The Indonesian Biomedical Journal (Prodia Education and Research Institute)
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Low Serum Nerve Growth Factor Levels Are Associated with Insulin Resistance, Beta Cell Dysfunction, and Neuropathy Screening Scores in Subjects with Type 2 Diabetes Mellitus
Get PDFBACKGROUND: Diabetic peripheral neuropathy (DPN) is a common complication of type 2 diabetes mellitus (T2DM), associated with chronic hyperglycemia, insulin resistance, and neuroinflammation. Despite the widespread use of Michigan Neuropathy Screening Instrument (MNSI) for early identification in neuropathy screening, studies assessing its relationship between NGF, insulin resistance, and neuropathy in T2DM patients, particularly in Indonesia, remain limited. Therefore, this study was conducted to evaluate associations between serum NGF, insulin resistance, β-cell function, and MNSI scores in T2DM.METHODS: Seventy-seven T2DM subjects were classified into DPN and non-DPN groups using MNSI. Subjects were excluded if they have comorbidities and conditions potentially affecting metabolic, immune, or organ function. Enzyme-linked immunosorbent assay (ELISA) was used for the measurement of serum NGF, enzymatic hexokinase method for fasting plasma glucose (FPG) and 2-hour postprandial glucose (2HPP), high-performance liquid chromatography (HPLC) for glycated hemoglobin (HbA1c), and chemiluminescent immunoassay for fasting insulin. Homeostatic model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-β) were then calculated.RESULTS: Most of the study subjects had NGF level of <11 pg/mL. NGF concentrations showed inverse correlations with HOMA-IR (r=–0.263, p=0.021) and HOMA-β (r=–0.316, p=0.005). In the DPN subgroup, NGF demonstrated a stronger negative correlation with HOMA-β (r=–0.425, p=0.009), whereas no significant correlation was found in non-DPN. HbA1c was higher in DPN (p=0.014). No significant associations were observed between NGF and HbA1c, FPG, or 2HPP. NGF was significantly associated with MNSI Part B scores (p=0.032), reflecting objective neuropathic findings, but not with MNSI Part A or total scores.CONCLUSION: Lower NGF levels were significantly associated with insulin resistance and β-cell dysfunction in T2DM. The association with MNSI part B suggests that physical examination findings may reflect NGF-related neuropathic alterations better than symptom-based assessments.KEYWORDS: diabetic peripheral neuropathy, HOMA-IR, HOMA-β, Michigan Neuropathy Screening Instrument, nerve growth factor, T2D
Safety Concerns of Tectona grandis L.f. Leaf Extract as a Natural Food Colorant: Evidence of Irreversible Organ Pathology in Subchronic Toxicity Study
Get PDFBACKGROUND: Tectona grandis Lf (TG) leaves are traditionally used in Indonesia for natural dyeing, and are gaining popularity as food colorants globally. However, their safety profile remains unclear. Acute toxicity studies reported no fatalities at doses up to 5000 mg/kg BW, histological analyses revealed inflammation and necrosis in the stomach, raising concerns regarding the long-term safety of TG leaf extract. Therefore, this study was performed to evaluate subchronic toxicity of TG leaf extract in both males and females Wistar rats.METHODS: TG leaf extracts were obtained by water extraction and extract powder was suspended in sodium carboxymethyl cellulose (Na-CMC). Male and female rats were administered TG leaf extract at doses of 0, 10, 20, and 40 mg/kg BW for 28 days, with a 14-days recovery phase in the satellite groups (as controls). Hematology profiles and biochemistry were analyzed using hematology analyzer and spectrophotometry. Histology analysis was performed to investigate TG effects on the organs.RESULTS: Hematological analysis revealed reversible reductions in hemoglobin, erythrocyte, and hematocrit levels, along with irreversible decreases in leukocyte and thrombocyte. While TG leaf extract did not significantly affect serum glutamic pyruvic transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT), or creatinine levels, bilirubin levels increased, but remained within normal ranges. However, histopathological findings at 40 mg/kg BW revealed congestion and inflammation in the digestive organs, as well as neutrophil infiltration and congestion in metabolism-related organs, the lungs, liver, kidneys, and lymph nodes. These pathological changes persisted throughout the recovery period.CONCLUSION: TG leaf extract raises safety concerns, particularly at a dose of 40 mg/kg BW, as it induces irreversible organ pathology despite reversible changes in blood parameters.KEYWORDS: Indonesian Tectona grandis Lf, subchronic, toxicity, natural, food, colorant
GSH-conjugation Reduces PGV-1 Cytotoxicity and Its Ability in Downregulating N-Myc, β-catenin, and p62 Protein in Huh-6 Cells
Get PDFBACKGROUND: Pentagamuvone-1 (PGV-1), a synthetic curcumin analogue, exhibits potent anticancer activity against Hepatocellular Carcinoma (HCC) by disrupting cell cycle regulation and downregulating key oncogenes such as N-Myc. Numerous studies have examined the role of glutathione (GSH) conjugation in modulating the anticancer properties of curcumin and its analogues. In contrast, the impact of PGV-1 metabolism, particularly GSH conjugation, and its implications for anticancer efficacy have not yet been elucidated. This study was performed to prepare GSH-conjugated PGV-1 (PGV-1-(GSH)2) as the model of PGV-1 metabolite and evaluate its potential distinct cytotoxicity on Huh-6 cells.METHODS: PGV-1 was synthesized via an acid-catalyzed reaction between 4-hydroxy-3,5-dimethylbenzaldehyde and cyclopentanone while PGV-1-(GSH)2 was obtained through reflux at 70oC for 2 hours. The cytotoxic effects of PGV-1 and PGV-1-(GSH)2 on Huh-6 and JHH4, two HCC cells, were assessed using a cell counting kit-8 (CCK-8) assay, while immunoblotting was performed to evaluate their impact on N-Myc and its downstream protein such as β-catenin, and p62.RESULTS: PGV-1-(GSH)2 was prepared through GSH conjugation of PGV-1 in orange color solution, as confirmed by Electrospray Ionization Mass Spectrometry (ESI-MS), Fourier Transform Infrared Spectroscopy (FT-IR), and Nuclear Magnetic Resonance (NMR) analysis. Cytotoxicity assays revealed that PGV-1-(GSH)2 exhibited less potent anticancer activity against HCC cells than PGV-1. GSH conjugation also decreased the ability of PGV-1 in downregulating the N-Myc, β-catenin, and p62 protein level.CONCLUSION: The prepared PGV-1-(GSH)2 reduces the cytotoxicity of PGV-1 and its ability on downregulating N-Myc, β-catenin, and p62 in Huh-6 cells. These findings highlight the need for further exploration about the study of PGV-1 metabolism which could affect the anticancer efficacy against HCC.KEYWORDS: curcumin, PGV-1, GSH, HCC, N-My
Sarcopenic Obesity: The Underlying Molecular Pathophysiology and Prospect Therapies
Get PDFBACKGROUND: Age contributes to body composition alteration, rises a common disorder in elderly known as sarcopenic obesity (SO), which is characterized by the combination of obesity (excess fat mass) and sarcopenia (reduced skeletal muscle mass) clinical form and function.CONTENT: The primary cause of SO is insulin resistance. Glucose transporter 4 (GLUT4) dysfunction results in impaired fatty acids oxidation. Decreased muscle mass results in lower mitochondria number and volume. Both will increase oxidative stress. Together with altered myokines in SO, oxidative stress was promoted and lead to higher M1 macrophages and failure in autophagy. The pro-inflammatory condition and dysbiosis links SO to a variety of cardiometabolic conditions, including non-alcoholic fatty liver disease, type 2 diabetes, and cardiovascular disease. The mortality, comorbidities, cardiometabolic diseases, and disability or impairment of SO is higher compare to obesity or sarcopenia alone. Some treatments have been developed for SO including adequate dietary intake, vitamin D and antioxidant supplementation, and exercises.SUMMARY: SO is more prevalent among the elderly and has a significant negative impact on their quality of life. Therefore, maintaining muscle mass and strength as well as preventing obesity should be the key goals of initiatives to support healthy aging.KEYWORDS: aging, body composition, obesity, sarcopenia, skeletal muscle, metabolic syndrom
Triglyceride-Glucose Index as A Crucial Marker for Polycystic Ovary Syndrome Women with Insulin Resistance
Get PDFBACKGROUND: Insulin resistance (IR) is considered as the main driver of polycystic ovary syndrome (PCOS) pathogenesis. In PCOS condition, IR is frequently related to glucose, anthropometric profile, lipid profile, and hormone profile parameters. However, not all PCOS phenotype show IR. Therefore, this study was conducted to determine the association the parameters mentioned above in PCOS subjects with and without IR.METHODS: Fifty PCOS women with IR and 26 PCOS women without IR were recruited. All subjects underwent physical examination for measurement of weight, waist circumference (WC), and body mass index (BMI). Ferriman Gallwey Score (FGS) was used to evaluate hirsutism. Blood sample was taken from each subject for measurement of fasting glucose, postprandial glucose, fasting insulin, low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol, triglyceride (TG), sex hormone binding globulin (SHBG), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating hormone (FSH), and prolactin. Homeostatic model assessment for IR (HOMA-IR), TG-glucose index (TyGI), and free testosterone index (FTI) were then calculated.RESULTS: From all the parameters examined, only fasting insulin (p<0.001), HOMA-IR (p<0.001), SHBG (p=0.012), TG (p<0.001), and TyGI (p=0.008) that show significant differences between PCOS subjects with and without IR. After multivariate analysis, TyGI was found to have strong association with IR occurrence in PCOS subjects (p=0.005) with an odd ratio of 5.26 (1.65–16.74).CONCLUSION: TyGI appears to have a significant association with the IR occurrence in PCOS subjects. Hence, it can be suggested that TyGI could be an important marker for PCOS women with IR.KEYWORDS: insulin resistance, lipid metabolism, polycystic ovary syndrome, triglyceride-glucose inde
Obesity: A Multi Perspective of Physiology and Neurobiology Energy Regulation
Get PDFBACKGROUND: World Health Organization has reported four million people die every year due to obesity comorbidity, and the prevalence of obesity is keep increasing, especially after COVID-19. Obesity has been defined as a chronic disease involving adipose tissue dysfunction which leads to metabolic diseases and psychosocial consequences. The review article will highlight some recent researches regarding the new conceptual framework that integrates both metabolic drives, as well as to summarize the numerous discussions about the current understanding of hypothalamic control of food intake and energy homeostasis.CONTENT: Obesity apparently is not simply regulated only by food and exercise. Hypothalamus takes part in controlling energy intake and expenditure via appetite regulation. Hedonic control in cortical and subcortical brain areas process cognitive, reward, information, and executive function. Managing metabolic adaptation, browning the white adipose tissue, and preserving lean mass can be another strategy to safely manage obesity.SUMMARY: Obesity need to be managed in a multimodal strategy including neurophysiology and physiology approach, together with environment support. Thus, a weight regain can be prevented. Commitment from both scientific and regulation point of view can shed a light to eradicate obesity.KEYWORDS: adipocyte, appetite, nutrition, obesity, physical activity, reward, satiet
Effect of the High-Intensity Interval Training on BDNF Level in Ischemic Stroke Rat Model on the Recovery of Motor Function
Get PDFBACKGROUND: Stroke is one of the major causes of disability in the world. High-intensity interval training (HIIT) is known as a novel treatment to promote stroke recovery. However, the results differ in their effects on irisin, which is a regulator of brain-delivered neurotrophic factor (BDNF). Therefore, this study was conducted to investigate the effect of HIIT on BDNF and irisin levels in a rat model of ischemic stroke with middle cerebral artery occlusion (MCAO) induction on recovery motor function.METHODS: Rats were categorized into 4 groups: sham, MCAO, MCAO+moderate-intensity interval training (MIIT), and MCAO+HIIT. MCAO induction was performed to create the ischemic stroke rats model. The motor function was assessed through rotarod and footprint tests. Blood samples were obtained 6 days before MCAO and 14 days after MCAO to examine BDNF and irisin levels with enzyme-linked immunosorbent assay (ELISA). Brain tissue samples were collected 14 days after MCAO for histopathological examination of cortical tissue with hematoxylin-eosin (HE) staining.RESULTS: Rats in the MCAO+HIIT group exhibited an enhanced ability to walk on the rotarod (p=0.016). The stride-length hind paw right in the MCAO+HIIT group demonstrated a noteworthy increase in comparison to baseline value (p=0.036), and the stride-length fore paw right showed a significant increase in both the MCAO+HIIT (p=0.036) and MCAO groups (p=0.034). BDNF significantly improved in the MCAO+MIIT (p=0.043) and MCAO+HIIT groups (p=0.018). The irisin level only showed a significant enhancement in the MCAO+HIIT group (p=0.018).CONCLUSION: HIIT increased motor function, while BDNF level increased with HIIT and MIIT intervention. This preclinical research is useful for supporting the recovery of stroke patients by HIIT intervention.KEYWORDS: BDNF, HIIT, MIIT, irisin, ischemic stroke, MCA
Propofol and Nigella sativa L Seeds Ethanol Extract Enhance Neuroprotection: A Histopathological Study in Rat Models with Traumatic Brain Injury
Get PDFBACKGROUND: Nigella sativa has been known for its neuroprotective properties, while propofol is an anesthetic induction drug that has been widely used in the treatment of traumatic brain injury (TBI). To determine the effectiveness of both active ingredients, it is necessary to compare their neuroprotective effects. This study was performed since not many studies have compared the effect of propofol and Nigella sativa seeds ethanol extract (NSSEE) or their combination on histopathological features in TBI cases.METHODS: Thirty male rat models were divided into 5 groups. Four groups received TBI induction with the methods of Feeney’s weight drop model, while another group (control group) did not receive TBI induction. Groups with TBI induction, later received no treatment, treatment with 500 mg/kg NSSEE orally, 10 mg/kg propofol intravenously, or a combination of NSSEE and propofol. After 8 days, rats were euthanized by cervical dislocation. Subsequently, a craniotomy was performed to obtain brain samples. The brain sample was placed in 10% neutral buffered formalin for histopathological examination, which includes brain hemorrhage, congestion, inflammatory cells, necrosis, apoptosis, and degeneration.RESULTS: The present study found that NSSEE showed greater efficacy in histopathological features (brain hemorrhage, congestion, inflammatory cells, necrosis, apoptosis, and degeneration) in rat models with TBI compared to propofol or a combination of propofol and NSSEE.CONCLUSION: NSSEE has superior potential compared to propofol and the combination of both in providing neuroprotection in TBI cases.KEYWORDS: traumatic brain injury, propofol, Nigella sativa seeds ethanol extract, histopathology, neuroprotectiv
Vegetables Spices Fermentation Extract Inhibit NAFLD Development by Attenuation of Steatosis through Suppression of C/EBPα and TNFα mRNA Expression
Get PDFBACKGROUND: Non-alcoholic fatty liver disease (NAFLD), characterized by inflammation and steatosis, is one of the metabolic problems that trigger serious complications. Statin is usually used for NAFLD therapy, however, statin intolerance and resistance reduce the effectiveness of NAFLD treatment. Therefore, this study was conducted to develop the phytopharmaca against NAFLD by elucidating the anti-inflammatory and steatosis suppression of vegetable spices fermentation extract (VSFE) in rabbits induced with high-fat diet (HFD).METHODS: Twenty New Zealand White rabbits were determined into 4 groups; which were groups receiving standard diet (SD), HFD, HFD and 100 mg/kgBW VSFE, as well as HFD and 200 mg/kgBW VSFE. mRNA expressions of tumor necrosis factor alpha (TNFα) and CCAAT/enhancer-binding protein alpha (C/EBPα) were evaluated. The TNFα concentration was quantified after protein and RNA isolation. Inflammation and steatosis were observed in liver hematoxylin-eosin-stained preparate using microscope.RESULTS: Macrophage cells and hepatic steatosis showed significant decrease in a drug dependent manner. An effective dose of 200 mg/kgBW decreased C/EBPα and TNFα expression to 0.45±0.32 and 0.72±0.29 (p=0.013 and p=0.002, compared to the HFD group), respectively. TNFα inflammatory cytokine concentrations also responded to the administration of 100 mg/kgBW and 200 mg/kgBW doses, with the value of 31.72±10.40 mg/dL and 48.35±7.15 mg/dL (p=0.009 and p=0.002, compared to the HFD group), respectively.CONCLUSION: VSFE might prevent NAFLD by inhibit steatosis and inflammation through suppression of C/EBPα expression and TNFα expression.KEYWORDS: C/EBPα, TNFα, fermentation, steatosis, NAFL
mRNA Expression and DNA Methylation of CXCL16 in Menstrual Blood and Endometrium Tissue of Subjects with Endometriosis and Pelvic Pain
Get PDFBACKGROUND: The cytokine chemokine ligand 16 (CXCL16) plays an important role in the pathophysiology of endometriosis by regulating the inflammatory response and contributing to the pain-associated endometriosis. Despite this, the impact of epigenetic modifications, such as DNA methylation, on CXCL16 has yet to be fully understood. Therefore, this research was conducted to assess both the mRNA expression and DNA methylation levels of the proinflammatory gene CXCL16 in the endometrium tissue and menstrual blood of patients with and without endometriosis.METHODS: Thirty-five women with and without endometriosis were involved in this research. Subjects' menstrual blood samples were collected using filter paper pads, meanwhile the endometrium tissue were collected by performing biopsy, from which DNA and RNA were extracted. The DNA methylation levels of the CXCL16 were measured using the pyrosequencing method following bisulfite conversion treatment. Meanwhile, the mRNA expression level was measured using the quantitative polymerase chain reaction (qPCR) method and analyzed with the Livak method.RESULTS: The mRNA expression of CXCL16 in menstrual blood of endometriosis subjects was 2.42 times higher compared to control group (p=0.030). Furthermore, the expression of CXCL16 in menstrual blood was identical to that in endometrial tissue (p=0.173). DNA methylation analysis showed that CXCL16 in the menstrual blood of endometriosis subjctes had lower methylation levels compared to controls (p=0.004), indicating hypomethylation.CONCLUSION: Increased mRNA expression and hypomethylation of CXCL16 in the menstrual blood of endometriosis patients could serve as a direct marker for diagnosing endometriosis. However, further study to validate these findings and explore the potential of CXCL16 as a diagnostic tool, and additional research involving larger patient for the cohorts study is necessary.KEYWORDS: CXCL16, DNA methylation, endometrium, menstrual blood, mRNA expression, pain