The Indonesian Biomedical Journal (Prodia Education and Research Institute)
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Placental LEP Promoter Hypomethylation is Associated with Increased Leptin and Umbilical Artery Vascular Resistance in Maternal Obesity
Full text linkBACKGROUND: Maternal obesity has been associated with altered fetal development involving metabolic, hormonal, vascular, and epigenetic processes. The leptin (LEP) gene is crucial for placental angiogenesis and fetal growth. However, evidence linking placental LEP promoter methylation status with both leptin levels and umbilical artery vascular resistance in the context of maternal obesity remains limited. Therefore, this study was conducted to investigate the association of placental LEP promoter hypomethylation with increased leptin levels and umbilical artery vascular resistance in maternal obesity.METHODS: A cross-sectional study was conducted in 35 obese and 35 normal-body mass index (BMI) pregnant women delivering at term. Genomic DNA was extracted from placental tissue for the placental LEP promoter methylation examination using bisulfite conversion and CpG pyrosequencing. Umbilical artery systolic/diastolic (S/D) ratio was measured by Doppler ultrasonography, and umbilical cord leptin levels were analyzed from umbilical cord blood using enzyme-linked immunosorbent assay (ELISA).RESULTS: Total LEP promoter methylation did not differ significantly between groups (p=0.252), but five CpG sites (CpG 5, 11, 13, 16, and 17) showed significant hypomethylation in the obesity group. Umbilical cord leptin levels were significantly higher in infants of obese mothers (p=0.002). The S/D ratio was also significantly higher in the obesity group (p<0.001), indicating increased placental vascular resistance. Maternal age, parity, and gestational age were comparable between groups.CONCLUSION: Placental LEP promoter hypomethylation at specific CpG sites (CpG 5, 11, 13, 16, and 17) in maternal obesity is associated with increased leptin levels and elevated umbilical artery vascular resistance, suggesting a potential epigenetic mechanism linking maternal obesity to placental vascular dysfunction and altered fetal development.KEYWORDS: maternal obesity, leptin, DNA methylation, placenta, umbilical artery Doppler, fetal programmin
Combined COX-2 and HER-2 Biomarker Profiling to Predict Neoadjuvant Chemoradiotherapy Response in Locally Advanced Rectal Cancer
Full text linkBACKGROUND: Locally advanced rectal cancer (LARC) is commonly treated with neoadjuvant chemoradiotherapy (nCRT), but highly variable response limits outcomes and highlights the need for predictive biomarkers. Cyclooxygenase-2 (COX‑2) and human epidermal growth factor receptor 2 (HER‑2) are overexpressed in a subset of colorectal cancers and are mechanistically linked to radioresistance. Both pathways are therapeutically targetable and exhibit molecular crosstalk, suggesting that combined assessment may improve prediction of nCRT response, but their combined predictive value in LARC remains unexplored. Therefore, this study was conducted to evaluate the association between COX‑2 and HER‑2 expression and radiotherapy response in patients with LARC.METHODS: This observational retrospective cohort study included 59 patients with stage II–III rectal adenocarcinoma treated with standardized nCRT. COX-2 and HER-2 expressions on pretreatment biopsies were assessed by immunohistochemistry, and radiologic response 4–8 weeks post nCRT dichotomized into good and poor responses using RECIST 1.1.RESULTS: High COX-2 expression was present in 67.8% of tumors and was associated with poor response (p<0.001; OR=10.08; 95% CI: 2.92–34.78). HER-2 positivity (32.2% of cases) was also associated with poor response (p=0.039; OR=4.28; 95% CI: 1.16–15.79). In multivariate analysis, high COX-2 (adjusted OR=0.110; p=0.002) and HER-2 positivity (adjusted OR=0.197; p=0.049) remained independent predictors of poor response. Tumors with combined COX-2 low/HER-2 negative and COX-2 high/HER 2 positive profiles showed good response rates of 86.7% and 13.3%, respectively, representing a 73.4% absolute difference.CONCLUSION: Since Low COX-2 expression and HER-2 negativity is mostly associated with good radiotherapy response, hence COX-2 and HER-2 might be independent molecular predictors of radiotherapy response in LARC, and combined biomarker profiling provides robust risk stratification that may guide treatment intensification or de escalation strategies.KEYWORDS: COX-2, HER-2, rectal cancer, radiotherapy response, biomarker, personalized medicin
Combined Vitamin D and Magnesium Supplementation Improves Insulin, HOMA Indices, Blood Glucose, and Oxidative Stress Markers in Diabetic Rats
Full text linkBACKGROUND: Diabetes mellitus (DM) is characterized by disturbances in glucose homeostasis, chronic low-grade inflammation, and heightened oxidative stress. Alterations in vitamin D status and magnesium homeostasis are frequently observed in DM and have been implicated in impaired insulin secretion, decreased insulin sensitivity, and dysregulated antioxidant responses. Although both micronutrients have independently demonstrated potential benefits on glycaemic regulation and oxidative balance, the synergistic therapeutic effects of combined vitamin D and magnesium supplementation remain insufficiently elucidated in experimental models of type 2 DM. Therefore, this study was conducted to determine the effects of combined vitamin D and magnesium supplementation on insulin dynamics, glycaemic control, and oxidative stress markers in streptozotocin-induced diabetic rats.METHODS: Twenty-four male Wistar white rats were divided into 4 groups: normal control, diabetic control, metformin group, and vitamin D + magnesium group. DM was induced using streptozotocin–nicotinamide injection. Glycaemic parameters including insulin, homeostasis model assessment for insulin resistance (HOMA-IR), and homeostatis model assessment of β-cell function (HOMA-β), were evaluated from fasting serum using immunoassay-based analyses; while oxidative stress markers including superoxide dismutase (SOD) and malondialdehyde (MDA) were measured from plasma using colorimetric spectrophotometric methods.RESULTS: Vitamin D and magnesium combination achieved the greatest reduction in blood glucose. The mean insulin level and HOMA-β index in the vitamin D + magnesium group were significantly higher than in both the diabetic control and metformin groups (p<0.001). In the same group, HOMA-IR and MDA levels were significantly lower, whereas SOD activity was significantly higher compared with diabetic group and metformin group (p<0.001).CONCLUSION: The combination of vitamin D and magnesium increases insulin and HOMA-β level and decreases HOMA-IR, SOD, and MDA expressions in diabetic Wistar rats.KEYWORDS: diabetes mellitus, magnesium, vitamin D, insulin resistance, inflammatio
Ternary Solid Dispersion Improves Anti-cancer Activity of Alpha-mangostin Against MCF-7 Breast Cancer Cells
Full text linkBACKGROUND: Alpha-mangostin (AM) exhibits potent anti-breast cancer activity but its therapeutic effectiveness is constrained due to low aqueous solubility and poor bioavailability. Ternary solid dispersions (TSDs) were developed by adding another excipient to address these challenges. Nevertheless, limited studies have systematically evaluated whether improvements in dissolution and stability achieved through TSD systems are translated into enhanced in vitro cytotoxicity of AM. Therefore, TSD system of AM with Eudragit (EUD) and Poloxamer (POL) was developed, and in vitro cytotoxicity activity was evaluated as a preliminary proof-of-concept in MCF-7 breast cancer cells.METHODS: TSD of AM was prepared by solvent evaporation and characterized by Power X-Ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC), and Fourier Transform Infrared (FT-IR) Spectroscopy. The pharmaceutical properties were evaluated by in vitro dissolution test using a standard paddle apparatus, while physical stability was assessed under two relative humidity environments. The in vitro anticancer efficacy was examined in MCF-7 breast cancer cell using an MTT assay.RESULTS: Amorphization of TSD was confirmed by a halo pattern with PXRD measurements and the absence of an AM melting peak in the DSC curve. FT-IR analysis revealed hydrogen bond interactions between the carbonyl group of AM and EUD/POL protons. TSD system significantly improved the dissolution profile and enhanced cytotoxic effects, reducing cell viability to 1.17% at 16 µg/mL with an IC50 of 7.11 μg/mL (CI 95%: 6.626-7.591).CONCLUSION: The TSD system significantly improved dissolution profile and in vitro cytotoxicity in MCF-7 breast cancer cells, providing proof-of-concept for enhancing the biological performance of AM. KEYWORDS: alpha-mangostin, ternary solid dispersions, dissolution, MCF-7, cytotoxicit
Insulin Resistance, Adiponectin, and Dyslipidemia as Key Determinants of Metabolic and Reproductive Dysregulation in Polycystic Ovary Syndrome
Full text linkBACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with insulin resistance, dyslipidemia, and metabolic dysfunction. However, the predictive value of insulin resistance (HOMA-IR), dyslipidemia, and adiponectin in identifying PCOS and stratifying metabolic risk remains unclear, particularly in underrepresented populations, such as Iraqi women. This study evaluated these parameters to improve risk stratification and early intervention strategies in resource-limited settings.METHODS: This case-control study included 100 women (50 with PCOS diagnosed using the Rotterdam criteria and 50 age-matched healthy controls). Anthropometric and clinical assessments, including BMI and hirsutism scores, were performed. Fasting blood samples were analyzed for glucose and lipid profile using colorimetric assays, insulin via electrochemiluminescence immunoassay (ECLIA), and adiponectin via enzyme-linked immunosorbent assay (ELISA), and HOMA-IR was calculated to quantify insulin resistance.RESULTS: Women with PCOS exhibited significantly higher BMI, fasting glucose, insulin, and HOMA-IR values (p<0.001 for all) than controls. Dyslipidemia was evident, characterized by elevated total cholesterol, LDL-C, and triglyceride levels, as well as lower HDL-C levels (p<0.001). Adiponectin levels were markedly reduced in the PCOS group (p<0.001) and showed strong inverse correlations with HOMA-IR (r=–0.554, p<0.001) and fasting insulin (r=–0.453, p<0.001). Logistic regression indicated that HOMA-IR was the most significant predictor of PCOS (OR=28, 95% CI 4.86–161.44, p=0.0002), whereas higher adiponectin levels offered significant protective effects (OR=0.54, 95% CI 0.36–0.82, p=0.0039).CONCLUSION: Insulin resistance, dyslipidemia, and low adiponectin levels are strongly associated with PCOS and metabolic dysfunction in Iraqi women. HOMA-IR is a key predictor, whereas adiponectin may have protective effects. These findings highlight the potential of these biomarkers in risk stratification and early intervention in resource-limited settings.KEYWORDS: PCOS, adiponectin, HOMA-IR, dyslipidemi
Nanocurcumin Enhances Antioxidant Defense through GPx Upregulation in Ovarian Granulosa Cells of Endometriosis Mouse Model
Full text linkBACKGROUND: Endometriosis impairs female reproductive function through oxidative stress and apoptosis, reducing oocyte quality and causing infertility. Current therapies are limited by suboptimal efficacy and side effects, including ovulation suppression. Curcumin offers antioxidant and anti-inflammatory benefits but has low bioavailability and poor solubility, which can be improved through nanoparticle formulation. Although nanocurcumin is suggested to act through multiple pathways, its mechanisms remain unclear. This study was conducted to evaluate the antioxidant and anti-apoptotic effects of nanocurcumin in a mouse model of endometriosis.METHODS: Thirty-five mice were allocated into five groups and induced to develop endometriosis using cyclosporine A, ethinyl estradiol, and human endometrial tissue. Nanocurcumin was formulated at three particle sizes (3.71; 3.98; and 25.60 nm) and administered orally at doses of 50, 100, or 200 mg/kg/day for 14 days. After treatment, the mice were euthanized, and ovarian tissues were collected for immunohistochemical analysis of glutathione peroxidase (GPx) and B-cell lymphoma-2 (Bcl-2) expression.RESULTS: The highest GPx expression was observed in the group receiving 50 mg/kg/day nanocurcumin (mean±SD= 6.31±1.97; p=0.042). The lowest expression of Bcl-2 was observed in control group with no treatment (mean±SD=4.15±2.48; p=0.582). Nanocurcumin administration significantly increased GPx expression in a dose-dependent manner compared with the untreated group, while no significant differences were found in Bcl-2 expression.CONCLUSION: Nanocurcumin increases GPx expression, particularly at 50 mg/kg/day, indicating its potential as an antioxidant in reducing oxidative damage associated with endometriosis. However, nanocurcumin did not significantly influence Bcl-2 expression. These findings support nanocurcumin’s role as an effective antioxidant agent in protecting ovarian granulosa cells in endometriosis.KEYWORDS: nanocurcumin, GPx, Bcl-2, endometriosis, granulosa cell
Red Rice Bran Ethanol Extract Reduces IL-1β as the Risk of Pancreas Fibrogenesis in Type 2 Diabetic Rat Model
Full text linkBACKGROUND: Oxidative stress and inflammation contribute to pancreatic cell dysfunction that promote insulin resistance in type 2 diabetes (T2D). Red rice bran contains bioactive substances with anti-inflammatory and antioxidant properties which improved insulin resistance in obese mice. However, no studies have explored the potential of ethanol extract of red rice bran (EERRB) to prevent T2D progression, particularly pancreatic fibrosis complications. This study was conducted to investigate the effect of EERRB on inflammation measured with interleukin (IL)-1β and fibrosis of pancreatic tissue in a rat model of T2D. METHODS: Rats were induced with streptozotocin and nicotinamide to induce diabetes, and then separated into five groups. One group received no treatment, while the other four received 9 mg/kg/day acarbose, 165, 330, or 660 mg/kg/day EERRB orally for 21 days. Immunohistochemistry was conducted on pancreas tissues to measure the expression of IL-1β, while pancreatic fibrosis was assessed with Masson’s Trichrome staining.RESULTS: EERRB reduced the expression of pro-inflammatory cytokine, IL-1β, in pancreas tissue in a dose dependent manner. Significantly lower IL-1β expression were found in group receiving 660 mg/kg/day EERRB (10%) compared to diabetic with no treatment group (50%) (p<0.0001). Additionally, the IL-1β expression in the highest dose of EERRB group was comparable to the group receiving acarbose (10%). CONCLUSION: This finding suggests the beneficial effect of EERRB in the hyperglycemic condition that causes oxidative stress through blocking the IL-1β expression, hence alleviating the inflammation in pancreas tissue, and have a tendency in preventing pancreatic fibrosis progression, a process implicated in T2D pathogenesis. KEYWORDS: diabetes, inflammation, pancreatic fibrosis, red rice bra
Serum CD44 Variant 6 to CD44 Ratio and Vascular Endothelial Growth Factor Levels as Predictors of Metastasis in Luminal Subtype Breast Cancer
Full text linkBACKGROUND: Metastasis is the leading cause of mortality in luminal subtype breast cancer. While cluster of differentiation (CD)44 has been widely studied, the prognostic relevance of its isoforms particularly the CD44v6/CD44s ratio remains unclear. This study evaluates CD44v6, CD44s, vascular endothelial growth factor (VEGF), and the CD44v6/CD44s ratio as potential prognostic biomarkers for metastasis in luminal breast cancer.METHODS: This case-control study included 38 luminal subtype breast cancer patients (18 with metastasis, 20 without metastasis). Serum levels of CD44v6, CD44s, VEGF, and the CD44v6/CD44s ratio were measured using Enzyme-Linked Immunosorbent Assay (ELISA). Statistical analyses included ROC analysis to determine optimal cut-off points, logistic regression to assess risk factors, and correlation analysis for biomarker relationships.RESULTS: A low CD44v6/CD44s ratio (<0.03) was identified as a significant independent factor for metastasis (adjusted OR 7.0, 95% CI: 1.2–40.6, p=0.03). While serum levels of CD44v6, CD44s, and VEGF were higher in the metastasis group, these individual markers showed a non-significant trend toward association with metastasis. A strong positive correlation was observed between CD44s and VEGF levels (r=0.7, p<0.01).CONCLUSION: The CD44v6/CD44s ratio showed a significant association with metastasis and may have potential as a prognostic marker in luminal breast cancer. Further studies with larger sample sizes are needed to confirm these findings.KEYWORDS: CD44v6, CD44s, VEGF, CD44v6/CD44s ratio, luminal breast cancer, metastasi
Alpha-Actinin-3 (ACTN3) R577X Polymorphism on Brain-derived Neurotrophic Factor (BDNF) Levels of Pre- and Post-Eccentric Exercised Male Subjects
Full text linkBACKGROUND: Eccentric exercise, characterized by muscle lengthening underload, elicits physiological responses, including alterations in brain-derived neurotrophic factor (BDNF) levels, crucial for neuroplasticity and exercise adaptations. The Alpha-Actinin-3 (ACTN3) gene encodes α-actinin-3, a protein in fast-twitch muscle fibers associated with explosive performance. The R577X polymorphism in ACTN3 is associated with athletic performance, particularly in power-based activities. However, its influence on the BDNF response to eccentric exercise remains unclear. This study investigated whether the ACTN3 R577X polymorphism modulates BDNF levels post-exercise.METHODS: Male subjects aged 18-30 years old, who were not involved in structured physical activity, and abstaining from alcohol and protein supplements within specified periods, were involved in this study. Subjects’ genotypes were identified using polymerase chain reaction (PCR) and classified into different ACTN3 genotypes (RR, RX, XX). All subjects underwent an eccentric exercise protocol. BDNF levels were measured pre-exercise, post-exercise, and 72 hours post-exercise using sandwich Enzyme-Linked Immunosorbent Assay (ELISA).RESULTS: Most of subjects had RX genotype (52.2%), followed by XX (39.1%) and RR genotypes (8.7%), respectively. BDNF levels decreased significantly across all time points. The RR genotype showed a decrease from approximately 270 pg/mL to 230 pg/mL, while RX and XX genotypes showed similar patterns of reduction. No significant differences in BDNF levels were observed between genotypes at any time point.CONCLUSION: Eccentric exercise leads to a consistent decrease in BDNF levels, with no significant modulation by ACTN3 genotype. These findings suggest a uniform response to exercise-induced stress across genotypes.KEYWORDS: ACTN3, BDNF, eccentric exercises, genotype, adaptatio
Transcriptional Regulation of CYP2D6 by Nrf2 and Its Implications in Breast Cancer Therapy: Bioinformatics and Experimental Evidence
Full text linkBACKGROUND: Tamoxifen (TAM) resistance in patient with breast cancer is the leading cause of mortality among women globally. Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of TAM, and recently NF-E2-related factor 2 (Nrf2) has recently been found as its regulator. However, the impact of Nrf2-mediated CYP2D6 regulation in the context of breast cancer and TAM resistance are currently unknown. Therefore, this study was conducted to examine the role of CYP2D6 and Nrf2 in breast cancer prognosis. MEDTHODS: The roles of CYP2D6 and Nrf2 were investigated in the T47D breast cancer cell line and T47D-derived TAM-resistant cells by examining the gene expression, cell viability, and transcriptional regulation by quantitative reverse transcription polymerase chain reaction (qRT-PCR), MTT, and reporter gene assay, respectively. Additionally, comprehensive in silico analysis of the transcriptomic and clinical data from The Cancer Genome Atlas database were performed to uncover the prognostic role of CYP2D6 and its regulator in breast cancer patients. RESULTS: CYP2D6 mRNA was low and Nrf2 protein was high in TAM-resistant T47D cells compared to parental cells. Nrf2 knockdown upregulated CYP2D6 mRNA levels and enhanced the cytotoxicity of TAM. Similarly, in silico analysis revealed that low CYP2D6 mRNA and high Nrf2 protein were related to a lower probability of survival. The rs1238662089 within the identified Nrf2-binding site was found to greatly affect CYP2D6 expression levels, indicating its role as predictor for better prognosis. CONCLUSION: This study revealed for the first time that Nrf2 regulates CYP2D6expression in breast cancer and is involved in TAM sensitivity; thus, plays a role in breast cancer patient prognosis.KEYWORDS: breast cancer, CYP2D6, Nrf2, pharmacoepigenetics, SNP