chemistry ; Constipation* ; Feces ; Gastrointestinal Transit ; Gravitation ; Humans ; Intestinal Mucosa ; Lactulose ; Loperamide ; Oligosaccharides* ; Posture ; Prebiotics ; Rats* ; Water

BACKGROUND/OBJECTIVES: The accumulation of amyloid-β (Aβ) in the brain is a hallmark of Alzheimer's disease (AD) and plays a key role in cognitive dysfunction. Perilla frutescens var. japonica extract (PFE) and its major compound, rosmarinic acid (RA), have shown antioxidant and anti-inflammatory activities. We investigated whether administration of PFE and RA contributes to cognitive improvement in an Aβ25-35-injected mouse model. MATERIALS/METHODS: Male ICR mice were intracerebroventricularly injected with aggregated Aβ25-35 to induce AD. Aβ25-35-injected mice were fed PFE (50 mg/kg/day) or RA (0.25 mg/kg/day) for 14 days and examined for learning and memory ability through the T-maze, object recognition, and Morris water maze test. RESULTS: Our present study demonstrated that PFE and RA administration significantly enhanced cognition function and object discrimination, which were impaired by Aβ25-35, in the T-maze and object recognition tests, respectively. In addition, oral administration of PFE and RA decreased the time to reach the platform and increased the number of crossings over the removed platform when compared with the Aβ25-35-induced control group in the Morris water maze test. Furthermore, PFE and RA significantly decreased the levels of nitric oxide (NO) and malondialdehyde (MDA) in the brain, kidney, and liver. In particular, PFE markedly attenuated oxidative stress by inhibiting production of NO and MDA in the Aβ25-35-injected mouse brain. CONCLUSIONS: These results suggest that PFE and its active compound RA have beneficial effects on cognitive improvement and may help prevent AD induced by Aβ.
Administration, Oral ; Alzheimer Disease ; Animals ; Brain ; Cognition* ; Discrimination (Psychology) ; Humans ; Kidney ; Learning ; Liver ; Male ; Malondialdehyde ; Memory* ; Mice ; Mice, Inbred ICR ; Nitric Oxide ; Oxidative Stress ; Perilla frutescens* ; Perilla* ; Water

BACKGROUND/OBJECTIVES: The accumulation of amyloid-β (Aβ) in the brain is a hallmark of Alzheimer's disease (AD) and plays a key role in cognitive dysfunction. Perilla frutescens var. japonica extract (PFE) and its major compound, rosmarinic acid (RA), have shown antioxidant and anti-inflammatory activities. We investigated whether administration of PFE and RA contributes to cognitive improvement in an Aβ25-35-injected mouse model. MATERIALS/METHODS: Male ICR mice were intracerebroventricularly injected with aggregated Aβ25-35 to induce AD. Aβ25-35-injected mice were fed PFE (50 mg/kg/day) or RA (0.25 mg/kg/day) for 14 days and examined for learning and memory ability through the T-maze, object recognition, and Morris water maze test. RESULTS: Our present study demonstrated that PFE and RA administration significantly enhanced cognition function and object discrimination, which were impaired by Aβ25-35, in the T-maze and object recognition tests, respectively. In addition, oral administration of PFE and RA decreased the time to reach the platform and increased the number of crossings over the removed platform when compared with the Aβ25-35-induced control group in the Morris water maze test. Furthermore, PFE and RA significantly decreased the levels of nitric oxide (NO) and malondialdehyde (MDA) in the brain, kidney, and liver. In particular, PFE markedly attenuated oxidative stress by inhibiting production of NO and MDA in the Aβ25-35-injected mouse brain. CONCLUSIONS: These results suggest that PFE and its active compound RA have beneficial effects on cognitive improvement and may help prevent AD induced by Aβ.
Administration, Oral ; Alzheimer Disease ; Animals ; Brain ; Cognition* ; Discrimination (Psychology) ; Humans ; Kidney ; Learning ; Liver ; Male ; Malondialdehyde ; Memory* ; Mice ; Mice, Inbred ICR ; Nitric Oxide ; Oxidative Stress ; Perilla frutescens* ; Perilla* ; Water

Phytantriol (PT), ethanol (ET) and water were used to prepare in situ cubic liquid crystal (ISV2). The pseudo-ternary phase diagram of PT-ET-water was constructed and isotropic solution formulations were chosen for further optimization. The physicochemical properties of isotropic solution formulations were evaluated to optimize the composition of ISV2. In situ hexagonal liquid crystals (ISH2) were prepared based on the composition of ISV2 with the addition of vitamin E acetate (VitEA) and the amount of VitEA was optimized by in vitro release behavior. The phase structures of liquid crystalline gels formed by ISV2 and ISH2 in excess water were confirmed by crossed polarized light microscopy and small angle X-ray scattering, respectively. Rheological properties of ISV2 and ISH2 were studied by a DHR-2 rheometer. In vitro drug release studies were conducted by using a dialysis membrane diffusion method. Pharmacokinetics was investigated by determination of sinomenine hydrochloride (SMH) concentration in synovial membrane after intra-articular injection of SMH-loaded ISH2 in adjuvant-induced arthritis rats. The optimal ISV2 (PT/ET/water, 64 : 16 : 20, w/w/w) loaded with 6 mg x g(-1) of SMH showed a suitable pH, injectable and formed a cubic liquid crystalline gel in situ with minimum water absorption in the shortest time. The optimal ISV2 was able to sustain the drug release for 144 h. The optimal ISH2 system was prepared by addition of 5% VitEA into PT in the optimal ISV2 system. This ISH2 (PT/VitEA/ET/water, 60.8 : 3.2 : 16 : 20, w/w/w/w) was an injectable isotropic solution with suitable pH. The new ISH2 was able to sustain the drug release for more than 240 h. Local pharmacokinetics study indicated that the retention time and AUC(0-∞) of ISH2 group were increased significantly compared with that of SMH solution group and the AUC(0-∞) of ISH2 group was 6.01 times higher than that of SMH solution group. The developed ISH2 was suitable for intra-articular injection that may apply to patients in the treatment of rheumatoid arthritis.
Animals ; Chemistry, Pharmaceutical ; Diffusion ; Ethanol ; Fatty Alcohols ; Gels ; Injections, Intra-Articular ; Liquid Crystals ; Morphinans ; administration & dosage ; chemistry ; Rats ; Rheology ; Water ; alpha-Tocopherol

BACKGROUNDPremature ovarian failure (POF) is a disease that affects female fertility but has few effective treatments. Ovarian reserve function plays an important role in female fertility. Recent studies have reported that hydrogen can protect male fertility. Therefore, we explored the potential protective effect of hydrogen-rich water on ovarian reserve function through a mouse immune POF model.

METHODSTo set up immune POF model, fifty female BALB/c mice were randomly divided into four groups: Control (mice consumed normal water, n = 10), hydrogen (mice consumed hydrogen-rich water, n = 10), model (mice were immunized with zona pellucida glycoprotein 3 [ZP3] and consumed normal water, n = 15), and model-hydrogen (mice were immunized with ZP3 and consumed hydrogen-rich water, n = 15) groups. After 5 weeks, mice were sacrificed. Serum anti-Müllerian hormone (AMH) levels, granulosa cell (GC) apoptotic index (AI), B-cell leukemia/lymphoma 2 (Bcl-2), and BCL2-associated X protein (Bax) expression were examined. Analyses were performed using SPSS 17.0 (SPSS Inc., Chicago, IL, USA) software.

RESULTSImmune POF model, model group exhibited markedly reduced serum AMH levels compared with those of the control group (5.41 ± 0.91 ng/ml vs. 16.23 ± 1.97 ng/ml, P = 0.033) and the hydrogen group (19.65 ± 7.82 ng/ml, P = 0.006). The model-hydrogen group displayed significantly higher AMH concentrations compared with that of the model group (15.03 ± 2.75 ng/ml vs. 5.41 ± 0.91 ng/ml, P = 0.021). The GC AI was significantly higher in the model group (21.30 ± 1.74%) than those in the control (7.06 ± 0.27%), hydrogen (5.17 ± 0.41%), and model-hydrogen groups (11.24 ± 0.58%) (all P < 0.001). The GC AI was significantly higher in the model-hydrogen group compared with that of the hydrogen group (11.24 ± 0.58% vs. 5.17 ± 0.41%, P = 0.021). Compared with those of the model group, ovarian tissue Bcl-2 levels increased (2.18 ± 0.30 vs. 3.01 ± 0.33, P = 0.045) and the Bax/Bcl-2 ratio decreased in the model-hydrogen group.

CONCLUSIONSHydrogen-rich water may improve serum AMH levels and reduce ovarian GC apoptosis in a mouse immune POF model induced by ZP3.

Animals ; Anti-Mullerian Hormone ; blood ; Apoptosis ; drug effects ; Female ; Granulosa Cells ; cytology ; Hydrogen ; chemistry ; pharmacology ; Mice ; Mice, Inbred BALB C ; Ovarian Reserve ; drug effects ; physiology ; Ovary ; drug effects ; metabolism ; Primary Ovarian Insufficiency ; blood ; metabolism ; prevention & control ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Water ; administration & dosage ; chemistry ; pharmacology ; Zona Pellucida ; drug effects ; physiology ; bcl-2-Associated X Protein ; metabolism

PURPOSE: We investigated the protective effects of the herbal formulation KH-204 in the bladder of androgen-deprived rats. MATERIALS AND METHODS: Male rats aged eight weeks were randomly divided into four groups, containing eight rats each: sham operation only (normal control group), androgen-deprived only (androgen-deprived control group), and androgen-deprived followed by treatment with 200 mg/kg or 400 mg/kg of KH-204. After 0.5 mg/kg of leuprorelin was subcutaneously injected in the androgen-deprived groups, the oral administration of either distilled water in the two control groups or KH-204 in the treatment group was continued for four weeks. Serum testosterone levels, RhoGEF levels, nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-related parameters, oxidative stress, and histologic changes were evaluated after treatment. RESULTS: Treatment with the herbal formulation KH-204 (1) increased serum testosterone levels; (2) restored the expression of RhoGEFs, endothelial NO synthase, and neuronal NO synthase; (3) increased the expression of superoxide dismutase; and (4) decreased bladder fibrosis. CONCLUSIONS: Our results suggest that the positive effects of KH-204 on the urinary bladder may be attributed to its antioxidant effects or to an elevation in NO-cGMP activity.
Administration, Oral ; Animals ; Antioxidants ; Fibrosis ; Guanosine Monophosphate ; Humans ; Hypogonadism ; Leuprolide ; Male ; Neurons ; Nitric Oxide ; Nitric Oxide Synthase ; Oxidative Stress ; Phytotherapy ; Rats* ; Rho Guanine Nucleotide Exchange Factors ; Superoxide Dismutase ; Testosterone ; Urinary Bladder* ; Water

Gastrodia elata Blume is a well-known kind of natural products used as a folk medicine for thousands of years. However, anti-atopic dermatitis-like effects of G. elata Blume had not been evaluated until now. The aim of the present study is to investigate the protective effects of water extract from the roots of G. elata Blume (GE) on 2, 4-dinitrochlorobenzene-induced atopic dermatitis-like skin lesions using balb/c mice. Combination treatment of GE (at a dose of 12.5 mg/kg body weight by administrated per os + 0.5 mg/cm2 as ointment to apply on ear and dorsal skin) was significantly inhibited spleen weight, ear thickness, levels of serum immunoglobulin E and number of mast cells, compared with that of 2, 4-dinitrochlorobenzene-included groups without GE. Furthermore, combination application by oral administration plus by ointment of GE significantly inhibited the histamine release from rat peritoneal mast cells. These results suggest that combination treatment of oral administration plus ointment form of GE could be helpful as a potentially natural pharmaceutical treatment on atopic-like dermatitis.
Administration, Oral ; Animals ; Biological Products ; Body Weight ; Dermatitis ; Dermatitis, Atopic ; Ear ; Gastrodia* ; Histamine Release ; Immunoglobulin E ; Immunoglobulins ; Mast Cells ; Medicine, Traditional ; Mice* ; Rats* ; Skin* ; Spleen ; Water