The Indonesian Biomedical Journal

66-91

Authors: Anna Meiliana, Andi Wijaya

BACKGROUND: The investigation of novel circulating serum and plasma biomarkers in patients with cardiovascular disease has been accelerating at a remarkable pace. New markers or tests are often presented too early to the medical profession, potentially leading to overuse and, thus, extra burden and costs to patients, the healthcare industry, and the economy. The challenge for clinicians and medical researchers is how to optimally apply existing and new markers/tests. CONTENT: Biomarkers are biological parameters that can be objectively measured and quantified as indicators of normal biologic processes, pathogenic processes, or responses to a therapeutic intervention. Typically thought of as disease process screening, diagnosing, or monitoring tools, biomarkers may also be used to determine disease susceptibility and eligibility for specific therapies. Cardiac biomarkers are protein components of cell structures that are released into circulation when myocardial injury occurs. They play a pivotal role in the diagnosis, risk stratification, and treatment of patients with chest pain and suspected acute coronary syndrome (ACS) as well as those with acute exacerbations of heart failure. SUMMARY: Active investigation has brought forward an increasingly large number of novel candidate markers but few have withstood the test of time and become integrated into contemporary clinical care because of their readily apparent diagnostic, prognostic, and/or therapeutic utility. With regard to the more novel biomarkers, careful thought is needed with regard to the appropriate target populations for discovery and validation, as well as the criteria used to sort out the contenders from the pretenders.

113-7

Authors: Ferry Sandra, Roya Khosravi-Far

BACKGROUND: Survivin is rarely expressed in normal healthy adult tissues, however, it is upregulated in the majority of cancers. Survivin, which belongs to IAPs family, has been widely reported to protect cells from apoptosis by inhibiting caspases pathway. Survivin’s mitotic activity is modulated by many kinases, and its phosphor status can also influence its ability to inhibit apoptosis. There are several important survivin’s phosphorylation sites, such as S20 and T34. We have continued our investigation on other potential survivin’s phosphorylation sites that could be important site for regulating survivin’s cyto-protection. METHODS: By assuming that S81 could be a potential target to modify activity of survivin, wild-type survivin (Survivin), antisense survivin (Survivin-AS), mutated-survivin Thr34Ala (Survivin-T34A) and mutated-survivin Ser81Ala (Survivin-S81A) were constructed and inserted into pMSCV-IRES-GFP vector with cytomegalovirus (CMV) promoter. Each retroviral product was produced in BOSC23 cells. LY294002 pretreatment and TRAIL treatment along with infection of retroviral products were performed in murine fibrosarcoma L929 cells. For analysis, flow cytometric apoptosis assay and western blot were performed. RESULTS: In our present study, survivin for providing cytoprotection was regulated by PI3K. The results showed that LY294002, an inhibitor of PI3K, effectively suppressed survivin-modulated cytoprotection in a TRAIL-induced apoptotic model. In addition, mutated survivin S81A showed marked suppression on survivin’s cytoprotection. Along with that, TRAIL’s apoptotic activity was enhanced for inducing apoptosis. CONCLUSION: We suggested that survivin could inhibit apoptosis through PI3K and S81A could be another potential target in order to inhibit Survivin-modulated cytoprotection as well as to sensitize efficacy of TRAIL or other related apoptotic inducers.

126-30

Authors: Trilis Yulianti, Mansyur Arif, Andi Wijaya

BACKGROUND: Adult obesity is rapidly increasing in the world including Indonesia. Tumor necrosis factor α (TNF-α) was chronically elevated in obese adipose tissue. TNF-α, a pleiotropic cytokine and also a regulator of bone formation, may might represent an important link between obesity and vascular calcification. Elegant genetic studies in mice and human have highlighted the important roles for Matrix Gla Protein (MGP) as an inhibitor of vascular calcification. The aim of this study was to examine the correlation between circulating levels of pro-inflammatory cytokines TNF-α and vascular calcification inhibitor MGP in obese men. METHODS: This was an observational cross-sectional study including 40 central obese men (waist circumference ≥90 cm) aged 31-60 years old. Serum MGP and serum TNF-α concentrations were quantified by ELISA principle. Fasting plasma glucose was assessed using hexokinase methods, triglyceride by GPO-PAP methods, and creatinine by Jaffe methods. All assays were performed according to the manufacture instruction. Statistical analysis was performed with SPSS for windows ver 16. Univariate analysis were performed to analyze mean, maximum, minimum value and SD. Pearson correlation statistic were performed to determine the correlation between variables. Significance value were define as alpha level = 0.05 based on two-tailed tests. RESULTS: The cross-sectional study (n=40) showed that the advancing age was correlated with plasma TNF-α concentration (r=0.348; p=0.028). The mean concentration of TNF-α and MGP were 8.323 and 8.368, respectively. We found a significant negative correlation between TNF-α with MGP (r=-0.425; p=0.006) and a significant correlation between TNF-α and triglyceride (r=0.375; p=0.017). CONCLUSIONS: Circulating level of TNF-α was inversely correlated with MGP concentration in obese men. This finding suggested that high level TNF-α leads to low MGP concentration obese men, hence, limits inhibitory capacity in vascular calcification.

137-42

Authors: Yusmiati Yusmiati, Burhanuddin Bahar, Andi Wijaya

BACKGROUND: Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) promotes the degradation of LDL receptor in hepatocytes. in vitro studies have proven that insulin increases the expression of PCSK9. Insulin resistance, a common condition in central obesity is characterized by dyslipidemia called Atherogenic Lipoprotein Phenotype (ALP). This study aimed to investigate the correlation between insulin resistance (HOMA-IR) and PCSK9, and to analyze whether this condition is related to the development of ALP in central obesity. METHODS: This is an observational study with crosssectional design. The subjects consisted of 62 male adults with central obesity, aged 30-60 years old. ELISA was used to measure plasma PSCK9. RESULTS: The mean plasma PCSK9 concentration of the samples was 283.7 ng/mL. PCSK9 had positive linear correlation with HOMA-IR (r=0.225, p=0.045) and Apo B (r=0.245, p=0.055). After controlling of HOMA-IR, PCSK9 had positive linear correlation with triglycerides (r=0.352, p=0.045). In population with HOMA-IR >2, crosstabs analysis showed that PCSK9 had significant correlation with triglycerides and Apo B with an odd ratio of 6,125 (r=0.376, p=0.037). Triglyceride showed significant negative correlation with HDL cholesterol and ratio of LDL/Apo B, but neither HOMA-IR nor PCSK9 did. CONCLUSION: In males with central obesity, PCSK9 is one of the factors mediating the occurence of ALP in insulin resistance.