Yusuf Y. Deeni

Cutaneous expression of cytochrome P450 CYP2S1: individuality in regulation by therapeutic agents for psoriasis and other skin diseases

BACKGROUND Treatment of common skin diseases such as psoriasis is complicated by differences between individuals in response to topical drug treatment and photochemotherapy. Individuality in hepatic expression of drug-metabolising enzymes is an important determinant of systemic drug handling; we investigated whether similar variation in cutaneous gene expression contributes to individuality in response to topical therapies. METHODS We used quantitative real-time RT-PCR to demonstrate the expression in skin of a recently identified cytochrome P450, CYP2S1, in healthy volunteers (n=27) and patients with psoriasis (n=29). We also investigated regulation of CYP2S1 by ultraviolet radiation, psoralen-ultraviolet A (PUVA), and topical drugs used to treat psoriasis. FINDINGS We found that CYP2S1 is expressed in skin and showed pronounced individuality in constitutive expression of the enzyme and its induction after ultraviolet irradiation or topical drug treatment. Cutaneous expression of CYP2S1 was induced by ultraviolet radiation, PUVA, coal tar, and all-trans retinoic acid; expression was significantly higher in lesional psoriatic skin than in adjacent non-lesional skin (geometric mean 3.38 [95% CI 2.64-4.34] times higher; p<0.0001), which implies that topical drugs are differentially metabolised in psoriatic plaque and non-lesional skin. We showed that all-trans retinoic acid is metabolised by CYP2S1, which has higher cutaneous expression than CYP26, previously described as the specific cutaneous P450 retinoic-acid-metabolising enzyme. INTERPRETATION These findings increase our understanding of the interaction between therapeutic agents and the skin and suggest a functional role for CYP2S1 in the metabolism of topical drugs and in mediating the response to photochemotherapy in psoriasis.

Plants in Kano Ethnomedicine; Screening for Antimicrobial Activity and Alkaloids

AbstractKano is a region of Nigeria located between latitude 10° 30′N and 13° 03′N. It has the Sudan savannah type of climate and vegetation that gradually gives way to semi-arid conditions northward. It is a part of the Hausaland where ethnomedicine is recognized and practiced. From our previous work (Hussain and Karatela, 1989) and additional information from herbalists, plants used to treat microbial diseases or disorders were selected. In addition Tapinanthus species growing on hosts that have been implicated in antibiosis (Lewis and Elvin-Lewis, 1979; Oliver, 1959 and Sofowora, 1982) were also included. Thus we thought it might be appropriate and useful, as with the flora of other lands (Al-Shamma and Mitscher, 1979; Chhabra et al, 1981 and Van Puyelde et al., 1981) to screen these plants to ascertain their antimicrobial efficacy and potential economic value.In this paper, alcoholic extracts of some plants have been tested for an in vitro antimicrobial activity against thirteen indicator organisms an...

Bioethanol in Nigeria: comparative analysis of sugarcane and sweet sorghum as feedstock sources

This review discusses the relative merits of sweet sorghum and sugarcane crops for the expanding bioethanol sector in Nigeria. We have compared, from a number of perspectives, sugarcane molasses and sweet sorghum stalk juice as biomass sources for Nigerian fuel alcohol fermentations and the findings indicate that sweet sorghum is most suited in terms of the adaptability of this crop to harsh climatic and cultivation conditions. In terms of environmental impact, sweet sorghum cultivation is more water efficient, requires less energy input, fertilization and agrochemical application. The concept of life cycle analysis was used to compare the environmental, social and economic impacts of using sweet sorghum stalk juice and sugarcane molasses. Sweet sorghum represents a more favourable biomass source and there is great potential for sustainable development and utilization of sweet sorghum for bioenergy production in Nigeria. However, there is need for well defined, structured, coordinated, targeted and monitored scientific efforts and investments in order to realize maximum associated benefits.

Engineering simulations for cancer systems biology

Computer simulation can be used to inform in vivo and in vitro experimentation, enabling rapid, low-cost hypothesis generation and directing experimental design in order to test those hypotheses. In this way, in silico models become a scientific instrument for investigation, and so should be developed to high standards, be carefully calibrated and their findings presented in such that they may be reproduced. Here, we outline a framework that supports developing simulations as scientific instruments, and we select cancer systems biology as an exemplar domain, with a particular focus on cellular signalling models. We consider the challenges of lack of data, incomplete knowledge and modelling in the context of a rapidly changing knowledge base. Our framework comprises a process to clearly separate scientific and engineering concerns in model and simulation development, and an argumentation approach to documenting models for rigorous way of recording assumptions and knowledge gaps. We propose interactive, dynamic visualisation tools to enable the biological community to interact with cellular signalling models directly for experimental design. There is a mismatch in scale between these cellular models and tissue structures that are affected by tumours, and bridging this gap requires substantial computational resource. We present concurrent programming as a technology to link scales without losing important details through model simplification. We discuss the value of combining this technology, interactive visualisation, argumentation and model separation to support development of multi-scale models that represent biologically plausible cells arranged in biologically plausible structures that model cell behaviour, interactions and response to therapeutic interventions.

Melanocortin 1 receptor (MC1R) genotype influences erythemal sensitivity to psoralen–ultraviolet A photochemotherapy

Background  The melanocortin 1 receptor (MC1R) is a highly polymorphic G protein‐coupled receptor. Inheritance of various MC1R alleles has been associated with a red hair/fair skin phenotype, increased incidence of skin cancer and altered sensitivity to ultraviolet (UV) radiation.

Systems analysis of drug-induced receptor tyrosine kinase reprogramming following targeted mono- and combination anti-cancer therapy

The receptor tyrosine kinases (RTKs) are key drivers of cancer progression and targets for drug therapy. A major challenge in anti-RTK treatment is the dependence of drug effectiveness on co-expression of multiple RTKs which defines resistance to single drug therapy. Reprogramming of the RTK network leading to alteration in RTK co-expression in response to drug intervention is a dynamic mechanism of acquired resistance to single drug therapy in many cancers. One route to overcome this resistance is combination therapy. We describe the results of a joint in silico, in vitro, and in vivo investigations on the efficacy of trastuzumab, pertuzumab and their combination to target the HER2 receptors. Computational modelling revealed that these two drugs alone and in combination differentially suppressed RTK network activation depending on RTK co-expression. Analyses of mRNA expression in SKOV3 ovarian tumour xenograft showed up-regulation of HER3 following treatment. Considering this in a computational model revealed that HER3 up-regulation reprograms RTK kinetics from HER2 homodimerisation to HER3/HER2 heterodimerisation. The results showed synergy of the trastuzumab and pertuzumab combination treatment of the HER2 overexpressing tumour can be due to an independence of the combination effect on HER3/HER2 composition when it changes due to drug-induced RTK reprogramming.

Quantitative analysis of NRF2 pathway reveals key elements of the regulatory circuits underlying antioxidant response and proliferation of ovarian cancer cells.

Cells are constantly exposed to Reactive Oxygen Species (ROS) produced both endogenously to meet physiological requirements and from exogenous sources. While endogenous ROS are considered as important signalling molecules, high uncontrollable ROS are detrimental. It is unclear how cells can achieve a balance between maintaining physiological redox homeostasis and robustly activate the antioxidant system to remove exogenous ROS. We have utilised a Systems Biology approach to understand how this robust adaptive system fulfils homeostatic requirements of maintaining steady-state ROS and growth rate, while undergoing rapid readjustment under challenged conditions. Using a panel of human ovarian and normal cell lines, we experimentally quantified and established interrelationships between key elements of ROS homeostasis. The basal levels of NRF2 and KEAP1 were cell line specific and maintained in tight correlation with their growth rates and ROS. Furthermore, perturbation of this balance triggered cell specific kinetics of NRF2 nuclear-cytoplasmic relocalisation and sequestration of exogenous ROS. Our experimental data were employed to parameterise a mathematical model of the NRF2 pathway that elucidated key response mechanisms of redox regulation and showed that the dynamics of NRF2-H2O2 regulation defines a relationship between half-life, total and nuclear NRF2 level and endogenous H2O2 that is cell line specific.

Cellulose expression in Pseudomonas fluorescens SBW25 and other environmental Pseudomonads

© 2013 Spiers et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cellulose Expression in Pseudomonas fluorescens SBW25 and Other Environmental Pseudomonads

A novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cells

Nuclear erythroid related factor-2 (NRF2) is known to promote cancer therapeutic detoxification and crosstalk with growth promoting pathways. HER2 receptor tyrosine kinase is frequently overexpressed in cancers leading to uncontrolled receptor activation and signaling. A combination of HER2 targeting monoclonal antibodies shows greater anticancer efficacy than the single targeting antibodies, however, its mechanism of action is largely unclear. Here we report novel actions of anti-HER2 drugs, Trastuzumab and Pertuzumab, involving NRF2. HER2 targeting by antibodies inhibited growth in association with persistent generation of reactive oxygen species (ROS), glutathione (GSH) depletion, reduction in NRF2 levels and inhibition of NRF2 function in ovarian cancer cell lines. The combination of antibodies produced more potent effects than single antibody alone; downregulated NRF2 substrates by repressing the Antioxidant Response (AR) pathway with concomitant transcriptional inhibition of NRF2. We showed the antibody combination produced increased methylation at the NRF2 promoter consistent with repression of NRF2 antioxidant function, as HDAC and methylation inhibitors reversed such produced transcriptional effects. These findings demonstrate a novel mechanism and role for NRF2 in mediating the response of cancer cells to the combination of Trastuzumab and Pertuzumab and reinforce the importance of NRF2 in drug resistance and as a key anticancer target.

The evolution of biofilm-forming Wrinkly Spreaders in static microcosms and drip-fed columns selects for subtle differences in wrinkleality and fitness

Experimental evolution studies are used to investigate bacterial adaptive radiation in simple microcosms. In the case of the Wrinkly Spreader, a class of biofilm-forming adaptive mutants of Pseudomonas fluorescens SBW25, the current paradigm is that they are only evolutionarily successful in static microcosms where they outcompete other lineages for O2 at the air-liquid interface. However, we have isolated Wrinkly Spreaders from drip-fed glass bead columns as an example of parallel evolution. These mutants are adaptive, with competitive fitness advantages on columns of 1.28-1.78. This might be explained by the enhanced attachment characteristically shown by Wrinkly Spreaders, allowing them to resist liquid flow through the column pore network. A comparison of column and static microcosm-isolated Wrinkly Spreaders showed that many aspects of wrinkleality, including colony reversion, microcosm growth, biofilm strength and attachment, as well as fitness in static microcosms, were significantly different within and between the two groups of mutants. These findings indicate that the two environments had selected for Wrinkly Spreaders with subtly differing degrees of wrinkleality and fitnesses, suggesting that aspects of the Wrinkly Spreader phenotype may have different relative values in static microcosms and drip-fed columns.