Seung Han Baek

CHIP Promotes Human Telomerase Reverse Transcriptase Degradation and Negatively Regulates Telomerase Activity

The maintenance of eukaryotic telomeres requires telomerase, which is minimally composed of a telomerase reverse transcriptase (TERT) and an associated RNA component. Telomerase activity is tightly regulated by expression of human (h) TERT at both the transcriptional and post-translational levels. The Hsp90 and p23 molecular chaperones have been shown to associate with hTERT for the assembly of active telomerase. Here, we show that CHIP (C terminus of Hsc70-interacting protein) physically associates with hTERT in the cytoplasm and regulates the cellular abundance of hTERT through a ubiquitin-mediated degradation. Overexpression of CHIP prevents nuclear translocation of hTERT and promotes hTERT degradation in the cytoplasm, thereby inhibiting telomerase activity. In contrast, knockdown of endogenous CHIP results in the stabilization of cytoplasmic hTERT. However, it does not affect the level of nuclear hTERT and has no effect on telomerase activity and telomere length. We further show that the binding of CHIP and Hsp70 to hTERT inhibits nuclear translocation of hTERT by dissociating p23. However, Hsp90 binding to hTERT was not affected by CHIP overexpression. These results suggest that CHIP can remodel the hTERT-chaperone complexes. Finally, the amount of hTERT associated with CHIP peaks in G2/M phases but decreases during S phase, suggesting a cell cycle-dependent regulation of hTERT. Our data suggest that CHIP represents a new pathway for modulating telomerase activity in cancer.

Beneficial immunostimulatory effect of short-term Chlorella supplementation: enhancement of Natural Killer cell activity and early inflammatory response (Randomized, double-blinded, placebo-controlled trial)

BackgroundIn vitro and animal studies have demonstrated that Chlorella is a potent biological response modifier on immunity. However, there were no direct evidences for the effect of Chlorella supplementation on immune/inflammation response in healthy humans.MethodsThis study was designed for an 8-week randomized, double-blinded, placebo-controlled trial: 5g of Chlorella (n=23) or Placebo (n=28) as form of tablets. Mainly, cytotoxic activities of Natural killer (NK) cells and serum concentrations of interferon-γ, interleukin-1β and interleukin-12 were measured.ResultsAfter the 8-week, serum concentrations of interferon-γ (p<0.05) and interleukin-1β (p<0.001) significantly increased and that of interleukin-12 (p<0.1) tended to increase in the Chlorella group. The increments of these cytokines after the intervention were significantly bigger in the Chlorella group than those in the placebo group. In addition, NK cell activities (%) were significantly increased in Chlorella group, but not in Placebo group. The increments of NK cell activities (%) were also significantly bigger in the Chlorella group than the placebo group. Additionally, changed levels of NK cell activity were positively correlated with those of serum interleukin-1β (r=0.280, p=0.047) and interferon-γ (r=0.271, p<0.005). Signficantly positive correlations were also observed among the changed levels of serum cytokines; between interferon-γ and interleukin-1β (r=0.448, p<0.001), between interleukin-12 and interleukin-1β (r=0.416, p=0.003) and between interleukin-12 and interferon-γ (r=0.570, p<001).ConclusionThese results may suggest a beneficial immunostimulatory effect of short-term Chlorella supplementation which enhances the NK cell activity and produces interferon-γ and interleukin-12 as well as interleukin-1β, the Th-1 cell-induced cytokines in healthy people.

Serum phospholipid monounsaturated fatty acid composition and Δ-9-desaturase activity are associated with early alteration of fasting glycemic status

Because alterations in blood fatty acid (FA) composition by dietary lipids are associated with insulin resistance and related metabolic disorders, we hypothesized that serum phospholipid FA composition would reflect the early alteration of fasting glycemic status, even in people without metabolic syndrome (MetS). To examine this hypothesis, serum phospholipid FA, desaturase activities, fasting glycemic status, and cardiometabolic parameters were measured in study participants (n = 1022; 30-69 years; male, n = 527; female, n = 495; nondiabetics without disease) who were stratified into normal fasting glucose (NFG) and impaired fasting glucose (IFG) groups. Total monounsaturated FA (MUFA), oleic acid (OA; 18:1n-9), dihomo-γ-linolenic acid (DGLA; 20:3n-6), Δ-9-desaturase activity (D9D; 18:1n-9/18:0), and DGLA/linoleic acid (20:3n-6/18:2n-6) in serum phospholipids were significantly higher in IFG subjects than NFG controls. Study subjects were subdivided into 4 groups, based on fasting glucose levels and MetS status. Palmitoleic acid (16:1n-7) was highest in IFG-MetS and lowest in NFG-non-MetS subjects. Oleic acid and D9D were higher in IFG-MetS than in the other 3 groups. Dihomo-γ-linolenic acid and DGLA/linoleic acid were higher in MetS than in non-MetS, regardless of fasting glucose levels. The high-sensitivity C-reactive proteins (hs-CRPs) and 8-epi-prostaglandin-F2α were higher in IFG than in NFG, regardless of MetS status. Oxidized low-density lipoproteins were higher in IFG-MetS than in the other 3 groups. Total MUFAs, OA, and D9D were positively correlated with homeostasis model assessment of insulin resistance, fasting glucose, triglyceride, hs-CRP, and 8-epi-prostaglandin-F2α. Palmitoleic acid was positively correlated with triglyceride and hs-CRP. Lastly, total MUFA, OA, palmitoleic acid, and D9D were associated with early alteration of fasting glycemic status, therefore suggesting that these may be useful markers for predicting the risk of type 2 diabetes and cardiometabolic diseases.

Association of Increased Hair Calcium Levels and Enhanced Augmentation Index (AIx): a Marker of Arterial Stiffness

Arterial stiffness is involved in the pathophysiology of cardiovascular disease, and the degree of arterial stiffness is associated with the extent of vascular calcification. This study aimed to investigate the association of hair calcium levels with augmentation index (AIx), a simple, non-invasive measurement for arterial stiffness. Healthy Koreans (male, n = 34, female, n = 70) were enrolled in this study. Anthropometric parameters, lipid profiles, fasting glucose, hair mineral levels, and AIx were measured. Pearson/partial correlations and multivariate linear regression analyses were used to assess the relationship between hair calcium levels and AIx. AIx positively correlated with hair calcium levels (r = 0.275, p = 0.005), age (r = 0.283, p = 0.004), systolic blood pressure (r = 0.282, p = 0.004), low-density lipoprotein (LDL)-cholesterol (r = 0.255, p = 0.009), and hair magnesium (r = 0.196, p = 0.046), and negatively correlated with heart rate (r = -0.563, p < 0.001) and fasting glucose (r = -0.262, p = 0.005). Hair calcium levels significantly correlated with hair magnesium (r = 0.926, p < 0.001). Significant relationship between AIx and hair calcium levels was maintained after adjustment for sex, age, height, hear rate, blood pressure, total cholesterol, LDL-cholesterol, fasting glucose, and hair magnesium (r = 0.244, p = 0.018). Logistic regression model showed that AIx increased with the increment of hair calcium levels; log-AIx increased by 0.403% (95% CI: 0.139–0.515, p = 0.001) per unit change in log-hair calcium level (sex-adjusted). After adjustment for all the variables above together with triglyceride and high-density lipoprotein-cholesterol, increased significance of the association was 0.513% (p = 0.016)]. This study supports the presence of the independent positive relationship between hair calcium levels and AIx. It suggests the possibility that hair calcium levels may be a useful index for reflecting arterial stiffness.

DNA-PKcs-interacting protein KIP binding to TRF2 is required for the maintenance of functional telomeres

Human telomeres associate with shelterin, a six-protein complex that protects chromosome ends from being recognized as sites of DNA damage. The shelterin subunit TRF2 (telomeric repeat-binding factor 2) protects telomeres by facilitating their organization into the protective capping structure. We have reported previously that the DNA-PKcs (DNA-dependent protein kinase catalytic subunit)-interacting protein KIP associates with telomerase through an interaction with hTERT (human telomerase reverse transcriptase). In the present study, we identify KIP as a novel interacting partner of TRF2. KIP is able to interact with both TRF2 and DNA-PKcs at telomeres. Because KIP is required for the association between TRF2 and DNA-PKcs, the interplay of these three proteins may provide a mechanism for the recruitment of DNA-PKcs to telomeres. We also show that KIP binding to TRF2 enhances the telomere-binding activity of TRF2, suggesting that KIP acts as a positive regulator of TRF2 function. Furthermore, depletion of KIP induces DNA-damage response foci at telomeres, thereby leading to induction of growth arrest, cellular senescence and altered cell cycle distribution. Collectively, our findings suggest that KIP, in addition to its association with catalytically active telomerase, plays important roles in the maintenance of functional telomeres and the regulation of telomere-associated DNA-damage response. Thus KIP represents a new pathway for modulating telomerase and telomere function in cancer.

Enriching plausible new hypothesis generation in PubMed

Background Most of earlier studies in the field of literature-based discovery have adopted Swansons ABC model that links pieces of knowledge entailed in disjoint literatures. However, the issue concerning their practicability remains to be solved since most of them did not deal with the context surrounding the discovered associations and usually not accompanied with clinical confirmation. In this study, we aim to propose a method that expands and elaborates the existing hypothesis by advanced text mining techniques for capturing contexts. We extend ABC model to allow for multiple B terms with various biological types. Results We were able to concretize a specific, metabolite-related hypothesis with abundant contextual information by using the proposed method. Starting from explaining the relationship between lactosylceramide and arterial stiffness, the hypothesis was extended to suggest a potential pathway consisting of lactosylceramide, nitric oxide, malondialdehyde, and arterial stiffness. The experiment by domain experts showed that it is clinically valid. Conclusions The proposed method is designed to provide plausible candidates of the concretized hypothesis, which are based on extracted heterogeneous entities and detailed relation information, along with a reliable ranking criterion. Statistical tests collaboratively conducted with biomedical experts provide the validity and practical usefulness of the method unlike previous studies. Applying the proposed method to other cases, it would be helpful for biologists to support the existing hypothesis and easily expect the logical process within it.

Metabolites distinguishing visceral fat obesity and atherogenic traits in individuals with overweight

To screen the metabolomes of both overweight subjects with low visceral fat area (LFO) and high visceral fat area (HFO) to identify potential metabolites that are associated with the different metabolic characteristics.

Relation extraction for biological pathway construction using node2vec

BackgroundSystems biology is an important field for understanding whole biological mechanisms composed of interactions between biological components. One approach for understanding complex and diverse mechanisms is to analyze biological pathways. However, because these pathways consist of important interactions and information on these interactions is disseminated in a large number of biomedical reports, text-mining techniques are essential for extracting these relationships automatically.ResultsIn this study, we applied node2vec, an algorithmic framework for feature learning in networks, for relationship extraction. To this end, we extracted genes from paper abstracts using pkde4j, a text-mining tool for detecting entities and relationships. Using the extracted genes, a co-occurrence network was constructed and node2vec was used with the network to generate a latent representation. To demonstrate the efficacy of node2vec in extracting relationships between genes, performance was evaluated for gene-gene interactions involved in a type 2 diabetes pathway. Moreover, we compared the results of node2vec to those of baseline methods such as co-occurrence and DeepWalk.ConclusionsNode2vec outperformed existing methods in detecting relationships in the type 2 diabetes pathway, demonstrating that this method is appropriate for capturing the relatedness between pairs of biological entities involved in biological pathways. The results demonstrated that node2vec is useful for automatic pathway construction.