Browsing by Author "Bhambra, Avninder S."
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Item Metadata only A structure-based virtual high-throughput screening, molecular docking, molecular dynamics and MM/PBSA study identified novel putative drug-like dual inhibitors of trypanosomal cruzain and rhodesain cysteine proteases(Springer, 2023-01-08) Bhambra, Avninder S.; Eurtivong, Chatchakorn; Zimmer, Collin; Schirmeister, Tanja; Butkinaree, Chutikarn; Saruengkhanphasit, Rungroj; Niwetmarin, Worawat; Ruchirawat, SomsakVirtual screening a collection of ~ 25,000 ChemBridge molecule collection identified two nitrogenous heterocyclic molecules, 12 and 15, with potential dual inhibitory properties against trypanosomal cruzain and rhodesain cysteine proteases. Similarity search in DrugBank found the two virtual hits with novel chemical structures with unreported anti-trypanosomal activities. Investigations into the binding mechanism by molecular dynamics simulations for 100 ns revealed the molecules were able to occupy the binding sites and stabilise the protease complexes. Binding affinities calculated using the MM/PBSA method for the last 20 ns showed that the virtual hits have comparable binding affinities to other known inhibitors from literature suggesting both molecules as promising scaffolds with dual cruzain and rhodesain inhibition properties, i.e. 12 has predicted ΔGbind values of − 38.1 and − 38.2 kcal/mol to cruzain and rhodesain, respectively, and 15 has predicted ΔGbind values of − 34.4 and − 25.8 kcal/mol to rhodesain. Per residue binding free energy decomposition studies and visual inspection at 100 ns snapshots revealed hydrogen bonding and non-polar attractions with important amino acid residues that contributed to the ΔGbind values. The interactions are similar to those previously reported in the literature. The overall ADMET predictions for the two molecules were favourable for drug development with acceptable pharmacokinetic profiles and adequate oral bioavailability.Item Open Access Analysis of plant secondary metabolism using stable isotope‐labelled precursors(Wiley, 2020-07-24) Arroo, R. R. J.; Bhambra, Avninder S.; Hano, Christophe; Renda, Gülin; Ruparelia, K. C.; Wang, Meng F.Introduction Analysis of biochemical pathways typically involves feeding a labelled precursor to an organism, and then monitoring the metabolic fate of the label. Initial studies used radioisotopes as a label and then monitored radioactivity in the metabolic products. As analytical equipment improved and became more widely available, preference shifted the use stable ‘heavy’ isotopes like deuterium (2H)‐, carbon‐13 (13C)‐ and nitrogen‐15 (15N)‐atoms as labels. Incorporation of the labels could be monitored by mass spectrometry (MS), as part of a hyphenated tool kits, e.g. Liquid chromatography (LC)–MS, gas chromatography (GC)–MS, LC–MS/MS. MS offers great sensitivity but the exact location of an isotope label in a given metabolite cannot always be unambiguously established. Nuclear magnetic resonance (NMR) can also be used to pick up signals of stable isotopes, and can give information on the precise location of incorporated label in the metabolites. However, the detection limit for NMR is quite a bit higher than that for MS. Objectives A number of experiments involving feeding stable isotope‐labelled precursors followed by NMR analysis of the metabolites is presented. The aim is to highlight the use of NMR analysis in identifying the precise fate of isotope labels after precursor feeding experiments. As more powerful NMR equipment becomes available, applications as described in this review may become more commonplace in pathway analysis. Conclusion and Prospects NMR is a widely accepted tool for chemical structure elucidation and is now increasingly used in metabolomic studies. In addition, NMR, combined with stable isotope feeding, should be considered as a tool for metabolic flux analyses.Item Open Access Bioproduction of Anticancer Podophyllotoxin and Related Aryltretralin-Lignans in Hairy Root Cultures of Linum Flavum L.(Springer, 2020-04-05) Mikac, Sara; Markulin, Lucija; Drouet, Samantha; Corbin, Cyrielle; Tungmunnithum, Duangjai; Kiani, Reza; Kabra, Atul; Abassi, Bilal Haider; Renouard, Sullivan; Fuss, Elisabeth; Hano, Christophe; Arroo, R. R. J.; Bhambra, Avninder S.; Laine, EricPodophyllotoxin (PPT) is the unique natural precursor of Etoposide, a topoisomerase II inhibitor drug, used in more than a dozen anticancer chemotherapy treatments. Etoposide is appearing on the list of essential medicines of the World Health Organization. PPT is still exclusively extracted from the rhizome of Podophyllum species, its main natural source. The supply of Podophyllum hexandrum plants is limited, since the occurrence of these plant species is scarce, collection is destructive, and the plants need a long regeneration period. As a consequence, this species is now endangered and listed on Appendix II of the Convention on International Trading of Endangered Species. Chemical synthesis of PPT is difficult due to the presence of four contiguous chiral centers and the presence of a base sensitive trans-lactone moiety. Alternatives are being actively searched, but so far, no wild plants have been described with similar PPT production capacity as compared to Podophyllum. However, several plants producing PPT or other related aryltetralin lignans (ATL) have been identified in recent decades, including the Linaceae. Given its high lignan accumulation capacity, Linum flavum is considered a promising alternative source of PPT and other related ATL. However, unlike the common flax L. usitatissimum, L. flavum has a low agricultural potential (e.g., slow growth and dehiscence of fruits). Therefore, in vitro cultures of plant cells and/or tissues provide an interesting alternative to whole L. flavum plants for the production of these valuable ATL. In particular, L. flavum hairy roots (HRs) accumulate high levels of ATL and it is also possible to further increase this ATL accumulation by the selection of the best genotype, optimization of cultures media and conditions and choice of carbon sources, use of plant growth regulators, elicitor treatments, or precursors’ addition. To date, the ATL accumulation levels can still be perceived insufficient for L. flavum HRs before being used as a commercially viable biotechnological production system. To reach this goal, a better knowledge of the mechanisms that regulate the metabolic flux of intermediates in the different branches of the ATL metabolic pathway will be an important prerequisite to direct the biosynthesis toward the production of a high amount of the desired PPT. In the future, metabolic engineering aiming at constructing the PPT pathway in a heterologous host is very appealing, but for that approach in-depth knowledge of the biosynthetic pathway toward PPT and other related ATL is necessary.Item Open Access Building a DMU e-Biology resource for health sciences’ students.(International Academy of Technology, Education and Development (IATED), 2017-11-18) Pena-Fernandez, A.; Sgamma, Tiziana; Young, Christopher N. J.; Randles, Michael J.; del Aguila, C.; Hurtado, C.; Evans, M. D.; Potiwat, N.; Izquierdo, F.; Pena, M. A.; Coope, J.; Armstrong, M.; Bhambra, Avninder S.The BSc Biomedical Science (BMS) programme at De Montfort University (DMU, Leicester, UK) is accredited by the Institute of Biomedical Science (IBMS). Students enrolled within this programme acquire highly sought after skills related with human health sciences to work in: pathology departments in hospitals; research institutions; biotechnology and pharmaceutical industries; and the education sector to name a few. The degree recruits a large number of students with currently around 600 students enrolled on this programme at DMU. Despite pre-entry requirements of knowledge of subjects related to human biology, biology or chemistry, we have noted that first year students require basic support in STEM subjects (biology, chemistry and mathematics) in modules such as “Basic Microbiology”, “Basic Anatomy and Physiology” and “Chemistry for the Biosciences”. This support is especially necessary for students that come from non-traditional routes such as Business and Technology Education Council (BTEC) routes. Moreover, usually topics related with microbiology and human diseases are challenging for students, often causing stress impacting their overall performance and experience. A group of BMS academics at DMU in conjunction with universities in the European Union (EU; e.g. University of San Pablo CEU, Spain) have started to design, create and develop a series of e-learning resources or units in human biology and BMS for undergraduate students that study health sciences degrees in the EU. These units are being uploaded onto the DMU web server (http://parasitology.dmu.ac.uk/) and will be only accessible for students from participating universities during the first phase of this project (2017/18 course) in which comprehensive feedback will be collected. This web server space has three sections or modules (theoretical section, virtual laboratory and microscope) in which the new e-learning resources will be preliminary accommodated. These units will be interactive and easy to follow, and will cover basic human biology (e.g. cells, cell structure), human anatomy and physiology, histology and basic microbiology, which will be embedded in a theoretical module named DMU e-Biology within the above URL link. They will include formative assessments and case studies throughout each unit. In addition, a series of practical units are being developed which describe routine practical elements in any biomedical laboratory such as laboratory materials, pipetting, molecular techniques (e.g. PCR), cell culture (e.g. use of biological safety cabinet) and histological techniques (e.g. use of microtome, staining techniques). The development of this teaching and learning resource will cover a gap in the traditional teaching and learning methods that are currently used and provided in the participating universities. The DMU e-Biology will aid to our undergraduate students to gain knowledge in human biology and microbiology by promoting self-learning. We consider that the DMU e-Biology will help overcome spatiotemporal, equipment and resource barriers. Additionally, it may help student retention as currently about a 10% of our first year students fail to continue BMS at DMU. Finally, the creation of the DMU e-Biology will also provide support to the DMU Student Retention and Attainment Strategy 2016-2020 through the DMU Student Learning Hub, which is currently under development.Item Open Access Building on-line materials for teaching parasitology to health sciences’ students: initial impressions.(2017-06-05) Pena-Fernandez, A.; Ollero, M.; Fenoy, S.; Magnet, A.; Mackenzie, S.; Pena, M. A.; Izquierdo, F.; Hurtado, C.; Ioannou, M.; Bornay, F.; Halliwell, R.; Acosta, L.; Torrus, D.; Singh, Harprit; Sgamma, Tiziana; Evans, M.; Bhambra, Avninder S.; Baho, S.; del Aguila, C.Background: It is widely recognised that the use of web-based teaching resources is an increasingly important method for delivering education, and it will be particularly important in the near future due to the progressively increasing number of health science students and the current number of academics in the “European Higher Education Area”. The study of parasitology and infectious diseases is essential to build professionals in the health sector with the key knowledge and skills to face global public health threats such as food-, water- or vector-borne infectious diseases outbreaks. However, the current time dedicated to the teaching of this discipline in all health sciences degrees at De Montfort University (DMU, Leicester, UK) is very little or non-existent depending on the degree/master. Methods: An innovative teaching group at DMU is trying to fill this gap in the currently available teaching offer in line with new trends in global health education, the large number of students enrolled in any health degree and the increasing number of students that would like to study this discipline (but due to different commitments do not have enough time or resources to study on a full time basis). Thus, an innovative teaching group from different EU Universities (DMU and the Spanish universities: University of San Pablo CEU, University of Alcalá, and University Miguel Hernández de Elche) and clinicians (University Hospitals of Leicester, UK) have started to design, create and develop a complete on-line package in Parasitology for undergraduate and postgraduate students that study health sciences. Results: The e-Parasitology package will be accessible through the DMU website (http://parasitology.dmu.ac.uk) in 2017 and will be focused on infection, prevention and treatment of major and emerging parasitological diseases. Conclusions: This teaching resource will aid our undergraduate and postgraduate students to gain a significant knowledge in parasitology by promoting self-learning and internationalization. This poster will explore one of the first mini-modules developed so far related with Toxocara, a helminthiasis with prevalence rates that can reach as high as 40% or more in parts of the world, and the challenges for its development.Item Embargo Can new digital technologies support student retention and engagement?(Higher Education Academy (HEA), 2018-02-01) Pena-Fernandez, A.; Randles, Michael J.; Young, Christopher N. J.; Potiwat, N.; Bhambra, Avninder S.University students in their first year face a myriad of challenges such as information overload, poor individual attention and/or minimal interaction with their peers, which can impede their progress through higher education. These challenges, together with other factors, have an impact on student retention and progression that needs to be addressed. We have established a range of strategies to improve retention and progression of new Biomedical Science (BMS) students at De Montfort University (DMU, UK) in 2016/17, including an intensive induction week with social and networking events with academics to enhance the development of constructive relationships. We have also increased the number of lectures on foundation in biology, chemistry and maths, introduced more tutorials and created “surgery” hours or weekly drop-in sessions in each module. These strategies could have been translated into a reduction in the percentage of students that abandon their BMS studies after their first year from 10.3% (24 students) in 2015/16 to 6.5% (13 students) in 2016/17, according to DMU reporting software (Tableau). However, we have noted that some of our BMS students require more basic support in STEM subjects (biology and chemistry), particularly those students that enter from the Business and Technology Education Council (BTEC) pathway, despite having met university-set entry requirements and the modifications to the curriculum to cater for such students. To address these limitations, we have started to develop a complete e-learning package designed to enhance learning and underpin the fundamental concepts of biology and biochemistry. The development of the DMU e-Biology package started in 2017 and covers the specifications for AS and A level described by the Assessment and Qualifications Alliance (AQA, 2017) for human biology as well as the basic concepts delivered in our first year modules. The DMU e-Biology also has interactive case studies related to topics of interest for our students, such as alcohol abuse and biomarkers of disease in clinical samples, to encourage self-learning and autonomous work on the part of the user. The main aim of the virtual case studies is to facilitate the development of students’ abilities to critically evaluate and use evidence from the literature, skills that are invaluable to any scientist and indeed key for future generations of biomedical scientists. The final package will be publicly available on the DMU website (http://parasitology.dmu.ac.uk/ebiology/home.htm) in 2018, after reviewing student feedback. The availability of this resource prior to students starting their course may enable earlier engagement and improve student retention.Item Embargo Chemopreventive Potential of Flavones, Flavonols, and their Glycosides.(Springer Nature, 2020-03-13) Arroo, R. R. J.; Wang, Meng F.; Bhambra, Avninder S.Epidemiological studies have long indicated a possible role for dietary flavonoids, notably flavones and flavonols, in the prevention of a range of degenerative diseases, e.g. cancer, diabetes, cardiovascular diseases and neurological disorders like Parkinson’s and Alzheimer’s disease. The flavonoids are a large and variable group of compounds, comprising thousands of different structures. The bulk of the dietary flavonoids occur as glycosides. The effect of flavonoid aglycones and their corresponding glycosides on cell metabolism and aetiology of degenerative diseases has been a topic of interest for a number of decades. In contrast, the role of the metabolic products of dietary flavonoid that reach all parts of the human body through systemic circulation, has received much less attention. Studies on animal and human metabolism have shown that the amount flavone and flavonol glycosides is absorbed intact is negligible; the bulk is absorbed only after deglycosylation. Thus, dietary glycosides are not likely to play a direct role in chemoprevention. However, the sugar groups on glycosides can greatly affect the bioavailability of flavones and flavonols. Flavonoids linked with indigestible sugars are not absorbed in the small intestine, but are transported through the digestive tract to be degraded by gut bacteria in the large intestine. The compounds that directly play a tole in the prevention of degenerative diseases are most likely not dietary flavones themselves, but rather their metabolites and conjugation products.Item Metadata only Curriculum design(Taylor and Francis, 2024-05-31) Bhambra, Avninder S.A curriculum is a key academic document, setting out the programme structure and content, also the rationale and vision for a course. It informs stakeholders and assures them a course is fit for purpose as well as demonstrates the level of quality required in the higher education sector. When considering curriculum design for biomedical science, designers must understand the needs of the profession and how to effectively educate those wishing to pursue a career as a Biomedical Scientist. However, not every student has this career aspiration in mind so each programme should be able to prepare students for diverse career paths. Such variation, combined with the already complex nature of the discipline, adds to the challenge of delivering a suitable curriculum which also considers professional development, as well as transferable and practical skills.Item Open Access Design, Synthesis and Antitrypanosomal Activities of 2,6-Disubstituted-4,5,7-Trifluorobenzothiophenes(Elsevier, 2015-11-30) Bhambra, Avninder S.; Edgar, Mark; Elsegood, Mark R. J.; Li, Yuqi; Weaver, George W.; Arroo, R. R. J.; Yardley, Vanessa; Burrell-Saward, Hollie; Krystof, VladimirCurrent treatments for Human African Trypanosomiasis (HAT) are limited in their application, have undesirable dosing regimens and unsatisfactory toxicities highlighting the need for the development of a safer drug pipeline. Our medicinal chemistry programme in developing rapidly accessible and modifiable heterocyclic scaffolds led to the design and synthesis of novel substituted benzothiophenes, with 6-benzimidazol-1-ylbenzothiophene derivatives demonstrating significant antitrypanosomal activities (IC50 <1 µM) against Trypanosoma brucei rhodesiense and no toxicity towards mammalian cells.Item Open Access The Discovery of Novel Antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines(Elsevier, 2020-09) Robinson, W. J.; Taylor, Annie; Lauga-Cami, S.; Weaver, G. W.; Arroo, R. R. J.; Kaiser, M.; Gul, S.; Kuzikov, M.; Ellinger, B.; Singh, K.; Schirmeister, T.; Botana, A.; Eurtivong, C.; Bhambra, Avninder S.Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense which seriously affects human health in Africa. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work herein describes the design and syntheses of novel antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines, with compound 13, the 4-(2-methoxyphenyl)-6-(pyridine-3-yl)pyrimidin-2-amine demonstrating an IC50 value of 0.38 µM and a promising off-target ADME-Tox profile in vitro. In silico molecular target investigations showed rhodesain to be a putative candidate, supported by STD and WaterLOGSY NMR experiments, however, in vitro evaluation of compound 13 against rhodesain exhibited low experimental inhibition. Therefore, our reported library of drug-like pyrimidines present promising scaffolds for further antikinetoplastid drug development for both phenotypic and target-based drug discovery.Item Open Access Effect of the Citrus Flavone Nobiletin on Circadian Rhythms and Metabolic Syndrome(MDPI, 2022-11-10) Neba Ambe, Gael Noel Neh; Breda, Carlo; Bhambra, Avninder S.; Arroo, R. R. J.The importance of the circadian clock in maintaining human health is now widely acknowledged. Dysregulated and dampened clocks may be a common cause of age-related diseases and metabolic syndrome Thus, circadian clocks should be considered as therapeutic targets to mitigate disease symptoms. This review highlights a number of dietary compounds that positively affect the maintenance of the circadian clock. Notably the polymethoxyflavone nobiletin has shown some encouraging results in pre-clinical experiments. Although many more experiments are needed to fully elucidate its exact mechanism of action, it is a promising candidate with potential as a chronotherapeutic agent.Item Embargo Electrochemical reactivity of TiO2 nanoparticles adsorbed onto boron-doped diamond surfaces(Elsevier, 2004-09-28) Bhambra, Avninder S.; Marken, Frank; Kim, Duk-Hyun; Mortimer, Roger J.; Stott, Susan J.TiO2 (anatase) nanoparticles of ca. 6–10 nm diameter are adsorbed from acidic aqueous solution onto polycrystalline industrially polished boron-doped diamond electrode surfaces. After immobilisation at the electrode surface, TiO2 nanoparticles are imaged in vacuum by electron microscopy (FEGSEM) and when immersed in a liquid film of aqueous 12MLiCl by in situ scanning tunnelling microscopy (STM). Mono-layer films of TiO2 particles are studied voltammetrically in different electrolyte media. Boron-doped diamond as an inert substrate material allows the reduction of TiO2 particles in phosphate buffer solution to be studied and two distinct steps in the reduction–protonation process are identified: (i) a broad reduction signal associated with the binding of an outer layer of protons and (ii) a sharper second reduction signal associated with the binding of an inner (or deeper) layer of protons. Voltammetric experiments in aqueous 0.1MNaClO4 with variable amounts of HClO4 suggest that the reduction of TiO2 particles is consistent with the formation of Ti(III) surface sites and accompanied by the adsorption of protons. Saturation occurs and the total amount of surface sites can be determined. Preliminary data for electron transfer processes at the reduced TiO2 surface such as the dihydrogen evolution process and the two-electron–two-proton reduction of maleic acid to succinic acid are discussed.Item Embargo Health Effects and Risks of Caffeine, Theobromine and Theophylline(Bentham Science, 2017-05-25) Pena-Fernandez, A.; Evans, M. D.; Bhambra, Avninder S.Methylxanthines, namely caffeine, theobromine and theophylline are found in several beverages and food products such as coffee, cocoa, tea and cola drinks. These substances can provide benefits to humans but also prove harmful mainly when consumed in high amounts. However, the beneficial and deleterious effects of methylxanthines are controversial in research findings, largely because of inconsistencies within research conducted and factors associated within studies. For instance, some authors have reported methylxanthines could have potential antioxidant activity under physiological conditions but opposing studies do not support these claims. Factors that influence the effects of methylxanthines include age, gender and health status of the individual. In addition to these, other factors such as doses, consumption of drugs or pharmaceuticals, alcohol and tobacco habits and diet also play a role in methylxanthine effects and metabolism. Therefore, our review is to provide a clearer understanding of the beneficial/adverse effects of methylxanthines in humans. A description of the physiological and toxicological effects of these methylxanthines is provided.Item Embargo Herbal appetite suppressants used to aid weight loss.(Springer, 2024-11-11) Malik, Sonia; Kuntawala, Dhivani H.; Neba Ambe, Gael Noel Neh; Jin, Yannan; Bhambra, Avninder S.; Arroo, R. R. J.Overweight and obesity are global health challenges associated with an increased risk of life-threatening comorbidities. Whereas a healthy diet and a lifestyle with a sufficient amount of exercise is the first recommendation to avert complications arising from overweight, a variety of prescription medicines is recognised as potential aids in weight loss. However, concerns about adverse effects of many prescription weight-loss agents has made that may drugs are now prohibited in some countries, though not in all countries. This has given rise to a clandestine market which has made proper monitoring of safety of products on sale increasingly complex. In addition to pharmaceutical products, a wide range of food substitutes or food supplements that are marketed as aids in weight loss is available. Regulation of food ingredients is considerably less stringent than regulation for pharmaceutical products; whereas pharmaceutical companies need to provide evidence of safety and efficacy before they are allowed marketing of any products, manufacturers of herbal and dietary supplements are just expected to ensure safety of their products. A sustainable reduction in food intake can be a major challenge, and people on weight-loss programmes have to fight cravings and hunger pangs. Appetite suppression-based therapies are the novel and promising treatments to control obesity. Recently, the peptide Semaglutide (Wegovy®, Ozempic®) has emerged as a very popular appetite suppressing prescription drug, which is administered by injection, though oral formulations have been developed too. Appetite suppressing herbal supplements have often been used traditionally since ages and are therefore generally regarded as safe. The aim of present review is to reflect on the most popular herbal supplements that are currently marketed as appetite suppressants, and that are widely promoted as aids in weight loss exercises. Notably, members of the family Apocynaceae, e.g. Caralluma spp. and Hoodia spp. contain pregnane glycosides that have been shown to restore sensitivity to the appetite suppressant hormone leptin in obese mice. The anti-obesity effect of Garcinia spp. (Clusiaceae) has been attributed to the presence of hydroxycitric acid (HCA), which inhibits fatty acid and triglyceride biosynthesis. In addition, HCA administration has been shown to increase serotonin levels, which in turn results in reduced appetite. A similar mechanism of action is seen with extracts of Griffonia simplicifolia (Fabaceae) that are particularly rich in the serotonin precursor 5-hydroxytryptophan. A third mechanism of action is seen in Gymnema sylvestre (Apocynaceae) which contains gymnemic acids that selectively inhibit oral sweet taste sensation in humans, thus lessening the appeal of sweets and pastries.Item Open Access Investigation of Linum flavum (L.) Hairy Root Cultures for the Production of Anticancer Aryltetralin Lignans.(MDPI, 2018-03-26) Arroo, R. R. J.; Hano, C.; Renouard, S.; Corbin, C.; Drouet, S.; Medvedec, B.; Doussot, J.; Colas, C.; Maunit, B.; Bhambra, Avninder S.; Gontier, E.; Jullian, N.; Mesnard, F.; Boitel, M.; Abbasi, B. H.; Lainé, E.Linum flavum hairy root lines were established from hypocotyl pieces using Agrobacterium rhizogenes strains LBA 9402 and ATCC 15834. Both strains were effective for transformation but induction of hairy root phenotype was more stable with strain ATCC 15834. Whereas similar accumulation patterns were observed in podophyllotoxin-related compounds (6-methoxy-podophyllotoxin, podophyllotoxin and deoxypodophyllotoxin), significant quantitative variations were noted between root lines. The influence of culture medium and various treatments (hormone, elicitation and precursor feeding) were evaluated. The highest accumulation was obtained in Gamborg B5 medium. Treatment with methyl jasmonate, and feeding using ferulic acid increased the accumulation of aryltetralin lignans. These results point to the use of hairy root culture lines of Linum flavum as potential sources for these valuable metabolites as an alternative, or as a complement to Podophyllum collected from wild stands.Item Metadata only Isolation, Purification and Identification of Cocin and Kaempferol, Powerful Antioxidants in Crocus sativus L. Flowers.(Phytochemical Society of Europe, 2014) Zeka, K.; Ruparelia, K. C.; Androutsopoulos, V. P.; Bhambra, Avninder S.; Pajewski, L. A.; Veglio, F.; Continenza, M. A.; Arroo, R. R. J.Crocus sativus L. is an autumn-flowering geophyte extensively grown and cultivated in countries such as Italy, Spain, Greece, Turkey, Iran and India. Commercially used saffron is dried stigma which has been used for some of its physiologic properties for centuries. Recently, attention has been paid to the identification of new sources of safe natural antioxidants from Crocus sativus flowers that are normally wasted. The antioxidant activities are mainly attributed to their carotenoid and flavonoid compounds, like Crocin and Kaempferol. These bioactive compounds have important biological activities; cancer and prevention and treatment of heart, vascular disease. Crocin is a diester formed from the disaccharide gentiobiose and the dicarboxylic acid crocetin and is known to inhibit proliferation and nucleic acid synthesis. It induces apoptosis in the human tongue squamous cell carcinoma cell line Tca8113 and hepatocarcinoma. Kaempferol is a natural flavonoid. Numerous reports have shown that Kaempferol and/or Kaempferol glycosides induce cell death in a variety of cancer cells from different tissues. Many of these reports have shown that it is effective in reducing vascular endothelial growth factor expression in ovarian and colon cancer cells. Extraction of these antioxidants was carried out using methanol and ethanol in different concentrations for each compound. Isolation and purification, in comparison with authentic standards, was achieved by Flash Column Chromatography and Thin Layer Chromatography (TLC). Crocin and Kaempferol were chemically characterised by infrared (IR), mass spectroscopy (MS) and nuclear magnetic resonance (1H & 13C NMR). The in-vitro cytotoxicity towards cancer cell lines will also be investigated. The presence of these important groups of medicinal natural products in saffron’s flowers that were considered waste, now paves the way of new biological effects.Item Metadata only A meta-analysis study of antimicrobial resistant E. coli in the environment.(2017-09-27) Knight, S.; Bhambra, Avninder S.; Lobo-Bedmar, M. C.; Pena-Fernandez, A.There is increasing evidence that urban animals could play a significant role in the spread of antibiotic-resistant (AR) bacterial infections. Wild birds and pigeons have been found as carriers of multidrug-resistance Escherichia coli (E. coli) in urban ecosystems, which could threaten public health. Although AR bacteria pose challenges to healthcare systems, little is known about the prevalence and distribution of such bacteria in the environment, particularly in the built-up environment. The aim of this study was to review the literature to identify what is known so far and to identify possible animal species that should be targeted in urban environments as part of the national and international response to tackle the AR phenomenon. A systematic review was performed following the Cochrane guidelines to identify peer-reviewed articles investigating AR strains of E. coli published from January 2006 onwards. Eligible studies were selected based on inclusion criteria: carried out in urban areas in Europe; determined E. coli in isolates from urban animals by molecular methods; and results were clear and easy to extract to determine the pooled prevalence according to previous methodologies. Only 18 studies were identified as eligible and were subjected to the meta-analysis following the Cochrane recommendations. The results have highlighted that the occurrence of AR E. coli in Europe has significantly increased since 2014. The study has indicated a different occurrence of such bacteria in urban environments in Europe. Thus, higher prevalence was observed in the Netherlands, Portugal and Spain, meanwhile Latvia and Sweden had the lowest. Finally, urban avian (pigeons and gulls) and canine (domestic) species have been identified as the most likely carriers of AR E. coli in urban environments. Although these results should be considered as preliminary, special attention should be drawn to consider urban animal species in any intervention to reduce the AMR phenomenon.Item Metadata only Novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives and their antitrypanosomal activities against T.brucei(Elsevier, 2024-06-05) Bhambra, Avninder S.; Taylor, Annie; Hering, Moritz; Elsegood, Mark R. J.; Teat, Simon J.; Weaver, George W.; Arroo, R. R. J.; Kaiser, Marcel; Maeser, PascalHuman African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense and is invariably fatal unless treated. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work, informed by previous findings, presents novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives with promising antitrypanosomal activity. In particular, 32 exhibits an in vitro EC50 value of 0.5 µM against Trypanosoma brucei rhodesiense, and analogues 29, 30 and 33 show antitrypanosomal activities in the <1 µM range. We have demonstrated that substituted 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidines present promising antitrypanosomal hit molecules with potential for further preclinical development.Item Open Access Novel Fluorinated Benzimidazole-Based Scaffolds and their Anticancer Activity in vitro(Elsevier, 2016-06-23) Bhambra, Avninder S.; Edgar, Mark; Elsegood, Mark R. J.; Horsburgh, Lynne; Kryštof, Vladimir; Lucas, Paul D.; Mojally, Mariam; Teat, Simon J.; Warwick, Thomas G.; Weaver, George W.; Zeinali, FatemehA small library of twelve, structurally diverse, fluoroaryl benzimidazoles was prepared using a simple synthetic strategy employing SNAr reactions. This allowed rapid assembly of heterocyclic structures containing linked and tethered fluoroaryl benzimidazoles. X-ray crystal structures of seven compounds were obtained including those of two macrocyclic compounds containing 21- and 24-membered rings. Three tethered fluoroaryl benzimidazole derivatives demonstrated micromolar inhibition against K-562 and MCF-7 cell lines. These compounds, in addition to 1-tetrafluoropyrid-4-yl-2-tetrafluoropyrid-4-ylsulfanyl-1H-benzimidazole, also demonstrated micromolar inhibition against G361 and HOS cell lines. Two of the compounds were found to activate caspases leading to apoptosis.Item Metadata only Phytoestrogens as natural prodrugs in cancer prevention: towards a mechanistic model(Springer, 2014-06-14) Arroo, R. R. J.; Beresford, Kenneth J. M.; Bhambra, Avninder S.; Boarder, M. R.; Budriesi, Roberta; Cheng, Zhong; Micucci, Matteo; Ruparelia, K. C.; Surichan, Somchaiya; Androutsopoulos, VasilisIt has been widely acknowledged that regular consumption of fresh fruits and vegetables is linked with a relatively low incidence of cancers (e.g. breast, cervix, and colon). Notably, dietary polyphenolic compounds that show some structural similarity to human estrogen, e.g. isoflavones, coumestans, lignans, flavones, have been proposed to play a role in cancer prevention. However, at present there is no satisfactory explanation for the cancer preventative properties of this group of compounds. Whereas polyphenolic compounds have been shown to inhibit proliferation of tumour cells in vitro, the results of in vivo tests have mostly been disappointing in this respect. It seems that mammalian phase II detoxification mechanisms make that dietary polyphenols are rapidly and effectively removed from the body, i.e. their concentration in the blood plasma hardly ever reaches levels high enough to have a possible effect on tumour growth. The polymethoxyflavones nobiletin and tangeretin, common constituents of Citrus peel, are better absorbed than polyhydroxy flavonoids, and maintain their biological activity for a longer period of time. The compounds are known to be substrates for the estrogen-converting cytochrome P450 enzymes CYP1A1 and CYP1B1, which are typically overexpressed in a range of tumour tissues. The enzymes catalyse regioselective hydroxylation and dealkylation of the polymethoxyflavones, resulting in reaction products that appear to inhibit cell proliferation via interference with the MAPK/ERK cell signalling pathway.