Serum Phosphorus Concentration and Coronary Artery Calcification in Subjects without Renal Dysfunction

Serum phosphorus (P) concentration is associated with coronary artery calcification (CAC) as well as cardiovascular events in patients with chronic kidney disease. It has been suggested that this relationship is extended to subjects without renal dysfunction, but further explorations in diverse races and regions are still needed. We performed a cross-sectional study of 2,509 Korean subjects (Far Eastern Asian) with an estimated glomerular filtration rate of ≥60 ml/min/1.73m² and who underwent coronary computerized tomography. Serum P concentration was divided into pre-determined 4 categories: ≤3.2, 3.2< to ≤3.6, 3.6< to ≤4.0 and >4.0 mg/dL. Agatston score (AS), an index of CAC, was divided into 3 categories: 0, 0< to ≤100, and >100. A multinomial logit model (baseline outcome: AS = 0) was applied to estimate the odds ratio (OR) for each serum P category (reference: ≤3.2mg/dL). Mean age of subjects was 53.5±9.1 years and 36.9% were female. In the adjusted model, serum P concentration of 3.6< to ≤4.0 mg/dL and >4.0 mg/dL showed high ORs for AS of >100 [OR: 1.58, 95% confidence interval (CI): 1.04–2.40 and OR: 2.11, 95% CI: 1.34–3.32, respectively]. A unit (mg/dL) increase in serum P concentration was associated with 50% increase in risk of AS >100 (OR: 1.50, 95% CI: 1.16–1.94). A higher serum P concentration, even within a normal range, may be associated with a higher CAC in subjects with normal renal function.     

Phenyl 2‐pyridyl ketoxime induces cellular senescence‐like alterations via nitric oxide production in human diploid fibroblasts

Phenyl‐2‐pyridyl ketoxime (PPKO) was found to be one of the small molecules enriched in the extracellular matrix of near‐senescent human diploid fibroblasts (HDFs). Treatment of young HDFs with PPKO reduced the viability of young HDFs in a dose‐ and time‐dependent manner and resulted in senescence‐associated β‐galactosidase (SA‐β‐gal) staining and G2/M cell cycle arrest. In addition, the levels of some senescence‐associated proteins, such as phosphorylated ERK1/2, caveolin‐1, p53, p16^ink4a, and p21^waf1, were elevated in PPKO‐treated cells. To monitor the effect of PPKO on cell stress responses, reactive oxygen species (ROS) production was examined by flow cytometry. After PPKO treatment, ROS levels transiently increased at 30 min but then returned to baseline at 60 min. The levels of some antioxidant enzymes, such as catalase, peroxiredoxin II and glutathione peroxidase I, were transiently induced by PPKO treatment. SOD II levels increased gradually, whereas the SOD I and III levels were biphasic during the experimental periods after PPKO treatment. Cellular senescence induced by PPKO was suppressed by chemical antioxidants, such as N‐acetylcysteine, 2,2,6,6‐tetramethylpiperidinyloxy, and L‐buthionine‐(S,R)‐sulfoximine. Furthermore, PPKO increased nitric oxide (NO) production via inducible NO synthase (iNOS) in HDFs. In the presence of NOS inhibitors, such as L‐NG‐nitroarginine methyl ester and L‐NG‐monomethylarginine, PPKO‐induced transient NO production and SA‐β‐gal staining were abrogated. Taken together, these results suggest that PPKO induces cellular senescence in association with transient ROS and NO production and the subsequent induction of senescence‐associated proteins .     

Inhibition of soluble epoxide hydrolase activity by compounds isolated from the aerial parts of Glycosmis stenocarpa

The aim of this study is to search for soluble epoxide hydrolase (sEH) inhibitors from natural plants, bioassay-guided fractionation of lipophilic n-hexane and chloroform layers of an extract of the aerial parts of Glycosmis stenocarpa led to the isolation of 12 compounds (1–12) including murrayafoline-A (1), isomahanine (2), bisisomahanine (3), saropeptate (4), (24?S)-ergost-4-en-3,6-dione (5), stigmasta-4-en-3,6-dion (6), stigmast-4-en-3-one (7), β-sitosterol (8), 24-methylpollinastanol (9), trans-phytol (10), neosarmentol III (11) and (+)-epiloliolide (12). Their structures were elucidated on the basis of spectroscopic data. Among them, neosarmentol III (11) was isolated from nature for the first time. All the isolated compounds were evaluated for their inhibitory activity against sEH. Among isolated carbazole-type compounds, isomahanine (2) and bisisomahanine (3) were identified as a potent inhibitor of sEH, with IC₅₀ values of 22.5?±?1.7 and 7.7?±?1.2?µM, respectively. Moreover, the inhibitory action of 2 and 3 represented mixed-type enzyme inhibition.     

Intestinal immunostimulatory activity of neutral polysaccharide isolated from traditionally fermented Korean brown rice vinegar

In this study, diverse intestinal immunostimulatory activities were demonstrated for polysaccharides (KBV-CP) isolated from Korean brown rice vinegar. Monosaccharide composition analysis indicated that KBV-CP was composed mainly of neutral sugar units, primarily glucose and mannose. In vitro, KBV-CP significantly augmented the productions of immunoglobulin A (IgA) and IgA-related cytokines such as interleukin-6 (IL-6) and transforming growth factor-β (TGF-β) in a dose-dependent manner. Furthermore, results of an in vitro co-culture system of intestinal Caco-2 cells and RAW 264.7 macrophage cells suggested that KBV-CP is not only cytotoxic to Caco-2 cells but also capable of being transported across the small intestinal barrier. Oral administration of KBV-CP every other day for 20 days induced the IgA production by Peyer’s patch cells as well as in intestinal fluid and fecal extract. In addition, the production of IgA-related cytokines such as TGF-β and IL-6, and granulocyte macrophage colony-stimulating factor was triggered.     

Production of genetically modified pigs expressing human insulin and C-peptide as a source of islets for xenotransplantation

Transgenic Research - Islet xenotransplantation is a promising treatment for type I diabetes. Numerous studies of islet xenotransplantation have used pig-to-nonhuman primate transplantation models....     

Investigation of B,C-ring truncated deguelin derivatives as heat shock protein 90 (HSP90) inhibitors for use as anti-breast cancer agents

On the basis of deguelin, a series of the B,C-ring truncated surrogates with N-substituted amide linkers were investigated as HSP90 inhibitors. The structure activity relationship of the template was studied by incorporating various substitutions on the nitrogen of the amide linker and examining their HIF-1α inhibition. Among them, compound 57 showed potent HIF-1α inhibition and cytotoxicity in triple-negative breast cancer lines in a dose-dependent manner. Compound 57 downregulated expression and phosphorylation of major client proteins of HSP90 including AKT, ERK and STAT3, indicating that its antitumor activity was derived from the inhibition of HSP90 function. The molecular modeling of 57 demonstrated that 57 bound well to the C-terminal ATP-binding pocket in the open conformation of the hHSP90 homodimer with hydrogen bonding and pi-cation interactions. Overall, compound 57 is a potential antitumor agent for triple-negative breast cancer as a HSP90 C-terminal inhibitor.     

ABCA3 is critical for lamellar body biogenesis in vivo

Mutations in ATP-binding cassette transporter A3 (human ABCA3) protein are associated with fatal respiratory distress syndrome in newborns. We therefore characterized mice with targeted disruption of the ABCA3 gene. Homozygous Abca3-/- knock-out mice died soon after birth, whereas most of the wild type, Abca3+/+, and heterozygous, Abca3+/-, neonates survived. The lungs from E18.5 and E19.5 Abca3-/- mice were less mature than wild type. Alveolar type 2 cells from Abca3-/- embryos contained no lamellar bodies, and expression of mature SP-B protein was disrupted when compared with the normal lung surfactant system of wild type embryos. Small structural and functional differences in the surfactant system were seen in adult Abca3+/- compared with Abca3+/+ mice. The heterozygotes had fewer lamellar bodies, and the incorporation of radiolabeled substrates into newly synthesized disaturated phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, and phosphatidylserine in both lamellar bodies and surfactant was lower than in Abca3+/+ mouse lungs. In addition, since the fraction of near term Abca3-/- embryos was significantly lower than expected from Mendelian inheritance ABCA3 probably plays roles in development unrelated to surfactant. Collectively, these findings strongly suggest that ABCA3 is necessary for lamellar body biogenesis, surfactant protein-B processing, and lung development late in gestation.