Amino acid transporters & amino acid metabolism in Trypanosoma brucei brucei

The development of new drugs against Human African Trypanosomiasis is much needed due to toxicity, efficacy and availability problems with current drug treatments for this resurgent parasitic disease. Delivery of drugs into cells is an important determinant of therapeutic efficacy of drugs. An effective means of selective drug delivery is to use plasma membrane transport systems to mediate the entry of drugs into the cell. Some amino acid transporters fulfil the criteria needed for successful exploitation of nutrient transport systems for drug delivery. The Trypanosoma brucei genomic database was screened to identify the full gene repertoire of amino acid transporters. From this, candidate genes were selected and functional genetic approaches were employed to characterise candidate amino acid transporter genes. Further characterisation of TbAATP1, a RNAi cell line shown to be a transporter of small neutral amino acids (serine, glycine, cysteine, asparagine and alanine), showed a role in threonine uptake. Amino acid analogues were tested for trypanocidal activity. Of the 96 tested, two (Azaserine and Levodopa) were investigated in more detail, paying special attention to the nature of their trypanocidal action and possible route of entry through an amino acid transporter. Azaserine showed a trypanostatic action as well multiple routes of entry into the protozoan interior (as shown by inhibition of glutamine, phenylalanine and tyrosine uptake). The trypanocidal Levodopa showed entry through a tyrosine specific transporter. However, it is possible that Levodopa’s trypanocidal activity may not be as a result of the analogue itself, but secondary products of the analogue. Amino acids are important for protozoa as energy sources as well as forming pools of soluble osmolites. Amino acid usage in trypanosomes was investigated. Upregulation of proline transport and catabolism in response to reduced glucose availability was exhibited by the genome strain of T. brucei. Moreover, this metabolic shift could be mimicked by addition of GlcNAc to the medium, which blocks the hexose transporter limiting glucose entry to the cell. Systems biology approaches were initiated to investigate the undergoing metabolic changes. More specifically, mass spectrometry methodologies were employed to investigate underlying metabolite changes in procyclic form trypanosomes grown in differing medium

Xiamen Call for Action: Building the Brain of the City- Universal Principles of Urban Health

The question of how to achieve healthy, sustainable urban futures demands a singular emphasis. The scale and rate of change of modern urbanisation is unprecedented—so much so that it threatens the health gains of the past century. Urbanisation is the greatest ecological shift in human history, and in modern times has attained dimensions never seen before. We have mere decades to enact the greatest transformational change the planet has ever seen, if we are to safeguard a sustainable future. Indeed, the scope, scale, and ambition of transformative efforts need to accelerate dramatically, if humanity is to achieve sustainability before being overwhelmed by global change.info:eu-repo/semantics/publishedVersio

Multisectoral interventions for urban health in Africa: a mixed-methods systematic review

Increasing evidence suggests that urban health objectives are best achieved through a multisectoral approach. This approach requires multiple sectors to consider health and well-being as a central aspect of their policy development and implementation, recognising that numerous determinants of health lie outside (or beyond the confines of) the health sector. However, collaboration across sectors remains scarce and multisectoral interventions to support health are lacking in Africa. To address this gap in research, we conducted a mixed-method systematic review of multisectoral interventions aimed at enhancing health, with a particular focus on non-communicable diseases in urban African settings. Africa is the world’s fastest urbanising region, making it a critical context in which to examine the impact of multisectoral approaches to improve health. This systematic review provides a valuable overview of current knowledge on multisectoral urban health interventions and enables the identification of existing knowledge gaps, and consequently, avenues for future research. We searched four academic databases (PubMed, Scopus, Web of Science, Global Health) for evidence dated 1989–2019 and identified grey literature from expert input. We identified 53 articles (17 quantitative, 20 qualitative, 12 mixed methods) involving collaborations across 22 sectors and 16 African countries. The principle guiding the majority of the multisectoral interventions was community health equity (39.6%), followed by healthy cities and healthy urban governance principles (32.1%). Targeted health outcomes were diverse, spanning behaviour, environmental and active participation from communities. With only 2% of all studies focusing on health equity as an outcome and with 47% of studies published by first authors located outside Africa, this review underlines the need for future research to prioritise equity both in terms of research outcomes and processes. A synthesised framework of seven interconnected components showcases an ecosystem on multisectoral interventions for urban health that can be examined in the future research in African urban settings that can benefit the health of people and the planet. Paper ContextMain findings: Multisectoral interventions were identified in 27.8% of African countries in the African Union, targeted at major cities with five sectors present at all intervention stages: academia or research, agriculture, government, health, and non-governmental. Added knowledge: We propose a synthesised framework showcasing an ecosystem on multisectoral interventions for urban health that can guide future research in African urban settings. Global health impact for policy and action: This study reveals a crucial gap in evidence on evaluating the long-term impact of multisectoral interventions and calls for partnerships involving various sectors and robust community engagement to effectively deliver and sustain health-promoting policies and actions

The Malaria Problem: short communication

Malaria is the world's most prevalent infectious disease, a major cause of mortality, and a barrier to social and economic development and growth in many countries throughout the world. Antimalarials represent an important part of strategy to curbing this debilitating disease. The spread of drug resistance is becoming increasingly important. To date, parasite resistance to all but one case of antimalarials exists in most endemic countries. Meaning, new drug to combat the disease are a priority

Health synergies across international sustainability and development agendas: pathways to strengthen national action

Since 2015 there has been a surge of international agendas to address a range of global challenges: climate change (Paris Agreement), sustainable development (Agenda 2030), disaster risk reduction (Sendai Framework) and sustainable urban transformation (New Urban Agenda). Health is relevant to all of these agendas. Policymakers must now translate these global agendas into national level policies to implement the agreed goals in a coherent manner. However, approaches to synergise health activities within and across these agendas are needed, in order to achieve better coherence and maximise national level implementation. This research evaluated the framing of human health within these agendas. A content analysis of the agendas was conducted. Findings indicate (i) the importance of increased awareness of health systems strengthening as a helpful framework to guide the integration of health issues across the agendas, (ii) only two health themes had synergies across the agendas, (iii) the lack of a governance mechanism to support the integration of these four agendas to enable national (and sub-national) governments to more feasibly implement their ambitions, and (iv) the vital component of health leadership. Finally, planetary health is a relevant and timely concept that can support the urgent shift to a healthy planet and people

A protocol for a systematic review on intersectoral interventions to reduce non-communicable disease risk factors in African cities

Objectives To present the protocol for a systematic review synthesising quantitative and qualitative evidence in academic and grey literature on intersectoral interventions to address non-communicable disease risk factors in urban Africa. Study design This protocol is developed in accordance with the Preferred Reporting Items for Systematic Review and Meta-analyses Protocols guidelines. Databases to be searched include PubMed, Global Health, SCOPUS, and Web of Science. Grey literature will be sourced from Google, local, regional, and international agencies, colleagues within the GDAR network, international organisations such as the WHO and UN-Habitat, UNICEF’s Child Friendly Cities Initiative, Partnership for Healthy Cities, WHO Alliance for Healthy Cities, the African Centre for Cities, as well as grey literature databases such as Greynet and Opengrey. Methods We will include all quantitative and qualitative study designs that describe any initiatives to address non-communicable disease risk factors through intersectoral interventions, and those that describe associations between such interventions and behavioural health or wellbeing outcomes. We will also include health service interventions that have an intersectoral component and are focused on noncommunicable disease prevention. Studies must have been conducted in African countries, published in the past 30 years, and contain primary or secondary data as well as an analysis of these data. Results We will use the qualitative checklist and the cohort study checklist of the Critical Appraisal Skills Programme (CASP), to appraise the quality of each study included in this review. While the specific framework for data synthesis will be concluded after reviewing the extracted data, we anticipate using a parallel convergent method to synthesise the parallel strands of our study, as it involves analysing the qualitative and quantitative papers separately and then integrating them. Conclusions This will be the first systematic review to explore intersectoral interventions to address noncommunicable disease risk in African cities, thus filling a crucial gap in the literature. The findings of this study will be disseminated across global organisations whose mandates cut across noncommunicable diseases prevention, health promotion and healthy urban development. These include but are not limited to the World Health Organization, UN-Habitat, the UN Interagency Task Force on Noncommunicable Diseases Prevention and Control and the NCD Global Coordination Mechanism. We also plan to disseminate our findings to national and provincial stakeholders such as local governments, Ministries of Health and grassroots organisations; intergovernmental organisations such as the African Development Bank, and local and international private foundations such as Dangote Foundation and the Gates Foundation. The pan-African scope of this study makes it eligible to serve as a regional body of work and a resource to inform future interventions, practices, and policies

Functional characterization of TbMCP5, a conserved and essential ADP/ATP carrier present in the mitochondrion of the human pathogen Trypanosoma brucei

Trypanosoma brucei is a kinetoplastid parasite of medical and veterinary importance. Its digenetic life cycle alternates between the bloodstream form in the mammalian host and the procyclic form (PCF) in the bloodsucking insect vector, the tsetse fly. PCF trypanosomes rely in the glucose-depleted environment of the insect vector primarily on the mitochondrial oxidative phosphorylation of proline for their cellular ATP provision. We previously identified two T. brucei mitochondrial carrier family proteins, TbMCP5 and TbMCP15, with significant sequence similarity to functionally characterized ADP/ATP carriers from other eukaryotes. Comprehensive sequence analysis confirmed that TbMCP5 contains canonical ADP/ATP carrier sequence features, whereas they are not conserved in TbMCP15. Heterologous expression in the ANC-deficient yeast strain JL1Δ2Δ3u - revealed that only TbMCP5 was able to restore its growth on the non-fermentable carbon source lactate. Transport studies in yeast mitochondria showed that TbMCP5 has biochemical properties and ADP/ATP exchange kinetics similar to those of Anc2p, the prototypical ADP/ATP carrier of S. cerevisiae. Immunofluorescence microscopy and Western blot analysis confirmed that TbMCP5 is e xclusively mitochondrial and is differentially expressed with 4.5-fold more TbMCP5 in the procyclic form of the parasite. Silencing of TbMCP5 expression in PCF T. brucei revealed that this ADP/ATP carrier is essential for parasite growth, particularly when depending on proline for energy generation. Moreover, ADP/ATP exchange in isolated T. brucei mitochondria was eliminated upon TbMCP5 depletion. These results confirmed that TbMCP5 functions as the main ADP/ATP carrier in the trypanosome mitochondrion. The important role of TbMCP5 in the T. brucei energy metabolism is further discussed. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc

Synthesis of novel benzamidine- and guanidine-derived polyazamacrocycles: Selective anti-protozoal activity for human African trypanosomiasis

Efficient synthetic routes have been developed for the preparation of two new polyazamacrocycles tagged with structural motifs recognised by the Trypanosoma brucei P2 aminopurine transporter. Biological testing of these compounds showed highly selective anti-protozoal activity against trypanosome

Cell-Penetrating Peptide TP10 Shows Broad-Spectrum Activity against both Plasmodium falciparum and Trypanosoma brucei brucei▿

Malaria and trypanosomiasis are diseases which afflict millions and for which novel therapies are urgently required. We have tested two well-characterized cell-penetrating peptides (CPPs) for antiparasitic activity. One CPP, designated TP10, has broad-spectrum antiparasitic activity against Plasmodium falciparum, both blood and mosquito stages, and against blood-stage Trypanosoma brucei brucei