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Fulltext Computational prediction of changes in brain metabolic fluxes during Parkinson's disease from mRNA expression

Supandi F, van Beek JHGM

PLoS One, 2018;13(9):e0203687.
PMID: 30208076 DOI: 10.1371/journal.pone.0203687

BACKGROUND: Parkinson's disease is a widespread neurodegenerative disorder which affects brain metabolism. Although changes in gene expression during disease are often measured, it is difficult to predict metabolic fluxes from gene expression data. Here we explore the hypothesis that changes in gene expression for enzymes tend to parallel flux changes in biochemical reaction pathways in the brain metabolic network. This hypothesis is the basis of a computational method to predict metabolic flux changes from post-mortem gene expression measurements in Parkinson's disease (PD) brain.
RESULTS: We use a network model of central metabolism and optimize the correspondence between relative changes in fluxes and in gene expression. To this end we apply the Least-squares with Equalities and Inequalities algorithm integrated with Flux Balance Analysis (Lsei-FBA). We predict for PD (1) decreases in glycolytic rate and oxygen consumption and an increase in lactate production in brain cortex that correspond with measurements (2) relative flux decreases in ATP synthesis, in the malate-aspartate shuttle and midway in the TCA cycle that are substantially larger than relative changes in glucose uptake in the substantia nigra, dopaminergic neurons and most other brain regions (3) shifts in redox shuttles between cytosol and mitochondria (4) in contrast to Alzheimer's disease: little activation of the gamma-aminobutyric acid shunt pathway in compensation for decreased alpha-ketoglutarate dehydrogenase activity (5) in the globus pallidus internus, metabolic fluxes are increased, reflecting increased functional activity.
CONCLUSION: Our method predicts metabolic changes from gene expression data that correspond in direction and order of magnitude with presently available experimental observations during Parkinson's disease, indicating that the hypothesis may be useful for some biochemical pathways. Lsei-FBA generates predictions of flux distributions in neurons and small brain regions for which accurate metabolic flux measurements are not yet possible.
Caudate lobe abscess: Challenging site with less invasive option of treatment: A case series

Supandi FN, Singh B, Roslan R, Husin I, Lee TS

Ann Hepatobiliary Pancreat Surg, 2021 Jun 30;25(Suppl 1):S240.
PMID: 34230345 DOI: 10.14701/ahbps.EP-39

Introduction: The rarity of caudate lobe abscess has made it difficult to outline a treatment algorithm for this pathology due to its anatomically challenging site. Caudate lobe abscesses also poses a risk of rupture, making its management more complicated. However, advances in imaging have made it possible for early detection and paradigm shift in its management from open surgery to non-operative intervention.
Methods: All patients with isolated caudate lobe abscess were selected retrospectively and diagnosis was confirmed by imaging. Patient in this case series underwent either percutaneous or endoscopic drainage and empirical antibiotic therapy alone.
Results: There are 5 patients in this case series, 3 of them underwent percutaneous drainage, 1 of them treated with antibiotic alone and another underwent endoscopic ultrasound (EUS)-guided drainage. All patients showed complete resolution of caudate lobe abscess without procedural complications.
Conclusions: The caudate lobe, which lies posterior to the hepatoduodenal ligament and anterior to the inferior vena cava exposes the patient to possible life-threatening complications when subjected to drainage via a percutaneous approach. EUS allows not only identification of intervening vessels which is the major reason for technical difficulty in percutaneous drainage, but excellent visualization of abscess cavities and the surrounding landmarks. In conclusion, non-surgical approach is our treatment of choice in management of caudate lobe liver abscess.
Ferroptosis-Related Long Noncoding RNA Signature Predicts Prognosis of Clear Cell Renal Carcinoma

Liu JW, Supandi F, Dhillon SK

Folia Biol (Praha), 2022;68(1):1-15.
PMID: 36201853

Clear cell renal cell carcinoma (ccRCC) is very common and accounts for most kidney cancer deaths. While many studies are being conducted in finding the prognostic signatures of ccRCC, we believe that ferroptosis, which involves programmed cell death dependent on iron accumulation, has therapeutic potential in ccRCC. Recent research has shown that long noncoding RNAs (lncRNAs) are involved in ferroptosis-related tumour processes and are closely related to survival in patients with ccRCC. Hence, in this study we aim to further explore the role of ferroptosis-related lncRNAs (FRLs) in ccRCC, hoping to establish a signature to predict the survival outcome of ccRCC. We analysed transcriptome data from The Cancer Genome Atlas database (TCGA) and ferroptosis-related genes (FRGs) from FerrDb to identify FRLs using Pearson's correlation. Lasso Cox regression analysis and multivariate Cox proportional hazards models screened seventeen optimal FRLs for developing prognostic signatures. Kaplan-Meier survival curves and ROC curves were then plotted for validating the sensitivity, specificity, and accuracy of the identified signatures. Gene Set Enrichment Analysis and CIBERSORT algorithm were deployed to explore the role of these FRLs in the tumour microenvironment. It was concluded that these models demonstrate excellent performance in predicting prognosis among patients with ccRCC, also indicating association with the clinicopathologic parameters such as tumour grade, tumour stage and tumour immune infiltration. In conclusion, our findings provide novel insights into ferroptosis-related lncRNAs in ccRCC, which are important targets for investigating the tumorigenesis of ccRCC.
Fulltext Docking Studies and Molecular Dynamics Simulation of Ipomoea batatas L. Leaves Compounds as Lipoxygenase (LOX) Inhibitor

Yeni Y, Supandi S, Dwita LP, Suswandari S, Shaharun MS, Sambudi NS

J Pharm Bioallied Sci, 2020 Nov;12(Suppl 2):S836-S840.
PMID: 33828386 DOI: 10.4103/jpbs.JPBS_103_20

Background: Inflammatory mediators produced by cyclooxygenase (COX) and lipoxygenase (LOX) pathways are responsible for many human diseases, such as cancer, arthritis, and neurological disorders. Flavonoid-containing plants, such as Ipomoea batatas leaves, have shown potential anti-inflammatory activity.
Objectives: This study aimed to predict the actions of 10 compounds in I. batatas leaves, which are YGM-0a [cyanidin 3-0-sophoroside-5-0-glucosede], YGM-0f [cyanidin 3-O-(2-0-(6-0-(E)-p-coumaroyl-β-D-glucopyranosyl)-β-D-glucopyranoside)-5-0-β-D-glucopyranoside], YGM-1a [cyanidin 3-(6,6'-caffeylp-hydroxybenzoylsophoroside) -5-glucoside], YGM-1b [cyanidin 3-(6,6'-dicaffeylsophor-oside)-5-glucoside], YGM-2 [cyanidin 3-(6-caffeylsophoroside)-5-glucoside], YGM-3 [cyanidin 3-(6,6'-caffeyl-ferulylsophoroside)-5-glucoside], YGM-4b [peonidin 3-(6,6'-dicaffeylsophoroside)-5- glucoside], YGM-5a [peonidin 3-(6,6'-caffeylphydroxybenzo-ylsophoroside)-5-gluco-side], YGM-5b [cyanidin 3-6-caffeylsophoroside)-5-glucosede], and YGM-6 [peonidin 3-(6,6'-caffeylferulylsophoroside)-5-glucoside] as LOX inhibitors, and also predict the stability of ligand-LOX complex.
Materials and Methods: The compounds were screened through docking studies using PLANTS. Also, the molecular dynamics simulation was conducted using GROMACS at 310K.
Results: The results showed that the most significant binding affinity toward LOX was shown by YGM-0a and YGM-0a, and the LOX complex in molecular dynamics simulation showed stability for 20 ns.
Conclusion: Based on Docking Studies and Molecular Dynamics Simulation of I. Batatas Leaves compounds, YGM-0a was shown to be the most probable LOX inhibitor.
Fulltext Using bioconductor package BiGGR for metabolic flux estimation based on gene expression changes in brain

Gavai AK, Supandi F, Hettling H, Murrell P, Leunissen JA, van Beek JH

PLoS One, 2015;10(3):e0119016.
PMID: 25806817 DOI: 10.1371/journal.pone.0119016

Predicting the distribution of metabolic fluxes in biochemical networks is of major interest in systems biology. Several databases provide metabolic reconstructions for different organisms. Software to analyze flux distributions exists, among others for the proprietary MATLAB environment. Given the large user community for the R computing environment, a simple implementation of flux analysis in R appears desirable and will facilitate easy interaction with computational tools to handle gene expression data. We extended the R software package BiGGR, an implementation of metabolic flux analysis in R. BiGGR makes use of public metabolic reconstruction databases, and contains the BiGG database and the reconstruction of human metabolism Recon2 as Systems Biology Markup Language (SBML) objects. Models can be assembled by querying the databases for pathways, genes or reactions of interest. Fluxes can then be estimated by maximization or minimization of an objective function using linear inverse modeling algorithms. Furthermore, BiGGR provides functionality to quantify the uncertainty in flux estimates by sampling the constrained multidimensional flux space. As a result, ensembles of possible flux configurations are constructed that agree with measured data within precision limits. BiGGR also features automatic visualization of selected parts of metabolic networks using hypergraphs, with hyperedge widths proportional to estimated flux values. BiGGR supports import and export of models encoded in SBML and is therefore interoperable with different modeling and analysis tools. As an application example, we calculated the flux distribution in healthy human brain using a model of central carbon metabolism. We introduce a new algorithm termed Least-squares with equalities and inequalities Flux Balance Analysis (Lsei-FBA) to predict flux changes from gene expression changes, for instance during disease. Our estimates of brain metabolic flux pattern with Lsei-FBA for Alzheimer's disease agree with independent measurements of cerebral metabolism in patients. This second version of BiGGR is available from Bioconductor.
Pancreatic angiosarcoma: A case report

Supandi FN, Singh B, Thamutaram H, Lim KF, Yusoff AR

Ann Hepatobiliary Pancreat Surg, 2021 Jun 30;25(Suppl 1):S388.
PMID: 34230285 DOI: 10.14701/ahbps.EP-189

Introduction: Pancreatic cancer has a relative 5-year survival of less than 10%. The most common neoplasm of the pancreas is ductal adenocarcinoma, which comprises 85% of all malignant pancreatic tumours. Primary pancreatic sarcomas are extremely rare which account for less than 0.1% of all pancreatic malignancies and pancreatic angiosarcomas attribute to 1% of all tissue sarcomas. Sarcomas of the pancreas are more aggressive and have a dismal prognosis.
Methods: A 69-year-old lady presented with obstructive jaundice, abdominal discomfort and associated constitutional symptoms. She was investigated and found to have obstructive jaundice with normal tumor marker assays. An endoscopic ultrasound was done followed by a needle biopsy which confirmed a pancreatic head angiosarcoma followed by an ERCP and a stent placement. A CT abdomen done revealed a pancreatic head and uncinate tumor with a stent in the common bile duct.
Results: Patient underwent a pylorus preserving pancreaticoduodenectomy with an uneventful post-operative recovery. She defaulted her oncology appointments and was followed up with serial imaging. She developed a local recurrence 18 months after surgery and succumbed to her disease after 3 years.
Conclusions: Pancreatic angiosarcoma is an aggressive tumor compared to other pancreatic malignancies. For a definite diagnosis of angiosarcoma, histopathologic and immunohistochemical analysis are necessary. Surgical resection offers the only possible cure, while oncological treatment has variable outcome. Currently, there are no treatment protocols available due to the small number of cases present in literature.
Fulltext Preliminary Phytochemical Screening, In Vitro Antidiabetic, Antioxidant Activities, and Toxicity of Leaf Extracts of Psychotria malayana Jack

Nipun TS, Khatib A, Ahmed QU, Nasir MHM, Supandi F, Taher M, et al.

Plants (Basel), 2021 Dec 07;10(12).
PMID: 34961160 DOI: 10.3390/plants10122688

Psychotria malayana Jack belongs to the Rubiacea and is widespread in Southeast Asian countries. It is traditionally used to treat diabetes. Despite its potential medicinal use, scientific proof of this pharmacological action and the toxic effect of this plant are still lacking. Hence, this study aimed to investigate the in vitro antidiabetic and antioxidant activities, toxicity, and preliminary phytochemical screening of P. malayana leaf extracts by gas chromatography-mass spectrometry (GC-MS) after derivatization. The antidiabetic activities of different extracts of this plant were investigated through alpha-glucosidase inhibitory (AGI) and 2-NBDG glucose uptake using 3T3-L1 cell line assays, while the antioxidant activity was evaluated using DPPH and FRAP assays. Its toxicological effect was investigated using the zebrafish embryo/larvae (Danio rerio) model. The mortality, hatchability, tail-detachment, yolk size, eye size, beat per minute (BPM), and body length were taken into account to observe the teratogenicity in all zebrafish embryos exposed to methanol extract. The LC50 was determined using probit analysis. The methanol extract showed the AGI activity (IC50 = 2.71 ± 0.11 μg/mL), insulin-sensitizing activity (at a concentration of 5 µg/mL), and potent antioxidant activities (IC50 = 10.85 μg/mL and 72.53 mg AAE/g for DPPH and FRAP activity, respectively). Similarly, the water extract exhibited AGI activity (IC50 = 6.75 μg/mL), insulin-sensitizing activity at the concentration of 10 μg/mL, and antioxidant activities (IC50 = 27.12 and 33.71 μg/mL for DPPH and FRAP activity, respectively). The methanol and water extracts exhibited the LC50 value higher than their therapeutic concentration, i.e., 37.50 and 252.45 µg/mL, respectively. These results indicate that both water and methanol extracts are safe and potentially an antidiabetic agent, but the former is preferable since its therapeutic index (LC50/therapeutic concentration) is much higher than for methanol extracts. Analysis using GC-MS on derivatized methanol and water extracts of P. malayana leaves detected partial information on some constituents including palmitic acid, 1,3,5-benzenetriol, 1-monopalmitin, beta-tocopherol, 24-epicampesterol, alpha-tocopherol, and stigmast-5-ene, that could be a potential target to further investigate the antidiabetic properties of the plant. Nevertheless, isolation and identification of the bioactive compounds are required to confirm their antidiabetic activity and toxicity.
Fulltext Characterization of α-Glucosidase Inhibitors from Psychotria malayana Jack Leaves Extract Using LC-MS-Based Multivariate Data Analysis and In-Silico Molecular Docking

Nipun TS, Khatib A, Ibrahim Z, Ahmed QU, Redzwan IE, Saiman MZ, et al.

Molecules, 2020 Dec 12;25(24).
PMID: 33322801 DOI: 10.3390/molecules25245885

Psychotria malayana Jack has traditionally been used to treat diabetes. Despite its potential, the scientific proof in relation to this plant is still lacking. Thus, the present study aimed to investigate the α-glucosidase inhibitors in P.malayana leaf extracts using a metabolomics approach and to elucidate the ligand-protein interactions through in silico techniques. The plant leaves were extracted with methanol and water at five various ratios (100, 75, 50, 25 and 0% v/v; water-methanol). Each extract was tested for α-glucosidase inhibition, followed by analysis using liquid chromatography tandem to mass spectrometry. The data were further subjected to multivariate data analysis by means of an orthogonal partial least square in order to correlate the chemical profile and the bioactivity. The loading plots revealed that the m/z signals correspond to the activity of α-glucosidase inhibitors, which led to the identification of three putative bioactive compounds, namely 5'-hydroxymethyl-1'-(1, 2, 3, 9-tetrahydro-pyrrolo (2, 1-b) quinazolin-1-yl)-heptan-1'-one (1), α-terpinyl-β-glucoside (2), and machaeridiol-A (3). Molecular docking of the identified inhibitors was performed using Auto Dock Vina software against the crystal structure of Saccharomyces cerevisiae isomaltase (Protein Data Bank code: 3A4A). Four hydrogen bonds were detected in the docked complex, involving several residues, namely ASP352, ARG213, ARG442, GLU277, GLN279, HIE280, and GLU411. Compound 1, 2, and 3 showed binding affinity values of -8.3, -7.6, and -10.0 kcal/mol, respectively, which indicate the good binding ability of the compounds towards the enzyme when compared to that of quercetin, a known α-glucosidase inhibitor. The three identified compounds that showed potential binding affinity towards the enzymatic protein in molecular docking interactions could be the bioactive compounds associated with the traditional use of this plant.
Synthesis of tungsten oxide/ amino-functionalized sugarcane bagasse derived-carbon quantum dots (WO3/N-CQDs) composites for methylene blue removal

Nugraha MW, Zainal Abidin NH, Supandi, Sambudi NS

Chemosphere, 2021 Aug;277:130300.
PMID: 33774232 DOI: 10.1016/j.chemosphere.2021.130300

In this present study, the tungsten oxide/amino-functionalized sugarcane bagasse derived-carbon quantum dots (WO3/N-CQDs) composite has successfully been prepared through a simple mixing process. The WO3 was synthesized through a precipitation method, and CQDs were amino-functionalized using ethylenedinitrilotetraacetic acid (EDTA) and ethylenediamine (EDA) through one-pot hydrothermal method. It is revealed that N-CQDs incorporation into WO3 alters the bandgap energy, crystallinity, surface area, and photoluminescence (PL) properties. The produced composites exhibit higher monoclinic WO3 crystallinity, larger surface area, lower bandgap energy and quenched photoluminescence intensity. The as-prepared WO3/N-CQDs composites exhibit better adsorption and photocatalytic degradation performance of methylene blue (MB) than the pristine WO3. It shows that the combination of N-CQDs and WO3 enhanced visible light absorption, by lowering the bandgap energy of WO3 from 2.175 to 1.495 eV. The best performance composite is WO3/N-CQDs EDA 2.5% with an efficiency of 96.86%, removal rate constant of 0.02017/min, and chemical oxidation demand (COD) removal efficiency achieved 84.61%. Moreover, the WO3/N-CQDs EDA 2.5% shows a significant photocatalytic activity even at higher MB initial concentration with 92.93% removal for 50 ppm MB. Subsequently, the composite also has good stability after a sequential 3-times cycle of degradation with 86.85% removal. The increasing photocatalytic performance is affected by the quenching effect of PL and lower bandgap energy. The lower intensity of the PL indicates the reduced charge carrier recombination resulting in increased photocatalytic activity. The combination of N-CQDs and WO3 resulted in improved photodegradation, which shows its significant potential to be utilized for wastewater treatment.