Medical and Health Sciences

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    Kappa carrageenan-based hydrogel for floating drug delivery system in the stomach
    (Universiti Teknologi Malaysia, 2016) Selvakumaran, Suguna
    The main objective of drug delivery system is to attain an optimum concentration of the drug/bioactive agents in blood or tissue at a desired release rate. A problem frequently encountered with drug dosage is its inability to increase their residence time in the gastrointestinal tract, consequently leading to a poor drug release profile and low bioavailability. Therefore, development of an effective carrier is needed. This research aims to develop a potential dual effect drug carrier for floating drug delivery system in the stomach which targets the upper part of stomach and also benefits the lower part of stomach (stomach lining). Kappa carrageenan-based floating hydrogel was formulated using calcium carbonate as pore forming agents where it was further optimized using genipin (1.5 mM) and magnesium oxide nanoparticles (0.10 g) as compared to non-floating hydrogels. Characterization of hydrogel was carried out using Fourier transform infrared spectroscopy, x-ray diffraction, thermogravimetric analysis and field emission scanning electron microscope. The release behaviour of a model drug, ranitidine hydrochloride was firstly studied in simulated gastric fluid condition at 37 °C. The results showed that optimized floating hydrogels provided high performance (70%, 7 h) of controlled drug release profile with reduced initial burst release (18%, 30 min). The Korsmeyer-Peppas model further demonstrated that ranitidine hydrochloride release from hydrogels followed non- Fickian diffusion. The optimized floating hydrogel was then subjected to cytotoxicity analysis which proved its biocompatibility, non-toxicity and it is safe to use. Secondly, beneficial effect towards the lower part of stomach was determined from the presence of magnesium oxide nanoparticles in the hydrogel. The antibacterial activity was studied on the optimized floating hydrogel using E. coli and it showed 8.44% of bacterial inhibition. The characteristics of the hydrogel with floating behaviour more than 12 hours, reduced initial burst release with controlled drug release, along with effective bacterial inhibition and good biocompatibility suggested that the developed floating nanocomposite hydrogel is a promising drug carrier in the stomach
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    Development of niosome-loaded bromelain as anti-inflammatory agent
    (Universiti Teknologi Malaysia, 2015) Chermahini, Siavash Hosseinpour
    Inflammation can be considered as common human being anxiousness. Nonsteroidal anti-inflammatory drugs (NSAIDS) are usually prescribed to reduce inflammation but they may lead to serious side-effects. Recently anti-inflammatory property of bromelain have been documented, but oral administration of bromelain requires higher concentration as compared to topical delivery. Hence, topical delivery of bromelain as a more favorable anti-inflammatory solution for skin inflammation, but it has to overcome stratum corneum (SC) skin barrier. The aims of this study were to design a bromelain delivery system based on niosome and to evaluate the efficacy of the bromelain-niosome system. Moreover, anti-inflammatory effect of niosome encapsulated bromelain was studied by Interleukin-6 (IL-6) and Tumor Necrotic Factor–alpha (TNF-a) response. This potential anti-inflammatory property of niosome encapsulated bromelain was investigated in-vitro and in-vivo, using human skin fibroblast cell line (HSF 1184) and mice, respectively. Lipopolysaccharide (LPS) was used in volume of 1.5 µg/mL in-vitro and 7.5 µg/mL in-vivo to induce inflammation. The current results showed that 20 µg/mL niosome encapsulated with 10% bromelain after four hours of post treatment significantly eliminated inflammation in HSF 1184 cell line as compared to non-encapsulated bromelain, vehicle (niosome), and controls. Similar result was achieved in mice where 20 mg niosome encapsulated with 10% bromelain was found able to eliminate inflammation after 30 minutes of post treatment. In conclusion, this research provides scientific evidence to show effective transdermal delivery of niosome encapsulated bromelain to reach targeted dermal cells and show its pharmaceutical potential to eliminate skin inflammation.
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    In silico identification of metabolites contributing to type 2 diabetes by integrating specific metabolic pathways
    (Universiti Teknologi Malaysia, 2016) Shia, Yoke Lin
    It is estimated in 2015 that one in eleven adults are suffering from diabetes, this is equivalent to a global population of 415 million. About 90% of the diabetes patients involve type 2 diabetes which is associated to the cellular impaired intermediates within the insulin signaling pathway. Three key intermediates, protein kinase B (PKB) /Akt, protein kinase C-zeta (PKC-ζ), and glucose transporter type 4 (GLUT4) are identified in most of the studies. The current study used a novel approach that integrates the cellular insulin signaling pathway with a systemic glucose regulation model via Michaelis–Menten equation that was able to estimate the insulin-dependent glucose consumption based on the concentration of plasma glucose and translocation percentage of glucose transporter GLUT4. Based on this model, the impact of a single intermediate such as PKB/Akt, PKC-ζ, and GLUT4 was investigated using the software COPASI parameter scan function by multiplying the phosphorylation or activation kinetic of each intermediate with a defective coefficient, dc. The coefficient dc was divided equally into five intervals ranging from 0-1. The same procedure was repeated to measure the effect of the combined impairment of two and subsequently three intermediates. The results showed that the combination of three impaired intermediates best represented the glucose consumption rate mimicking that in diabetic patients. Through the integration of cellular insulin signalling pathway with systemic glucose regulation, the first and second objectives of the study were fulfilled as the major metabolic and signalling pathways link to type 2 diabetes were modeled and a better understanding of the interaction between metabolic and signalling pathways was developed. The integration also fulfilled the third objective of the study as the single and combinational effect of insulin intermediates over the insulin-dependent glucose consumption in normal subject was analyzed. In short, the current study has provided insight into understanding of the underlying impaired glucose uptake in diabetic patients based on the combined impairment of three key intermediates in insulin signalling pathway
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    Synthesis and characterization of spions-bromelan-folic acid on folic acid receptor positive cancer model
    (Universiti Teknologi Malaysia, 2016) Nasiri, Rozita
    Engineering of a physiologically compatible, stable and targetable delivery vehicle superparamagnetic iron oxide nanoparticles-Bromelain-folic acid (SPIONs-Br- FA) was reported. Initially, the synthesized bare SPIONs were coated with citric acid (CA) in order to increase biocompatibility, stability and solubility of the SPIONs. Moreover, through CA coating, carboxyl functional groups for further reactions were produced. Br (as an anti-cancer agent) and FA (as a targeting agent to the folic acid receptor positive (FAR+) cancer cells) were conjugated to the synthesized nanocarrier through 1-ethyl-3-(3-dimethylaminpropyl)carbodiimide hydrochloride/ Nhydroxysuccinimide (EDC/NHS) click chemistry. Subsequently, characterization and physico-chemical analyses were carried out through methods such as Fourier transform infrared spectroscopy, atomic absorption spectroscopy (AAS), dynamic light scattering, vibrating sample magnetometer, x-ray diffraction, transmission electron microscopy (TEM) and field emission scanning electron microscopy. The in vitro tetrazolium dye (MTT) assay and blood compatibility tests were performed to confirm the biocompatibility of the engineered nano delivery system. High level of SPIONs-FA binding to FAR+ cell lines (HeLa, MDA-MB-231 and 4 T1) compared to folic acid receptor negative (FAR-) cell lines (HSF 1184 and MDA-MB-468) was assured via qualitative and quantitative in vitro binding studies (Prussian blue assay and AAS analysis). The reason may be higher transport of SPIONs-FA through the mechanism of receptor endocytosis pathway into FAR+ cells in comparison with the mechanism of passive diffusion of SPIONs into the FAR- cells. Cytotoxicity studies carried out in human cell lines (HSF 1184, MDA-MB-468, MDA-MB-231 and HeLa) and mouse breast cancer cells (4 T1) showed significant dose advantage with SPIONs-Br-FA in reducing the half maximal inhibitory concentration (IC50) values compared with neat Br. Through morphological observation studies by inverted microscope and acridine orange/ethidium bromide fluorescent staining method, it was disclosed that the cells had undergone apoptosis since the shrinkage as well as the apoptotic bodies were obviously seen. The results showed that SPIONs-Br-FA was a rewarding candidate to suppress the migration of the FAR+ cancer cells as well as to inhibit colony formation of the FAR+ cancer cells compared to neat Br. The percentage of apoptotic cells (apoptotic index) with more condensed and fragmented chromatin increased sharply in SPIONs-Br-FA treated cells compared to the neat Br. Overall, the SPIONs-Br-FA induced higher percentage of apoptotic cells than the neat Br. Moreover, after treatment protocol performance on 4 T1 tumor bearing mice, the qualitative and quantitative biodistribution study were carried out in vital organs and tumor using colorimetric method (AAS) and TEM method which indicate significant tumor targetability of SPIONs-FA. Finally, the tumor volume and inhibition growth rate were measured in 4 T1 tumor bearing mice treated with different SPIONs formulations to investigate the effectiveness of SPIONs- Br-FA. Administration of SPIONs-Br-FA through tail vein (three times a week) during the four-week treatment period reduced the tumor burden of tumor bearing mice and also increased their life-span when compared with SPIONs-Br and neat Br at same concentration of bromelain. In conclusion, the current results indicated the dualfunctional synthesized SPIONs-Br-FA is a promising tool in the field of biomedicine, chiefly cancer therapy.
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    Andrographis paniculata crude extract and its polymeric nanoparticles fraction for inhibition of cervix cancer cells
    (Universiti Teknologi Malaysia, 2018) Sanati, Parisa
    Cervix cancer contributes to high mortality rate around the world and various efforts have been done to identify suitable treatments and remedies, including the use of Andrographis paniculata, a plant rich in andrographolide (AG) with remarkable anti-cancer properties. AG in the form of nanoparticles has been proven to increase the efficiency and bioavailability of the herbal medicine. So far, no studies have been reported on the use of spontaneous emulsion solvent diffusion (SESD) method to produce polymeric nanoparticles (PNPs) of AG. Therefore, this study was conducted to produce crude extract and AG rich fraction, and SESD method was used to prepare the extracts into PNPs, which were then characterized and tested on cervix cancer cells. The crude extract and AG rich fraction were prepared by reflux technique, followed by successive soxhlet extraction. Polyvinyl alcohol (1%) was found to be the best concentration of emulsifier to prepare the PNPs at 2400 rpm for 5 min in a homogenizer. The nanomization achieved 80 % encapsulation efficiency with the particle size, 149.38 and 163.40 nm for crude extract and AG rich fraction, respectively. The low polydispersity index (0.23-0.38) also revealed uniform crude extract and AG rich fraction PNPs. The zeta potential values -37.30 and -57.85 mV for crude extract and AG rich fraction, respectively indicated stables PNPs. No significant chemical interaction was found between AG and polylactic-co-glycolic acid polymer on attenuated total reflection images. In vitro AG release showed a high initial burst release for both PNPs. The AG extracts, as well as their PNPs showed dose and time dependent anti-proliferative activities against hela cells. AG rich fraction exhibited higher anti-cancer activity than crude extract. Both extracts and their PNPs did not have any inhibition effect on proliferation of normal cells. Therefore, AG rich fraction PNPs was selective against the growth of cervix cancer cells. The findings of this study will be beneficial for relevant healthcare and therapeutic industries