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Professor Randolph Arroo

Job: School of Pharmacy Head of Research

Faculty: Health and Life Sciences

School/department: Leicester School of Pharmacy

Research group(s): Chemistry for Health

Address: De Montfort University, The Gateway, Leicester, LE1 9BH

T: +44 (0)116 250 6386

E: rrjarroo@dmu.ac.uk

W: http://www.dmu.ac.uk/hls

 

Publications and outputs 

 

  • The Discovery of Novel Antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines
    The Discovery of Novel Antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines Taylor, Annie; Robinson, W.J.; 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.
  • In vitro and in silico assessment of DNA interaction, topoisomerase I and II inhibition properties of Chrysosplenetin
    In vitro and in silico assessment of DNA interaction, topoisomerase I and II inhibition properties of Chrysosplenetin Sohretoglu, Didem; Barut, Burak; Sari, Suat; Ozel, Arzu; Arroo, R. R. J. Chrysosplenetin is a methoxyflavone with reported anti-cancer effect. We tested its cytotoxic effect on the MCF-7 breast cancer cell line, and determined its effect on DNA intercalation and on the activity of topoisomerases I and II. The compound inhibited proliferation MCF-7 with an IC50 value of 0.29 µM. Chrysosplenetin did not initiate plasmid DNA cleavage but, in a concentration-dependent manner, protected plasmid DNA against damage induced by Fenton reagents. Furthermore, it possessed dual Topoisomerase I and II inhibitory properties. Especially, it inhibited topoisomerase II by 83-96% between the range 12.5-100 µM. In the light of these experimental findings, molecular docking studies were performed to understand binding mode, interactions and affinity of chrysosplenetin with DNA, and with topoisomerases I and II. These studies showed that of 4-chromone core and the hydroxyl and methoxy groups important for both intercalation with DNA and topoisomerase I and II inhibition. The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.
  • Effect of antidepressant drugs on the brain sphingolipid system
    Effect of antidepressant drugs on the brain sphingolipid system Zetterstrom, Tyra; Jaddoa, Estabraq; Masania, Jinit; Masiero, Eva; Sgamma, Tiziana; Arroo, R. R. J.; Sillence, Daniel Background: Major depression is a common mood disorder and the central sphingolipid system has been identified as a possible drug target of this condition. Here we investigated the action of antidepressant drugs on sphingolipid levels in rat brain regions, plasma and in cultured mouse macrophages. Methods: Two antidepressant drugs were tested; the serotonin reuptake inhibitor paroxetine and the noradrenaline reuptake inhibitor desipramine, either following acute or chronic treatments. Content of sphingosine and ceramide were analysed using LC-MS or HPLC-UV respectively. This from samples of brain, plasma and cultured mouse macrophages. Antidepressant induced effects on mRNA expression for two key genes of the sphingolipid pathway, SMPD1 and ASAH1 were also measured by using quantitative Real-Time PCR. Results: Chronic but not acute administration of paroxetine or desipramine reduced sphingosine levels in the prefrontal cortex and hippocampus (only paroxetine) but not in the striatum. Ceramide levels were also measured in the hippocampus following chronic paroxetine and likewise to sphingosine this treatment reduced its levels. The corresponding collected plasma samples from chronically treated animals did not show any decrease of sphingosine compared to the corresponding controls. Both drugs failed to reduce sphingosine levels from cultured mouse macrophages. The drug-induced decrease of sphingolipids coincided with reduced mRNA expression of two enzymes of the central sphingolipid pathway, i.e. acid sphingomyelinase (SMPD1) and acid ceramidase (ASAH1). Conclusions: This study supports the involvement of brain sphingolipids in the mechanism of action by antidepressant drugs and for the first time highlights their differential effects on brain versus plasma levels. The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.
  • Bioproduction of Anticancer Podophyllotoxin and Related Aryltretralin-Lignans in Hairy Root Cultures of Linum Flavum L.
    Bioproduction of Anticancer Podophyllotoxin and Related Aryltretralin-Lignans in Hairy Root Cultures of Linum Flavum L. 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, Eric Podophyllotoxin (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.
  • Dihydromyricetin Attenuates Streptozotocin-induced Liver Injury and Inflammation in Rats via Regulation of NF-κB and AMPK Signaling Pathway
    Dihydromyricetin Attenuates Streptozotocin-induced Liver Injury and Inflammation in Rats via Regulation of NF-κB and AMPK Signaling Pathway Chen, Lei; Yao, Maojun; Fan, Xiaoyun; Lin, Xiujun; Arroo, R. R. J.; Silva, Aline; Sungthong, Bunleu; Dragan, Simona; Paoli, Paolo; Wang, Shaoyun; Teng, Hui; Xiao, Jianbo Dihydromyricetin (DHM) dramatically improved the quality of life for Streptozotocin (STZ)-induced diabetic rats and significantly increased the activity of antioxidant enzymes in the liver. Moreover, DHM successfully ameliorated diabetes-induced liver damage by suppression of apoptosis in the liver, as indicated by the decreased levels of Bax and cleaved caspase-3. In diabetic rats, the levels of tumor necrosis factor-α and interleukin-1β in the liver were significantly increased. However, the administration of DHM (100–400 mg/kg/day) for 6 weeks restored the cytokine levels to their normal values in a dose-dependent manner in diabetic rats by the regulation of nuclear factor-kappa B signaling pathway. In addition, DHM significantly induced 5' AMP-activated protein kinase (AMPK) phosphorylation and decreased MyD88, TLR4, p38, GSK-3β protein expression levels in the liver of diabetic rats. In conclusion, DHM could improve STZ-induced liver impairment by preventing oxidative stress, apoptosis, and inflammation. open access article
  • Flavones as tyrosinase inhibitors: kinetic studies in vitro and in silico.
    Flavones as tyrosinase inhibitors: kinetic studies in vitro and in silico. Sari, Suat; Barut, Burak; Arroo, R. R. J.; Ozel, Arzu; Ruparelia, K. C.; Sohretoglu, Didem Introduction – Tyrosinase is a multifunctional copper-containing oxidase enzyme that catalyzes the first steps in the formation of melanin pigments. Identification of tyrosinase inhibitors is of value for applications in cosmetics, medicine and agriculture. Objective – To develop an analytical method that allows identification of drug-like natural products that can be further developed as tyrosinase inhibitors. Results of in vitro and in silico studies will be compared in order to gain a deeper insight into the mechanism of action of enzyme inhibition. Method – Using an in vitro assay we tested tyrosinase inhibitor effects of five structurally related flavones, i.e. luteolin (1), eupafolin (2), genkwanin (3), nobiletin (4), and chrysosplenetin (5). The strongest inhibitors were further investigated in silico, using enzyme docking simulations. Results - All compounds tested showed modest tyrosinase inhibitory effect compared to the positive control, kojic acid. The polymethoxy flavones 4 and 5 exhibited the strongest tyrosinase inhibitory effect with IC50 values of 131.92 ± 1.75 μM and 99.87 ± 2.38 μM respectively. According to kinetic analysis 2, 4 and 5 were competitive inhibitors, whereas 1 and 3 were noncompetitive inhibitors of tyrosinase. Docking studies indicated that methoxy groups on 4 and 5 caused steric hindrance which prevented alternative binding modes in the tyrosinase; the methoxy groups on the B-ring of these flavones faced the catalytic site in the enzyme. Conclusions – The docking simulations nicely complemented the in vitro kinetic studies, opening the way for the development of predictive models for use in drug design. Collaboration between DMU-Leicester School of Pharmacy (UK), Hacettepe University, Faculty of Pharmacy, Ankara (Turkey) and Karadeniz Technical University, Faculty of Pharmacy, Trabzon (Turkey).
  • Flavonols with a catechol or pyrogallol substitution pattern on ring B readily form stable dimers in phosphate buffered saline at four degrees Celsius.
    Flavonols with a catechol or pyrogallol substitution pattern on ring B readily form stable dimers in phosphate buffered saline at four degrees Celsius. Cao, Hui; Högger, Petra; Arroo, R. R. J.; Xiao, Jianbo Phosphate buffered saline (PBS) is a buffer commonly used in biological research. The stability of a series of flavonoids, i.e. myricetin, kaempferol, baicalein, luteolin and quercetin in PBS was assessed. Apigenin proved very stable when incubated with PBS and was used as a control. Kaempferol and baicalein were less stable, and small amounts of oxidized and hydroxylated products could be detected. Flavonols with catechol or pyrogallol structure in ring B are unstable in PBS (pH=7.4) at 4 ºC and were converted into their stable dimers and oxidized products within 5 seconds. The chosen experimental conditions improved the stability of dimers and allowed their detection. Collaboration between: College of Food Science, Fujian Agriculture and Forestry University, Fuzhou China; Institut für Pharmazie und Lebensmittelchemie, Universität Würzburg, Würzburg, Germany; De Montfort University – Leicester School of Pharmacy, Leicester, UK; Institute of Food Safety and Nutrition, Jinan University, Guangzhou, China The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.
  • miRNAs as Regulators of Antidiabetic Effects of Fucoidans
    miRNAs as Regulators of Antidiabetic Effects of Fucoidans Zhao, Chao; Lai, Shanshan; Wu, Desheng; Liu, Dan; Zou, Xiaobo; Ismail, Amin; El-Seed, Hesham; Arroo, R. R. J.; Xiao, Jianbo Diabetes mellitus is a metabolic disease with a high mortality rate worldwide. MicroRNAs (miRNAs), and other small noncoding RNAs, serve as endogenous gene regulators through binding to specific sequences in RNA and modifying gene expression toward up- or down-regulation. miRNAs have become compelling therapeutic targets and play crucial roles in regulating the process of insulin resistance. Fucoidan has shown potential function as an a-amylase inhibitor, which may be beneficial in the management of type 2 diabetes mellitus. In recent years, many studies on fucoidan focused on the decrease in blood glucose levels caused by ingesting low-glucose food or glucose-lowering components. However, the importance of miRNAs as regulators of antidiabetic effects was rarely recognized. Hence, this review emphasizes the antidiabetic mechanisms of fucoidan through regulation of miRNAs. Fucoidan exerts a vital antidiabetic effect by regulation of miRNA expression and thus provides a novel biological target for future research. open access article
  • Over 3 decades of research on dietary flavonoid antioxidants and cancer prevention: What have we achieved?
    Over 3 decades of research on dietary flavonoid antioxidants and cancer prevention: What have we achieved? Alfa, Hajara H.; Arroo, R. R. J. Epidemiological studies keep confirming that the so-called Mediterranean Diet, which is characterised by a relatively high intake of fruit and vegetables, enhances health and provides protection against cancer. The first step in carcinogenesis, and possibly in a range of other degenerative diseases such as heart disease or degenerative dementia, is most likely damage to DNA and other macromolecules. Radical oxygen species - i.e. superoxide anion, hydrogen peroxide, and the hydroxyl radical - are generally considered a major cause of damage to macromolecules. It was long suggested that the antioxidant properties of food ingredients are essential to understanding the mechanism of action of what constitutes a healthy diet, i.e. a diet that prevents the onset of degenerative diseases. However, since the levels of antioxidants in blood plasma required to see any health benefits is much higher that what we get through our diet, the role of dietary phytochemicals acting as anti-oxidants is now in in doubt. Nevertheless, a correlation between presence of flavonoids in the diet and prevention of degenerative diseases has remained. Though there is a putative role for dietary flavonoids in the prevention of degenerative diseases, the exact mechanism of action of these phytonutrients is still a matter of debate. The human body has its own defences against oxidative stress in the form of the enzymes superoxide dismutase (SOD) and catalase (CAT), and reduced glutathione (GSH). Rather than being antioxidants in their own right, plant constituents are more likely to act as triggers or inducers of expression of the human antioxidants SOD, CAT, and GSH. HHA was supported via IBB University, Faculty of Natural Sciences, Lapai, Niger State, Nigeria The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.
  • Use of Natural Products in the Prevention and Management of Type 2 Diabetes
    Use of Natural Products in the Prevention and Management of Type 2 Diabetes Zeka, Keti; Alfa, Hajara H; Ruparelia, Ketan C; Arroo, R. R. J. Metabolic syndrome is an umbrella term for a group of disorders related to imbalance of energy utilization and storage. It includes obesity, hypertension, increased triglyceride levels, aberrant cholesterol levels, and insulin resistance with resulting elevated fasting blood glucose levels that usually result in diabetes. Metabolic syndrome is associated with chronic low-grade local tissue inflammation and increased susceptibility to a variety of degenerative diseases. Lifestyle changes, e.g. more physical exercise, a diet rich in fruits and vegetables, etc. can help prevent or delay metabolic syndrome related problems. In addition, certain food supplements or herbal extracts are commonly believed to make an important contribution to a healthy life style, i.e glucomannan. Whereas there is a consensus that a vegetable-rich diet contributes to a lower occurrence of metabolic syndrome related disorders, the exact nature of the compounds in the diet that contribute to the prevention of degenerative diseases is still a matter of debate. This chapter book sets out to evaluate several natural products that are currently considered to play a role in the prevention or management of type 2 diabetes. Phytochemicals with antioxidant activity were long believed to be a major contributing factor in the suppression of chronic inflammation. However, not all antioxidant compounds have anti-inflammatory properties. Further, the peroxisome proliferator-activated receptor gamma (PPARγ)-activating potential of a wide range of natural products has been explored in great detail, and resulted in a credible model. A third model considers the potential role of phytoestrogens on human physiology. These compounds are known to interact with oestrogen receptors and can modulate a range of cell signalling pathways, either as agonists or as antagonists. The efficacy of several of the identified pharmaceutically active compounds and plant extracts, either as supplements, dietary factors or as part of a healthy life style, may be supported by laboratory results. However, caution is justified when considering food supplements in doses that greatly exceed the amounts that would be obtained through a regular diet. Book chapter, jointly written with authors from University of Cambridge, UK (Department of Haematology) and IBB University, Nigeria (Faculty of Natural Sciences)

Click here for a full listing of Randolph Arroo's publications and outputs. 

Research interests/expertise

  • Phytochemistry
  • Natural products
  • Pharmacognosy 
  • Alkaloids
  • Lignans
  • Sesquiterpenes
  • Anticancer drugs
  • Malaria 

Areas of teaching

  • Chemistry of medicinal natural products
  • Phytotherapy, complementary and alternative medicine 

Membership of professional associations and societies

Conference attendance

International Symposium on Phytochemicals in Medicine and Food (ISPMF 2015), Shanghai, China, June 26-29 2015 – Invited key note lecture: ‘Dietary Flavonoids and The Prevention of Degenerative Diseases’.

 

University of L'Aquila, Department of Life, Health & Environmental Sciences, L’Aquila, Italy, 13-15 April 2015 – Visiting professor lecture: ‘Chemopreventive effects of orange peel extract’.

 

International Conference on Natural products in Cancer Therapy. Naples, 25-28 June 2013 – Invited key note lecture: ‘Phytoestrogens as natural prodrugs in cancer prevention: Towards a mechanistic model’.

 

Dana Centre/Science Museum, London, 8 November 2012 – Public lecture: ‘Shakespeare's Medicine Cabinet’.

 

International Conference on Natural Anticancer Drugs. Olomouc, Czech Republic, 30 June – 4 July, 2012 – Invited key note lecture: ‘Plant cell factories: Industrial revolution or green revolution?’

 

International Conference of Folk and Herbal Medicine. Udaipur (Rajasthan), 25-27 November, 2010 – Invited key note lecture: ‘Self treatment of malaria with preparations of Artemisia annua Linn.’

Current research students

Saeed Nazir (1st supervisor)

Externally funded research grants information

February 2011 - July 2011 Removal of Chewing Gum using Nut-based Compounds, funded by the EMDA Innovation Fellowship

October 2009 - July 2010 Phytochemicals Conference 2010, funded by paying delegates

July 2009 - August 2009 Antibacterial Compounds from Osha root (Ligusticum porteri), funded by the Nuffield Foundation

August 2008 - September 2008 Exploration of Cow Parsley (Anthriscus Sylvestris) funded by the Nuffield Foundation

March 2006 - April 2010 Development of Artemisia annua Linn as a UK crop for the production of antimalarial medicine, funded by DEFRA-LINK

Professional esteem indicators

  • Phytotherapy Research - Editorial Board
  • Phytochemical Analysis - Editorial Board
  • Plant Resources of Tropical Africa / Medicinal Plants - Co-editor

Case studies

High-artemisia-yielding Artemisia annua cultivars developed in Dr. Arroo's DEFRA-LINK project (see Externally funded research grants information) are now commercially grown in Madagascar.

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