The Indonesian Biomedical Journal

119-28

Authors: Anna Meiliana, Andi Wijaya

BACKGROUND: Mitochondrial function and behavior are central to the physiology of humans and, consequently, "mitochondrial dysfunction" has been implicated in a wide range of disease. CONTENT: Mitochondrial ROS might attack various mitochondrial constituents, causing mitochondrial DNA mutations and oxidative damage to respiratory enzymes. A defect in mitochondrial respiratory enzymes would increase mitochondrial production of ROS, causing further mitochondrial damage and dysfunction. Mitochondrial dysfunction is associated with diseases, such as neurodegenerative disorders, cardiomyopathies, metabolic syndrome, obesity, and cancer. Pathways that improve mitochondrial function, attenuate mitochondrial oxidative stress, and regulate mitochondrial biogenesis have recently emerged as potential therapeutic targets. SUMMARY: Mitochondria perform diverse yet interconnected functions, produce ATP and many biosynthetic intermediates while also contribute to cellular stress responses such as autophagy and apoptosis. Mitochondria form a dynamic, interconnected network that is intimately integrated with other cellular compartments. It is therefore not suprising that mitochondrial dysfunction has emerged as a key factor in a myriad of diseases, including neurodegenerative, cancer, and metabolic disorders. Interventions that modulate processes involved in regulation of mitochondrial turnover, with calorie restriction and induction of mitochondrial biogenesis, are of particular interest. KEYWORDS:

143-50

Authors: Oeij Anindita Adhika, M Nurhalim Shahib

BACKGROUND: Inflammation is a key component of the tumor microenvironment. Cancer-associated inflammation is marked by the presence of specific inflammatory cells and inflammatory mediators. Moreover, immune cells in the tumor microenvironment not only fail to mount an effective antitumor immune response, but also interact intimately with the tumor cells to actively promote oncogenesis. CONTENT: Their roles in regulating cytokine-dependent inflammation and immunity make the signal transducer and activator of transcription (STAT) proteins critical players in determining whether immune responses in tumor microenvironment promote or inhibit cancer. Recent evidence suggests a crucial role for STAT family proteins, especially STAT3 (signal transducer and activator of transcription 3), which is a point of convergence for numerous oncogenic signaling pathways, in selectively inducing and maintaining a procarcinogenic inflammatory microenvironment, both at the initiation of malignant transformation and during cancer progression. The persistent activation of STAT3 increases tumor cell proliferation, survival, and invasion while supressing antitumor immunity. SUMMARY: STAT3 signaling pathway constitutes a potential preventive and therapeutic target for cancer immunotherapy.

157-63

Authors: Yenny Surjawan, Suryani As'ad, Teguh A S Ranakusuma, Andi Wijaya

BACKGROUND: C-Reactive protein (CRP) and matrix metalloproteinase (MMP)-9 are inflammatory mediators that are often associated with the evolution of stroke. In this study, we aimed to find out whether concentration of these biomarkers were associated with the severity of discharge National Institute of Health Stroke Scale (NIHSS) in ischemic stroke patient. METHODS: In prospective stody, we involved 143 ischemic stroke patient who were admitted to hospital not more than 72 hours after the onset and who met the criteria. The concentration of CRP was assessed by High Sensitivity CRP reagent from Siemens and the concentration of MMP-9 was measure with Quantikine Human MMP-9 (total) Immunoassay from R&D. The outcome of stroke was determined by NIHSS score at discharge. RESULTS: There was a significant correlation between the CRP level and the severity of NIHSS at discharge (r = 0.288, p = 0.000). Subjects with intermediate/high level of CRP had a higher probability to have a moderate or even severe NIHSS (OR = 1.7, p = 0.004). Subjects with high MMP level showed a higher probability to have a severe NIHSS. CONCLUSION: The measurement of CRP and MMP-9 at 48-72 hours after stroke onset were associated with the severity of ischemic stroke based on NIHSS score at discharge.

174-9

Authors: Aloysius Suryawan, Johanes C Mose, Budi Handono

BACKGROUND: Abortion remains a problem in the obstetric care as it is one of the causes of maternal and fetal death. Bleeding or miscarriage threat in the first trimester comprises 20% to 25% of all pregnant women, and 50% of them will end as spontaneous abortion. The major cause of maternal death in abortion is hemorrhage. Some recent studies have indicated that MMP-9 is important in the process of embryo implantation into the endometrium and spontaneous abortion occurs when there is an overwhelming increase of MMP-9. This data indicate the importance of a further research to elucidate the role of MMP-9 in spontaneous abortion. METHODS: This was a cross sectional study, included 70 pregnant women with gestational age <20 weeks who came for examination and treatment at the Department of Obstetrics and Gynecology, Medical Faculty of Padjadjaran University/Hasan Sadikin Hospital, Bandung. RESULTS: There were differences in the MMP-9 levels in spontaneous abortion compared to normal pregnancy and MMP-9 had a cut-off point >1221.7 with the sensitivity of 48.6% specificity of 80%, and accuracy of 60.9%. SUMMARY: The MMP-9 level in spontaneous abortion was higher than in normal pregnancy.

59-72

Authors: Yani Lina, Andi Wijaya

BACKGROUND: The potential use of stem cell-based therapies for repair and regeneration of various tissues and organs offers a paradigm shift that may provide alternative therapeutic solutions for a number of disease. Despite the advances, the availability of stem cells remaining a challenge for both scientist and clinicians in pursuing regenerative medicine. CONTENT: Subcutaneous human adipose tissue is an abundant and accessible cell source for applications in tissue engineering and regenerative medicine. Routinely, the adipose issue is digested with collagenase or related lytic enzymes to release a heterogeneous population for stromal vascular fraction (SVF) cells. The SVF cells can be used directly or can be cultured in plastic ware for selection and expansion of an adherent population known as adipose-derived stromal/stem cells (ASCs). Their potential in the ability to differentiate into adipogenic, osteogenic, chondrogenic and other mesenchymal lineages, as well in their other clinically useful properties, includes stimulation of angiogenesis and suppression of inflammation. SUMMARY: Adipose tissue is now recognized as an accessible, abundant and reliable site for the isolation of adult stem cels suitable for the application of tissue engineering and regenerative medicine applications. The past decade has witnessed an explosion of preclinical data relating to the isolation, characterization, cryopreservation, differentiation, and transplantation of freshly isolated stromal vascular fraction cells and adherent, culture-expanded, adipose-derived stromal/stem cells in vitro and in animal models.

84-92

Authors: Anggi Kartikawati, Yani Lina, Andi Wijaya

BACKGROUND: Studies have shown that change of calcium and vitamin D homeostasis is associated with insulin resistance, decreased beta cell function, metabolic syndrome, glucose intolerance and diabetes. Evidence suggests that vitamin D insufficiency is inversely related to risk of metabolic disorders including type-2 Diabetes Mellitus (T2DM), although the underlying mechanisms are not yet understood. Hence, current study was conducted to investigate correlation between 25(OH)D and insulin resistance through adiponectin or High Sensitivity C-Reactive Protein (hsCRP) in centrally obese men. METHODS: This was a cross-sectional study involving 80 centrally obese men with waist circumference (WC) >90 cm and age 30-60 years. Total 25(OH)D concentration was measured by Enzyme-Linked Immunosorbent Assay (ELISA) method. Insulin resistance was calculated by HOMA model. RESULTS: This study showed there was no correlation of 25(OH)D-WC (r=0.006 and p=0.957), 25(OH)D-adiponectin (r=0.179 and p=0.111) abd 25(OH)D-hsCRP (r=-0.223 and p=0.334), but we observed statistically significant negative correlation between 25(OH)D and insulin resistance index (HOMA-IR) (r=0.461 and p=0.041). CONCLUSIONS: We conclude that low 25(OH)D concentration was significantly associated with increased risk of insulin resistance. Since the adiponectin or hsCRP was not correlated, the possible pathways need to be futher investigated.

101-6

Authors: Priscilla Dian Ari, Ellis Susanti, Ilhamjaya Patellongi

BACKGROUND: Obesity is closely associated with atherosclerosis. Obesity and atherosclerosis are closely associated with inflammatory disease. Atherosclerosis constitutes a multifactorial disorder affecting the arterial wall, which is initiated by dyslipidemia and excerbated by inflammation. Plasma levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) and oxidized low density lipoprotein (ox-LDL) have been identified as risk factors for cardiovascular disease. Lp-PLA2 is the sole enzyme responsible for the hydrolysis of oxidized phospholipids (oxPL) on LDL particles in atherosclerosis plaque. Plasma level of oxLDL is associated with inflammation and plays an important role in the development of atherosclerosis. The aim of this study was to assess the correlation between Lp-PLA2 and atherosclerosis (oxLDL) in centrally obese men. METHODS: This was a cross-sectional study involving 71 men with central obesity with waist circumference >90 cm, aged 30-60 years old. Lp-PLA2 measurement was done by sandwich enzyme immunoassay. oxLDL measurement was done by ELISA method. RESULTS: Results of this study showed that central obesity correlated positively with oxLDL (r=0.258; p=0.040) and Lp-PLA2 >422 ng/mL correlated positively with oxLDL (r=0.331; p=0.042). CONCLUSIONS: We conclude that there is a correlation of Lp-PLA2 with atherosclerosis (oxLDL) in men with central obesity.

112-7

Authors: Yenny Surjawan, Suryani As'ad, Teguh A S Ranakusuma, Andi Wijaya

BACKGROUND: Patient with larger ischemic lesion will suffer more severe neurogical deficit. The utility of MRI for lesion size measurement is still limited, therefore additional approach was pursued through examination of markers released by damaged brain cell, GFAP and S100B protein. The aim of this study is to know whether both markers are associated with the neurological deficit of anterior circulation ischemic stroke. METHODS: This observational prospective study enrolled 74 patients with anterior circulation ischemic stroke diagnosis. GFAP and S100B protein were measured with ELISA using blood collected at 48 to 72 hours after onset. The neurological deficit was assessed with NIHSS ad discharged. RESULTS: There was a significant association between GFAP level and discharged NIHSS (p=0.008) with 100% sensitivity and 100% negative predictive value. S100B protein also showed a significant correlation with discharged NIHSS (r=0.488; p=0.000) and this correlation could be described with an equation (OR=1.009; 95% CI=1.0003-1.0188; p=0.044). S100B protein at 78.3215 ng/L would give true prediction as 73.9% (95% CI=62.7%-85.2%, p=0.001). CONCLUSIONS: GFAP and S100B protein that were measured at 48 to 72 hours after onset were significantly associated with NIHSS at discharge.

3-11

Authors: Yani Lina, Andi Wijaya

BACKGROUND: Mesenchymal stromal cells are multipotent cells considered to be of great promise for use in regenerative medicine. However, the cell dose may be a critical factor in many clinical conditions and the yield resulting from the ex vivo expansion of mesenchymal stromal cells derived from bone marrow may be insufficient. Thus, alternative sources of mesenchymal stromal cells need to be explored. CONTENT: There are multiple extra-embryonic tissues emerging during gestation including umbilical cord blood (UCB), amniotic fluid (AF), Wharton’s jelly, the amniotic membrane and the placenta, which are all discarded following birth. Fetal stem cells from these sources actually represent a new class of stem cells developmentally and operationally located between the state of embryonic stem cells and adult stem cells, sharing and exhibiting features of pluripotency and multipotency, without necessarily implying that they can generate every type of tissue. SUMMARY: Fetal stem cells have been recently isolated from several tissues (amniotic fluid, umbilical cord, Wharton’s jelly, amnion and placenta). They are derived either from the fetus proper or from the supportive extra-embryonic structures. They represent ideal sources for regenerative medicine since they are easily accessible, exhibit high proliferation rates, do not form teratomas and present no ethical reservations like embryonic stem cells (ESC). Their functional features indicate that they actually represent intermediates between ESC and adult stem cells.

17-23

Authors: Imelda Novianti, Andi Wijaya, Marsetio Donosepoetro

BACKGROUND: Central obesity is the accumulation of visceral (intra-abdominal) fat and is strongly known to be associated with insulin resistance and type 2 diabetes mellitus (T2DM). Obesity can cause adipocyte hypertrophy that results in dysregulation of adipokine expression. The abnormal function of adipocytes may play an important role in the development of a chronic low-grade proinflammatory state associated with obesity. Adiponectin, RETINOL binding protein (RBP)-4 and fetuin-A play a role in the pathophysiology of insulin resistance. Expression of fetuin-A is increased due to fat accumulation in the liver. Elevated concentration of fetuin-A in the circulation can impair insulin signaling in muscle and liver as well as suppress adiponectin secretion, although its molecular mechanism is still unclear. The aim of this study was to identify the relationship of fetuin-A, adiponectin, RBP-4 and hsCRP with insulin resistance in obese non diabetic men. METHODS: This was an observational study with a cross-sectional design. The study subjects were 64 men with non diabetic abdominal obesity, characterized by waist circumference of 98.47 ± 5.88 cm and fasting blood glucose of 85.75±8.36 mg/dL. RESULTS: This study showed that fetuin-A was positively correlated with HOMA-IR in obese non diabetic men with insulin resistance (r = 0.128; p = 0.570), although not significant. Fetuin-A was found to be correlated with adiponectin, RBP-4 and hsCRP (r=0.150; p=0.233; r=0.050; p=0.711; r=-0.04; p=0.445), although not significant. CONCLUSIONS: The concentration of fetuin-A showed a tendency to be positively correlated with HOMA-IR and with RBP-4 in obese non diabetic men, although statistically not significant. The concentration of fetuin-A showed a tendency to be negatively correlated with adiponectin and hsCRP although statistically not significant. There was no interrelationship between fetuin-A, adiponectin, RBP-4, hsCRP and HOMA-IR. Elevated concentrations of fetuin-A were noted in obese subjects, which in turn might impair insulin signaling. This finding might suggest that fetuin-A may represent a new target for the prevention of insulin resistance. Further studies might be needed on obese population with fatty liver.

29-34

Authors: Diah Kumalasari, Andi Wijaya, Anwar Santoso

BACKGROUND: Myocardial infarction is one of the coronary artery diseases caused by plaque rupture, plaque erosion or calcified nodules, with the occurence of thrombus formation and artery occlusion. YKL-40 has a functional role in plaque fibrous formation because of its high expression during fibrosis development, vascular smooth muscle cells differentiation, elevated matrix turnover and tissue remodelling in old myocardial infarction, whereas CD40 ligand, which is stored in the cytoplasm of resting platelets, rapidly presents on the surface. After cleavage, a soluble functional CD40 ligand (sCD4OL) is generated. The aim of this study was to assess the association between YKL-40 and sCD4OL in old myocardial infarction. METHODS: This study used the cross sectional study design. Fifty six patients with old myocardial infarction were selected based on their electrocardiographical results. Among these patients, 23 subjects had hypertension and 15 subjects had hsCRP >3-l0 mg/L. YKL-40 and sCD40L were measured by ELISA method. RESULTS: There was no significant correlation between YKL-40 and sCD40L (r=0.078; p=0.569) in old myocardial infarction and in subjects with hsCRP >3-10 mg/L (r=0.524; p=0.045). However, significant positive correlations Were found in subjects with hypertension (r=0.447; p=0.029). CONCLUSIONS: Our findings showed that YKL 40 correlated significantly with sCD4OL in subjects with hypertension.

43-9

Authors: Bayu Winata Putera, Cynthia Retna Sartika, Andi Wijaya

BACKGROUND: Obesity is a major health problem in the world today. Obesity is closely associated with insulin resistance and type 2 diabetes. Epidemiological studies have shown that obese persons are in a state of insulin resistance, however, most of them do not progress to type 2 diabetes. This occurs because the beta cell function is still good enough for maintaining normal glucose level. Obestatin and visfatin are cytokines that are known to have a role in beta cell function. The aim of this study was to assess the relationship between visfatin and obestatin and Homeostasis Model Assessment of beta cell function (HOMA-β) and Homeostasis Model Assessment of insulin resistance (HOMA-IR). METHODS: This was a cross-sectional study involving 80 central obesity men with waist circumference >90 cm, age 30-65 years old. Visfatin and obestatin were measured by ELISA method. Beta pancreas cell dysfunction and insulin resistance were calculated by HOMA model. RESULTS: Our study showed a correlation between visfatin and HOMA-β (r=0.244 and p = 0.029) and visfatin with HOMA-IR (r=0.287 and p=0.001) and no correlation was found between obestatin with HOMA-β (r=0.010 and p=0.990) and obestatin with HOMA-IR (r=0.080 and p=0.480). We also found visfatin and obestatin concentrations were fluctuative depending on the measurements of the waist circumferences. CONCLUSIONS: High visfatin and low obestatin concentration were independently associated with increased beta pancreas cell dysfunction and insulin resistance.