Synthesis of nordihydroguaiaretic acid (NDGA) analogues and their oxidative metabolism

Nordihydroguaiaretic acid (NDGA), is a naturally-occurring lignan isolated from the creosote bush (Larrea tridentata). The aqueous extract of this shrub, commonly referred to as Chaparral tea, was listed in the American pharmacopeia as an ethnobotanical used to treat tuberculosis, arthritis and cancer. Other documented traditional applications of creosote bush extract include treatment for infertility, rheumatism, arthritis, diabetes, gallbladder and kidney stones, pain and inflammation among many others. In spite of the numerous pharmacological properties, NDGA use has been associated with toxicities including hepatotoxicity in humans. Previous studies in our group showed that oxidative cyclization of NDGA (a di-catechol) at physiological pH forms a dibenzocyclooctadiene that may have therapeutic benefits whilst oxidation to ortho-quinone likely mediates toxicological properties. In order to investigate the structural features responsible for pharmacological and toxicological properties, a series of NDGA analogues were designed, synthesized and characterized for the purpose of studying their oxidative metabolism. Literature procedures were modified to successfully prepare seven lignan analogues via multi-step synthesis. In our effort to understand the mechanisms of NDGA intramolecular cyclization, the prepared analogues were incubated under previously established conditions where NDGA autoxidized to yield the dibenzocyclooctadiene derivative. We also evaluated the stability of the analogues under the conditions of this study. Furthermore, we evaluated bioactivation potential of the prepared analogues with a goal of eliminating reactive metabolite liability through rational structural modification. We incubated NDGA and its analogues in rat liver microsomes (RLM) in the presence of glutathione as a nucleophilic trapping agent. Standards for comparison were generated by performing glutathione trapping experiments with chemical and enzyme oxidation systems. The potential of the dibenzocyclooctadiene lignan 2 derived from NDGA under physiological conditions to contribute to toxicological properties via reactive metabolite formation was also evaluated. Glutathione conjugates were detected by electrospray ionization-mass spectrometry (ESI-MS) scanning for neutral loss (NL) 129 Da or 307 Da in positive ion mode or precursor ion (PI) scanning for 272 Da in negative ion mode and further characterized by liquid chromatography–tandem mass spectrometry (LC–MS/MS) or in a single LC-MS run using multiple reactions monitoring (MRM) as a survey scan to trigger acquisition of enhanced product ion (EPI) data. We determined that NDGA autoxidation at pH 7.4 is dependent on substituents and/or substitution pattern on the two aromatic rings. In particular, spontaneous intramolecular cyclization to a dibenzocyclooctadiene required a di-catechol lignan, raising the possibility that o-Q formation may not be necessary for cyclization to occur. Cyclization was significantly inhibited in the presence of excess GSH which supports the involvement of free radicals as opposed to o-Q in the intramolecular cyclization process. The mono-catechol analogues A1 and A4 underwent oxidation to o-Q but no evidence of cyclization was found implying that electrophilic substitution cannot account for NDGA cyclization. The phenol-type analogues were oxidatively more stable in comparison with the catechol-type analogues at pH 7.4. The results demonstrate that electrophilic substitution makes no contribution to the intramolecular cyclization process and that a radical mediated process accurately describes the situation for NDGA. Oxidative metabolism and bioactivation studies on NDGA and its analogues revealed that reactive metabolites formation is dependent on substitution and/or substitution pattern of the aromatic rings. Cytochrome P450-mediated oxidation of NDGA and its catechol-type analogues yielded electrophilic intermediates which reacted with GSH. The GSH mono-conjugates were identified as ring adducts derived from o-Q although the position at which the GSH binds to the aromatic rings could not be determined. We also found that NL 129 or 307 scanning in positive ionization mode has potential diagnostic utility in distinguishing between aromatic and benzylic GSH conjugates although further studies may be required for validation. We found no evidence of p-QM either directly or via isomerization of o-Q intermediates suggesting that o-Q is the major reactive toxicophore responsible for reactive metabolite mediated toxicities associated with NDGA use. In addition, we demonstrated that the NDGA-derived dibenzycyclooctadiene lignan (cNDGA 2) undergoes P450-mediated oxidation to a reactive metabolite which might have toxicological implications. There was no evidence of P450-mediated oxidation to reactive metabolites for the phenol-type NDGA analogues. It is concluded that structural modification efforts should focus on phenol-type analogues to potentially enhance the safety profile of NDGA

The Nexus Between and Enhancement of Youth’s Involvement in Agriculture: The Case of Eastern Region, Ghana

This paper examines youth’s involvement and the factors hindering youth’s involvement in agriculture. The main objective is to access the engagement of Ghanaian youth in the Eastern Region in agriculture and the figure out factors hindering the youth’s involvement in agriculture. The paper finds answers to the following questions; what really induce the youth to enter into agriculture? What conditions prevents youth from engaging in agriculture? Qualitative research techniques (interviews) were used. The choice model as well as the probit model was used in this paper. It was revealed that most of the youth engaged in agriculture are male as compared to female. Also, most of the youth are not interested in agriculture because of lack of credit facilities, limited startup capital, poor faming technology, use of primitive tools, soil degradation and limited farm lands. It was further revealed the youth migrate to the urban areas to search for job, good industries to work with, good social amenities, good education, and access to loans and enjoy high standard of living in the urban areas. Attention should be given to the factors leading to youth migrating to the urban areas. In addition, the limitations facing the youth in agriculture must be examined. Keywords: Agriculture, Job choice, Migration, Unemployment, Youth. DOI: 10.7176/JBAH/9-10-03 Publication date:May 31st 201

Developing and Deploying Security Applications for In-Vehicle Networks

Radiological material transportation is primarily facilitated by heavy-duty on-road vehicles. Modern vehicles have dozens of electronic control units or ECUs, which are small, embedded computers that communicate with sensors and each other for vehicle functionality. ECUs use a standardized network architecture--Controller Area Network or CAN--which presents grave security concerns that have been exploited by researchers and hackers alike. For instance, ECUs can be impersonated by adversaries who have infiltrated an automotive CAN and disable or invoke unintended vehicle functions such as brakes, acceleration, or safety mechanisms. Further, the quality of security approaches varies wildly between manufacturers. Thus, research and development of after-market security solutions have grown remarkably in recent years. Many researchers are exploring deployable intrusion detection and prevention mechanisms using machine learning and data science techniques. However, there is a gap between developing security system algorithms and deploying prototype security appliances in-vehicle. In this paper, we, a research team at Oak Ridge National Laboratory working in this space, highlight challenges in the development pipeline, and provide techniques to standardize methodology and overcome technological hurdles.Comment: 10 pages, PATRAM 2

Diaspora Entrepreneurs’ Push and Pull Institutional Factors for Investing in Africa: Insights from African Returnees from the United Kingdom

Applying the institution-based views, this article conceptualises how diaspora entrepreneurs take stimuli from the push and pull institutional factors to develop business enterprises in their countries of origin. Using cases of African diaspora entrepreneurs in the UK and the grounded theory methodological approach, our conceptualised model demonstrates that the diasporas use the new knowledge, skills and wealth they have gained in the UK in tandem with support from trusted family, kinship and business ties at home to develop enterprises. It further demonstrates that diaspora entrepreneurs foster resilience to withstand weak formal institutions in their countries of origin and the discriminatory obstacles in the UK. We also found that institutional barriers which served as push factors that encouraged or forced migrants to leave their home countries to seek greener pastures abroad may later become pull factors that enable them to engage in diaspora entrepreneurship which is often characterised by paradoxes. Particularly, the informal institutions that constrain foreign investors can become assets for African diaspora entrepreneurs and help them set up new businesses and exploit market opportunities in Africa. The implications of the study for diaspora entrepreneurship literature are outlined

Drug discovery research in Ghana, challenges, current efforts, and the way forward

We have a long-term vision to develop drug discovery research capacity within Ghana, to tackle unmet medical needs in Ghana and the wider West African region. However, there are several issues and challenges that need to be overcome to enable this vision, including training, human resource, equipment, infrastructure, procurement, and logistics. We discuss these challenges from the context of Ghana in this review. An important development is the universities and research centres within Ghana working together to address some of these challenges. Therefore, while there is a long way to go to fully accomplish our vision, there are encouraging signs

Effects of climate change awareness on green purchase behaviour, biking, and walking time: moderated mediation by sustainability knowingness

Walking and biking are central to the growing health-sustainability debate for favouring the planet and protecting individuals against disease. Research has shown that environmental knowledge factors such as Climate Change Awareness (CCA) and Sustainability Knowingness (SK) can positively influence pro-environmental behaviours [e.g., Green Purchase Behaviour (GPB)]. However, no study has tested the effect of CCA and SK on bicycling (biking) and walking time. This study, therefore, investigated whether there is a moderated mediation by SK in the association of CCA with GPB, walking, and biking time. A cross-sectional design characterised by common methods bias assessment and sensitivity analyses was utilised. The participants were 830 adult residents in Accra, Ghana (mean age = 30 years). Data were collected with standardised scales and analysed with Hayes’ Process Model through structural equation modelling. A positive direct effect of CCA on GPB (β = 0.26; p<0.001) and biking (β = 0.13; p<0.001), as well as walking time (β = 0.16; p<0.001), was found. GPB had a positive effect on biking time (β = 0.10; p<0.001) but a negative effect on walking time (β = -0.093; p<0.001). CCA had a positive effect on biking time but a negative indirect effect on walking time through GPB. There was evidence of a moderated mediation in the sense that the indirect effects of CCA on biking and walking were stronger with higher SK. Individuals with higher CCA are more likely to perform GPB and biking, especially with higher SK

The Burden and Trend of Blood-Borne Pathogens among Asymptomatic Adult Population in Akwatia: A Retrospective Study at the St. Dominic Hospital, Ghana

Background. This study was aimed at evaluating the seroprevalence and trend of blood-borne pathogens (HIV, HCV, HBV, and Syphilis) among asymptomatic adults at Akwatia during a four-year period (2013–2016). Materials and Methods. The study was a retrospective analysis of secondary data of blood donors who visited the hospital from January 2013 to December 2016. Archival data from 11,436 prospective donors was extracted. Data included age, sex, and place of residence as well as results of infectious markers (HIV, HBV, HCV, and Syphilis). Results. The prevalence of blood-borne pathogens in the donor population was 4.06%, 7.23%, 5.81%, and 10.42% for HIV, HBV, HCV, and Syphilis infections, respectively. A significant decline in HBV and HCV infections was observed in the general donor population and across genders. HIV infection rate remained steady while Syphilis infections recorded a significantly increasing trend, peaking in the year 2015 (14.20%). Age stratification in HBV infection was significant, peaking among age group 40–49 years (8.82%). Conclusion. Asymptomatic blood-borne pathogen burden was high among the adult population in Akwatia. Gender variations in HBV, HCV, and Syphilis infections in the cumulative four-year burden were observed. Awareness needs to be created, especially in the older generation

Development and validation of a diagnostic aid for convulsive epilepsy in sub-Saharan Africa: a retrospective case-control study

Background: Identification of convulsive epilepsy in sub-Saharan Africa relies on access to resources that are often unavailable. Infrastructure and resource requirements can further complicate case verification. Using machine-learning techniques, we have developed and tested a region-specific questionnaire panel and predictive model to identify people who have had a convulsive seizure. These findings have been implemented into a free app for health-care workers in Kenya, Uganda, Ghana, Tanzania, and South Africa. Methods: In this retrospective case-control study, we used data from the Studies of the Epidemiology of Epilepsy in Demographic Sites in Kenya, Uganda, Ghana, Tanzania, and South Africa. We randomly split these individuals using a 7:3 ratio into a training dataset and a validation dataset. We used information gain and correlation-based feature selection to identify eight binary features to predict convulsive seizures. We then assessed several machine-learning algorithms to create a multivariate prediction model. We validated the best-performing model with the internal dataset and a prospectively collected external-validation dataset. We additionally evaluated a leave-one-site-out model (LOSO), in which the model was trained on data from all sites except one that, in turn, formed the validation dataset. We used these features to develop a questionnaire-based predictive panel that we implemented into a multilingual app (the Epilepsy Diagnostic Companion) for health-care workers in each geographical region. Findings: We analysed epilepsy-specific data from 4097 people, of whom 1985 (48·5%) had convulsive epilepsy, and 2112 were controls. From 170 clinical variables, we initially identified 20 candidate predictor features. Eight features were removed, six because of negligible information gain and two following review by a panel of qualified neurologists. Correlation-based feature selection identified eight variables that demonstrated predictive value; all were associated with an increased risk of an epileptic convulsion except one. The logistic regression, support vector, and naive Bayes models performed similarly, outperforming the decision-tree model. We chose the logistic regression model for its interpretability and implementability. The area under the receiver operator curve (AUC) was 0·92 (95% CI 0·91–0·94, sensitivity 85·0%, specificity 93·7%) in the internal-validation dataset and 0·95 (0·92–0·98, sensitivity 97·5%, specificity 82·4%) in the external-validation dataset. Similar results were observed for the LOSO model (AUC 0·94, 0·93–0·96, sensitivity 88·2%, specificity 95·3%). Interpretation: On the basis of these findings, we developed the Epilepsy Diagnostic Companion as a predictive model and app offering a validated culture-specific and region-specific solution to confirm the diagnosis of a convulsive epileptic seizure in people with suspected epilepsy. The questionnaire panel is simple and accessible for health-care workers without specialist knowledge to administer. This tool can be iteratively updated and could lead to earlier, more accurate diagnosis of seizures and improve care for people with epilepsy

Applications of molecular docking in natural products-based drug discovery

Natural products have a long history of use in the treatment of various diseases particularly in developing countries. The use of compounds of natural origin as lead compounds for the development of conventional drugs is widely recognised. Natural product-based drug discovery efforts in developing countries mostly involve the use of crude extracts in in-vitro and/or in-vivo assays. There are limited efforts at isolating active principles for structure elucidation studies. Studies that isolate pure secondary metabolites and characterize their structures have limited bioactivity evaluations. In conventional drug discovery programs, molecular docking serves as a useful tool for predicting interactions of small molecules with drug target(s) to guide synthesis decisions. Medicinal chemists use this tool to predict and synthesize compounds likely to have pharmacological activity and thus save time and cost for drug discovery. Efforts have been made to incorporate molecular docking techniques into natural products-based drug discovery. The objective of this review is to discuss molecular docking in natural product drug discovery programs with the goal of providing easy-to-understand information to help beginners interested in incorporating molecular docking in their research. This is expected to enhance natural product screening programs by predicting which phytochemicals are likely to show success, especially in new disease situations such as COVID-19. Applications in the repositioning of plants for emerging conditions are also discussed