A Decreased Level of Serum Soluble Klotho Is an Independent Biomarker Associated with Arterial Stiffness in Patients with Chronic Kidney Disease

Background

Klotho was originally identified in a mutant mouse strain unable to express the gene that consequently showed shortened life spans. In humans, low serum Klotho levels are related to the prevalence of cardiovascular diseases in community-dwelling adults. However, it is unclear whether the serum Klotho levels are associated with signs of vascular dysfunction such as arterial stiffness, a major determinant of prognosis, in human subjects with chronic kidney disease (CKD).

Methods

We determined the levels of serum soluble Klotho in 114 patients with CKD using ELISA and investigated the relationship between the level of Klotho and markers of CKD-mineral and bone disorder (CKD-MBD) and various types of vascular dysfunction, including flow-mediated dilatation, a marker of endothelial dysfunction, ankle-brachial pulse wave velocity (baPWV), a marker of arterial stiffness, intima-media thickness (IMT), a marker of atherosclerosis, and the aortic calcification index (ACI), a marker of vascular calcification.

Results

The serum Klotho level significantly correlated with the 1,25-dihydroxyvitamin D level and inversely correlated with the parathyroid hormone level and the fractional excretion of phosphate. There were significant decreases in serum Klotho in patients with arterial stiffness defined as baPWV≥1400 cm/sec, atherosclerosis defined as maximum IMT≥1.1 mm and vascular calcification scores of ACI>0%. The serum Klotho level was a significant determinant of arterial stiffness, but not endothelial dysfunction, atherosclerosis or vascular calcification, in the multivariate analysis in either metabolic model, the CKD model or the CKD-MBD model. The adjusted odds ratio of serum Klotho for the baPWV was 0.60 (p = 0.0075).

Conclusions

Decreases in the serum soluble Klotho levels are independently associated with signs of vascular dysfunction such as arterial stiffness in patients with CKD. Further research exploring whether therapeutic approaches to maintain or elevate the Klotho level could improve arterial stiffness in CKD patients is warranted.     

Inhibition of the NAD-Dependent Protein Deacetylase SIRT2 Induces Granulocytic Differentiation in Human Leukemia Cells

Sirtuins, NAD-dependent protein deacetylases, play important roles in cellular functions such as metabolism and differentiation. Whether sirtuins function in tumorigenesis is still controversial, but sirtuins are aberrantly expressed in tumors, which may keep cancerous cells undifferentiated. Therefore, we investigated whether the inhibition of sirtuin family proteins induces cellular differentiation in leukemic cells. The sirtuin inhibitors tenovin-6 and BML-266 induce granulocytic differentiation in the acute promyelocytic leukemia (APL) cell line NB4. This differentiation is likely caused by an inhibition of SIRT2 deacetylase activity, judging from the accumulation of acetylated α-tubulin, a major SIRT2 substrate. Unlike the clinically used differentiation inducer all-trans retinoic acid, tenovin-6 shows limited effects on promyelocytic leukemia–retinoic acid receptor α (PML-RAR-α) stability and promyelocytic leukemia nuclear body formation in NB4 cells, suggesting that tenovin-6 does not directly target PML-RAR-α activity. In agreement with this, tenovin-6 induces cellular differentiation in the non-APL cell line HL-60, where PML-RAR-α does not exist. Knocking down SIRT2 by shRNA induces granulocytic differentiation in NB4 cells, which demonstrates that the inhibition of SIRT2 activity is sufficient to induce cell differentiation in NB4 cells. The overexpression of SIRT2 in NB4 cells decreases the level of granulocytic differentiation induced by tenovin-6, which indicates that tenovin-6 induces granulocytic differentiation by inhibiting SIRT2 activity. Taken together, our data suggest that targeting SIRT2 is a viable strategy to induce leukemic cell differentiation.     

Comparison of Barium and Arsenic Concentrations in Well Drinking Water and in Human Body Samples and a Novel Remediation System for These Elements in Well Drinking Water

Health risk for well drinking water is a worldwide problem. Our recent studies showed increased toxicity by exposure to barium alone (≤700 µg/L) and coexposure to barium (137 µg/L) and arsenic (225 µg/L). The present edition of WHO health-based guidelines for drinking water revised in 2011 has maintained the values of arsenic (10 µg/L) and barium (700 µg/L), but not elements such as manganese, iron and zinc. Nevertheless, there have been very few studies on barium in drinking water and human samples. This study showed significant correlations between levels of arsenic and barium, but not its homologous elements (magnesium, calcium and strontium), in urine, toenail and hair samples obtained from residents of Jessore, Bangladesh. Significant correlation between levels of arsenic and barium in well drinking water and levels in human urine, toenail and hair samples were also observed. Based on these results, a high-performance and low-cost adsorbent composed of a hydrotalcite-like compound for barium and arsenic was developed. The adsorbent reduced levels of barium and arsenic from well water in Bangladesh and Vietnam to <7 µg/L within 1 min. Thus, we have showed levels of arsenic and barium in humans and propose a novel remediation system.     

Morphology and Molecular Phylogeny of a New Marine,Sand-dwelling Dinoflagellate Genus,Pachena (Dinophyceae), with Descriptions of Three New Species

Marine benthic dinoflagellates are interesting not only because some epiphytic genera can cause harmful algal blooms but also for understanding dinoflagellate evolution and diversification. Our understanding of their biodiversity is far from complete, and many thecate genera have unusual tabulation patterns that are difficult to relate to the diverse known phytoplankton taxa. A new sand-dwelling genus, Pachena gen. nov., is described based on morphological and DNA sequence data. Three species were discovered in distant locations and are circumscribed, namely, P. leibnizii sp. nov. from Canada, P. abriliae sp. nov. from Spain, and P. meriddae sp. nov. from Italy. All species are tiny (about 9–23 μm long) and heterotrophic. Species are characterized by their tabulation (APC 4′ 3a 6′′ 5c 5s 5′′′ 2′′′′), an apical hook covering the apical pore, an ascending cingulum, and a sulcus with central list. The first anterior intercalary plate is uniquely “sandwiched” between two plates. The species share these features and differ in the relative sizes and arrangements of their plates, especially on the epitheca. The ornamentation of thecal plates is species-specific. The new molecular phylogenies based on SSU and LSU rDNA sequences contribute to understanding the evolution of the planktonic relatives of Pachena, the Thoracosphaeraceae.     

Effects of Zinc Acetate on Serum Zinc Concentrations in Chronic Liver Diseases: a Multicenter,Double-Blind,Randomized, Placebo-Controlled Trial and a Dose Adjustment Trial

Biological Trace Element Research - The essential trace element zinc maintains liver functions. Liver diseases can alter overall zinc concentrations, and hypozincemia is associated with various...     

α-Amylase expressed in human small intestinal epithelial cells is essential for cell proliferation and differentiation

α-Amylase, which plays an essential role in starch degradation, is expressed mainly in the pancreas and salivary glands. Human α-amylase is also detected in other tissues, but it is unclear whether the α-amylase is endogenously expressed in each tissue or mixed exogenously with one expressed by the pancreas or salivary glands. Furthermore, the biological significance of these α-amylases detected in tissues other than the pancreas and salivary glands has not been elucidated. We discovered that human α-amylase is expressed in intestinal epithelial cells and analyzed the effects of suppressing α-amylase expression. α-Amylase was found to be expressed at the second-highest messenger RNA level in the duodenum in human normal tissues after the pancreas. α-Amylase was detected in the cell extract of Caco-2 intestinal epithelial cells but not secreted into the culture medium. The amount of α-amylase expressed increased depending on the length of the culture of Caco-2 cells, suggesting that α-amylase is expressed in small intestine epithelial cells rather than the colon because the cells differentiate spontaneously upon reaching confluence in culture to exhibit the characteristics of small intestinal epithelial cells rather than colon cells. The α-amylase expressed in Caco-2 cells had enzymatic activity and was identified as AMY2B, one of the two isoforms of pancreatic α-amylase. The suppression of α-amylase expression by small interfering RNA inhibited cell differentiation and proliferation. These results demonstrate for the first time that α-amylase is expressed in human intestinal epithelial cells and affects cell proliferation and differentiation. This α-amylase may induce the proliferation and differentiation of small intestine epithelial cells, supporting a rapid turnover of cells to maintain a healthy intestinal lumen.     

Evidence for expression of 11β-hydroxysteroid dehydrogenase type3 (HSD11B3/HSD11B1L) in neonatal pig testis

11β-hydroxysteroid dehydrogenase (HSD11B) catalyzes the interconversion between active and inactive glucocorticoid, and is known to exist as two distinct isozymes: HSD11B1 and HSD11B2. A third HSD11B isozyme, HSD11B1L (SCDR10b), has recently been identified. Human HSD11B1L, which was characterized as a unidirectional NADP⁺-dependent cortisol dehydrogenase, appears to be specifically expressed in the brain. We previously reported that HSD11B1 and abundant HSD11B2 isozymes are expressed in neonatal pig testis and the Km for cortisol of NADP⁺-dependent dehydrogenase activity of testicular microsomes obviously differs from the same activity catalyzed by HSD11B1 from pig liver microsomes. Therefore, we hypothesized that the neonatal pig testis also expresses the third type of HSD11B isozyme, and we herein examined further evidence regarding the expression of HSD11B1L. (1) The inhibitory effects of gossypol and glycyrrhetinic acid on pig testicular microsomal NADP⁺-dependent cortisol dehydrogenase activity was clearly different from that of pig liver microsomes. (2) A highly conserved human HSD11B1L sequence was observed by RT-PCR in a pig testicular cDNA library. (3) mRNA, which contains the amplified sequence, was evaluated by real-time PCR and was most strongly expressed in pig brain, and at almost the same levels in the kidney as in the testis, but at lower levels in the liver. Based on these results, neonatal pig testis appears to express glycyrrhetinic acid-resistant HSD11B1L as a third HSD11B isozyme, and it may play a physiologically important role in cooperation with the abundantly expressed HSD11B2 isozyme in order to prevent Leydig cell apoptosis or GC-mediated suppression of testosterone production induced by high concentrations of activated GC in neonatal pig testis.     

Ab initio fragment molecular orbital calculations on the specific interactions between human,mouse and rat PPARα and GW409544

To elucidate the specific interactions between the peroxisome proliferator-activated receptor (PPARα) and ligand GW409544 (GW), we obtained the solvated structures of the PPARα+GW complexes for human, mouse and rat by classical molecular mechanics calculations, and investigated their electronic properties by ab initio fragment molecular orbital calculations. The results indicate that the positively charged amino acids (Lys and Arg) of PPARα make a major contribution to the binding between PPARα and GW. In addition, it was clarified that Ser280 and Tyr314 of human and rat PPARα have a large attractive interaction with GW, while Ser280, Tyr314 and His440 of mouse PPARα have large interaction. These results on the difference in specific interactions between human and mouse/rat PPARα will be useful for predicting the effects of new chemicals on the human body based on the biomedical studies for the experimental animals such as mouse and rat.     

Functional tooth units and nutritional status of older people in care homes in Indonesia

Gerodontology 2012; doi: 10.1111/j.1741‐2358.2012.00673.x Functional tooth units and nutritional status of older people in care homes in Indonesia Objectives: To investigate the relationship between functional tooth units (FTUs) and nutritional status. Methods: One hundred females (mean age: 72.4 ± 8.2 years) at four private care homes in Jakarta, Indonesia were interviewed and clinically examined. The oral examination included the assessment of teeth, prosthetic status, and number of FTUs. The total number of FTUs was further divided by tooth composition: natural tooth against natural tooth (NN‐FTUs), natural tooth against denture (ND‐FTUs), and denture against denture (DD‐FTUs). Nutritional status was evaluated using the body mass index (BMI) and the Mini Nutritional Assessment (MNA). Results: The mean numbers of teeth present, NN‐FTUs, ND‐FTUs, DD‐FTUs, and total FTUs were 13.1 ± 10.4, 1.7 ± 3.0, 1.2 ± 3.3, 0.4 ± 1.2 and 3.3 ± 4.4, respectively. The mean BMI and MNA scores were 24.8 ± 5.0 and 22.6 ± 2.8, respectively. Subjects with a normal BMI had a significantly higher total number of FTUs (3.6 ± 4.6) compared with underweight subjects (0.1 ± 0.3). Subjects with a normal MNA had a significantly higher number of NN‐FTU (2.6 ± 3.7) compared to those who were at risk or in a state of under‐nutrition (1.2 ± 2.4). Conclusion: This study revealed significant relationships between the number of FTUs and nutritional status. Keeping the posterior occlusion should be emphasized in order to maintain good nutritional status in older subjects.