In Deok Kong

Biological Role of Anti-aging Protein Klotho.

Klotho-deficient mice have accelerated aging phenotypes, whereas overexpression of Klotho in mice extends lifespan. Klotho is an anti-aging single-pass membrane protein predominantly produced in the kidney, with shedding of the amino-terminal extracellular domain into the systemic circulation. Circulating levels of soluble Klotho decrease with age, and the klotho gene is associated with increased risk of age-related diseases. The three forms of Klotho protein have distinct functions. Membrane Klotho forms a complex with fibroblast growth factor (FGF) receptors, functions as an obligatory co-receptor for FGF23, which is involved in aging and the development of chronic diseases via regulation of Pi and vitamin D metabolism. Secreted Klotho functions as a humoral factor with pleiotropic activities including regulation of oxidative stress, growth factor signaling, and ion homeostasis. Secreted Klotho is also involved in organ protection. The intracellular form of Klotho suppresses inflammation-mediated cellular senescence and mineral metabolism. Herein we provide a brief overview of the structure and function and recent research about Klotho.

Serum levels of angiopoietin-related growth factor are increased in metabolic syndrome.

Angiopoietin-related growth factor (AGF), a novel hepatokine, showed therapeutic implications in diabetic and obese animal models. Although the physiologic functions of human AGF have not yet been identified, serum levels of AGF displayed up-regulation in groups with diseases including preeclampsia and diabetes; and there was little association between genetic variability of AGF and metabolic syndrome-related phenotypes. We analyzed serum levels of AGF and other biochemical and anthropometric markers in 216 Korean persons--the numbers of healthy controls and those with metabolic syndrome were 138 and 78, respectively--to confirm research data from animal models. Women had higher AGF than men (265.01 vs 311.84 ng/mL, P = .003). This study showed that serum AGF levels were significantly higher in subjects with metabolic syndrome (325.89 ng/mL) than those in the healthy group (272.44 ng/mL) (P = .003). Among the components of metabolic syndrome, subjects with high waist circumference or decreased high-density lipoprotein cholesterol had significantly increased serum AGF (271.92 vs 313.68 ng/mL, P = .013; 271.01 vs 310.58 ng/mL, P = .023, respectively). According to multivariate regression analysis, metabolic syndrome itself and waist circumference could be used, in addition to sex and age, as predictors of serum AGF level. In conclusion, serum AGF levels were paradoxically increased in metabolic syndrome, in comparison with data from animal experiments and data on sex, age, and waist circumference. Metabolic syndrome can be a predictor of serum AGF level. Further studies are needed to explore the possibilities of compensatory up-regulation, or AGF resistance, to explain the physiologic roles of AGF in metabolic syndrome.

Dual effect of ATP on glucose-induced insulin secretion in HIT-T15 cells

Objectives: The study investigated the dual effect of purinergic nucleotides on the secretion of insulin from pancreatic &bgr; cells. Methods: The level of insulin secretion in HIT-T15 cells of static incubation was measured using a radioimmunoassay. Results: The adenine nucleotides reduced the level of glucose-induced insulin secretion in a concentration-dependent manner, and the relative potency order (IC50; &mgr;M) was BzATP (6.9) > ATP (20.4) ≥ &agr;, &bgr;-methylene ATP (23.3) ≥ 2-methylthio-ATP (24.9). Suramin and PPADS (200 &mgr;M), which are blockers of the purinergic receptors, had a little influence on the activity of ATP. However, the inhibitory effect of ATP was reversed by preincubation with oxidized ATP (200 &mgr;M), which is a P2X7 antagonist. The level of insulin secretion in these preincubated cells exposed to the purinergic nucleotides increased in the following order: ATP > &agr;, &bgr;-methylene ATP ≥ 2-methylthio-ATP. A pretreatment with foskolin and PDBu (100 nM) potentiated the increasing effect of ATP on insulin secretion. The Western blotting showed the expression of P2X7 and P2Y11 receptors. Conclusions: Purinergic stimulation has inhibitory activity on glucose-dependent insulin secretion through the activation of the P2X7 receptor, whereas it has enhancing effect through the activation of the P2Y11 receptor in HIT-T15 cells.

Expression profiles of high voltage-activated calcium channels in sympathetic and parasympathetic pelvic ganglion neurons innervating the urogenital system.

Among the autonomic ganglia, major pelvic ganglia (MPG) innervating the urogenital system are unique because both sympathetic and parasympathetic neurons are colocalized within one ganglion capsule. Sympathetic MPG neurons are discriminated from parasympathetic ones by expression of low voltage-activated Ca2+ channels that primarily arise from T-type α1H isoform and contribute to the generation of low-threshold spikes. Until now, however, expression profiles of high voltage-activated (HVA) Ca2+ channels in these two populations of MPG neurons remain unknown. Thus, in the present study, we dissected out HVA Ca2+ channels using pharmacological and molecular biological tools. Reverse transcription-polymerase chain reaction analysis showed that MPG neurons contained transcripts encoding all of the known HVA Ca2+ channel isoforms (α1B, α1C, α1D and α1E), with the exception of α1A. Western blot analysis and pharmacology with ω-agatoxin IVA (1 μM) confirmed that MPG neurons lack the α1A Ca2+ channels. Unexpectedly, the expression profile of HVA Ca2+ channel isoforms was identical in the sympathetic and parasympathetic neurons of the MPG. Of the total Ca2+ currents, ω-conotoxin GVIA-sensitive N-type (α1B) currents constituted 57 ± 5% (n = 9) and 60 ± 3% (n = 6), respectively; nimodipine-sensitive L-type (α1C and α1D) currents made up 17 ± 4% and 14 ± 2%, respectively; and nimodipine-resistant and ω-conotoxin GVIA-resistant R-type currents were 25 ± 3% and 22 ± 2%, respectively. The R-type Ca2+ currents were sensitive to NiCl2 (IC50 = 22 ± 0.1 μM) but not to SNX-482, which was able to potently (IC50 = 76 ± 0.4 nM) block the recombinant α1E/β2a/α2δ Ca2+ currents expressed in human embryonic kidney 293 cells. Taken together, our data suggest that sympathetic and parasympathetic MPG neurons share a similar but unique profile of HVA Ca2+ channel isoforms.

Characteristics of P2X7-like receptor activated by adenosine triphosphate in HIT-T15 cells.

Objectives: The study examined the presence of a P2X7 receptor subtype and its functional roles in pancreatic &bgr; cells. Methods: In a hamster &bgr;-cell line, HIT-T15 cells, purinergic stimulation was investigated using fluorometry, electrophysiology, flow cytometry, and electrophoresis. Results: Adenosine triphosphate (ATP) and 2&vprime;-3&vprime;-O-(4-benzoylbenzoyl)adenosine 5&vprime;-triphosphate (BzATP) increased in the intracellular free Ca2+ concentration, with an EC50 of 398.0 and 136.6 &mgr;M, respectively. Preincubation with oxidized ATP, a P2X7 receptor antagonist, inhibited the ATP- and BzATP-induced increase in the intracellular Ca2+ level. The BzATP-induced increase in the intracellular Ca2+ level was dependent on the extracellular Ca2+ concentration. The extracellular Mg2+ had a significant effect on the ATP-induced increase in the intracellular Ca2+ level. The ATP also induced depolarization like high potassium chloride. In the voltage-clamp experiments, ATP evoked inward currents, which were reversed at almost 0 mV. The ATP stimulated the slow influx of ethidium bromide, indicating permeability to larger molecules. Flow cytometry showed that the number of hypodiploid cells (A0), which are indicative of apoptosis, increased when the cells were exposed to ATP for 24 hours. The ATP also induced DNA fragmentation. Conclusions: These results suggest that the HIT-T15 cells have endogenous P2X7-like receptors and that purinergic stimulation increased the level of intracellular Ca2+, depolarization, inward current, permeability, and apoptosis.

Effects of exercise training on circulating levels of Dickkpof-1 and secreted frizzled-related protein-1 in breast cancer survivors: A pilot single-blind randomized controlled trial.

Background Wingless and integration site growth factor (Wnt) signaling is a tumorigenesis-related signaling pathway. Dickkpof-1 (DKK1) and secreted frizzled-related protein-1 (SFRP1) are endogenous negative regulators of Wnt/β-catenin signaling. Accumulating evidence indicates that higher serum levels of DKK1 are correlated with poor prognosis of various types of cancer. Here, we investigated whether exercise training causes changes in the serum levels of DKK1 and SFRP1 in patients with breast cancer. Methods Twenty-four breast cancer survivors, after chemo- or radiotherapy, participated in this single-blind randomized, controlled pilot study. Subjects were randomized to either an exercise program or a control group for 12 weeks and completed pre- and post-training tests for health-related fitness and body composition as well as blood biomarkers. The serum levels of DKK1 and SFRP1 were measured using enzyme-linked immunosorbent assay as the primary outcome. Results Exercise training for 12 weeks remarkably increased muscle strength, endurance, and flexibility and decreased body fat percentage, waist circumference, and visceral fat area (all p < 0.05). Exercise training lowered serum insulin levels and leptin/adiponectin ratios (all p < 0.05). The levels of DKK1 and SFRP1 were also significantly decreased by exercise training in breast cancer survivors (all p < 0.01). Conclusions Our results indicate that DKK1 and SFRP1 may be potentially useful biomarkers for evaluating the beneficial effects of long-term exercise on physical fitness and metabolism as well as the prognosis of patients with cancer. Trial registration ClinicalTrials.gov NCT02895178

Circulating irisin levels as a predictive biomarker for sarcopenia: A cross-sectional community-based study

Myokines are peptides released by the skeletal muscle, and have gained popularity as potential biomarkers for sarcopenia. Irisin is a recently identified myokine, but its role in pathological sarcopenia remains unclear. We investigated the validity and accuracy of circulating irisin levels as a potential biomarker for sarcopenia.

Intense Walking Exercise Affects Serum IGF-1 and IGFBP3.

Background Insulin-like growth factor (IGF-1) is associated with chronic diseases such as diabetes, cardiovascular disease, and hypertension, as well as muscle dysfunction. Previous studies of exercise interventions yield controversial results regarding plasma IGF-1, IGFBP3, and IGF-1/IGFBP3 ratio. In this study, we examined whether 100 km walking exercise affects serum levels of IGF-1 and IGFBP3 and IGF-1/IGFBP3 ratio. We also investigated several metabolic-related blood parameters before and after walking. Methods Participants were 14 healthy middle aged men (41.0 ± 6.78 years of age). We assessed body composition and measured metabolic-related blood indicators, such as such as lipid profiles, glucose, renal and hepatic metabolic bio-markers before and after a 100 km walking race. Blood samples from all participants were taken before and immediately after the walkathon. We also analyzed serum levels of IGF-1 and IGFBP3, and calculated the IGF-1/IGFBP3 ratio. Results After participants completed a 100 km walking race, some of their metabolic profiles were markedly changed. Serum levels of IGF-1 and IGFBP3 were significantly decreased, and therefore the IGF-1/IGFBP3 ratio also decreased before and after 100 km of walking. Conclusion Our results indicate that intense walking exercise affects serum levels of IGF-1 and IGFBP3 as well as metabolic bio-markers including high density cholesterol, glucose and triglycerides.

Qualitative muscle mass index as a predictor of skeletal muscle function deficit in Asian older adults

The present cross‐sectional study was carried out among community‐dwelling Koreans to determine the validity of various muscle mass indices and to propose more clinically relevant diagnostic criteria.

Effects of Exercise Training on Physical Fitness and Biomarker Levels in Breast Cancer Survivors

Background Exercise has been identified as a beneficial intervention to enhance quality of life in breast cancer survivors. In addition, there has been a noteworthy increase in studies emphasizing the benefits of exercise in cancer. We sought to summarize the empirical literature concerning the effects of exercise on physical fitness and biomarker levels in breast cancer survivors according to the type of exercise. Methods We searched PubMed and PubMed Central for studies on the association of exercise with the levels of various biomarkers and physical fitness in breast cancer survivors. We investigated the effects of different types of exercise (aerobic, resistance, or combined) on breast cancer survivors, with changes in physical fitness and biomarker levels as the primary outcomes. Results In total, 118 research papers published from 2012 to July 2016 were retrieved from PubMed and PubMed Central. Of these, 24 papers met our inclusion criteria. All types of exercise were found to improve physical fitness in breast cancer survivors. However, the results with regard to biomarkers were controversial. Conclusion The findings of this review suggest that combined exercise is associated with better outcomes than aerobic or resistance exercise alone in breast cancer survivors.