The environmental, socioeconomic, and health impacts of woodfuel value chains in Sub-Saharan Africa: A systematic map

Background: In Sub-Saharan Africa (SSA), the production and use of woodfuel remains an important socio-economic activity with more than 70% of the population relying on woodfuel as their primary household energy source. Despite their socio-economic significance, woodfuel value chains are often viewed negatively due to their association with detrimental health and environmental impacts. However, the lack of sound evidence and limited understanding of the role of contextual factors in influencing the various impacts of woodfuel value chains have prevented the formulation of properly guided policy interventions. Thus the objective of this systematic map is to provide a comprehensive review of the environmental, socio-economic, and health impacts of woodfuel value chains across SSA. Methods: The search strategy for this review map was defined in a peer-reviewed protocol and refined by iterative testing. Search strings were composed of population, intervention, and location terms and combined using Boolean operators. The bibliographic databases Web of Science, Scopus, and CAB Abstracts were used as the main sources of literature for this review, and a total of 4728 results were initially retrieved. Following title and abstract screening, 659 entered full text screening. Critical appraisal of 219 articles led to the exclusion of studies that did not set meet quality criteria for this map, resulting in a final total of 131 articles for inclusion in data extraction and analysis. Results: From the 131 included articles, 152 individual studies were identified during data extraction. Studies came from 26 of the 49 Sub Saharan African countries, with a particular preponderance of articles published in the last 10 years. Critical appraisal found significant weaknesses in the experimental design of woodfuel value chain studies with the exception of health impact studies, which frequently utilized controls or other relevant comparators. Findings suggest that woodfuel value chains have environmental, socioeconomic and health consequences with the frequent presence of trade-offs. The reporting of contextual factors in the studies challenge the widespread perception of deforestation as being directly caused by bush fires, overgrazing and woodcutting. Instead, agricultural expansion (which often includes forest clearing) and pre-existing biophysical factors were the most frequently cited factors in shaping environmental outcomes. Conclusions: This systematic map suggests that there are environmental, socioeconomic and health consequences associated with woodfuel value chains in Sub-Saharan Africa. However, the literature also shows a weak and geographically limited evidence base to justify the above claims. We argue that policy formulation processes targeting woodfuels in SSA require more solid, coherent and broad body of knowledge, especially for such a vital sector in rural economies. Thus, there is an urgent need to design and undertake research using robust methodologies, at appropriate scales that further takes into account the interrelationships between environmental and socio-economic outcomes in order to generate substantial and reliable evidence for informed policy formulation. (Résumé d'auteur

Polyamine homoeostasis as a drug target in pathogenic protozoa: peculiarities and possibilities

New drugs are urgently needed for the treatment of tropical and subtropical parasitic diseases, such as African sleeping sickness, Chagas' disease, leishmaniasis and malaria. Enzymes in polyamine biosynthesis and thiol metabolism, as well as polyamine transporters, are potential drug targets within these organisms. In the present review, the current knowledge of unique properties of polyamine metabolism in these parasites is outlined. These properties include prozyme regulation of AdoMetDC (S-adenosylmethionine decarboxylase) activity in trypanosomatids, co-expression of ODC (ornithine decarboxylase) and AdoMetDC activities in a single protein in plasmodia, and formation of trypanothione, a unique compound linking polyamine and thiol metabolism in trypanosomatids. Particularly interesting features within polyamine metabolism in these parasites are highlighted for their potential in selective therapeutic strategies

Novel Synthetic Polyamines Have Potent Antimalarial Activities in vitro and in vivo by Decreasing Intracellular Spermidine and Spermine Concentrations

Twenty-two compounds belonging to several classes of polyamine analogs have been examined for their ability to inhibit the growth of the human malaria parasite Plasmodium falciparum in vitro and in vivo. Four lead compounds from the thiourea sub-series and one compound from the urea-based analogs were found to be potent inhibitors of both chloroquine-resistant (Dd2) and chloroquine-sensitive (3D7) strains of Plasmodium with IC₅₀ values ranging from 150 to 460 nM. In addition, the compound RHW, N1,N7-bis (3-(cyclohexylmethylamino) propyl) heptane-1,7-diamine tetrabromide was found to inhibit Dd2 with an IC₅₀ of 200 nM. When RHW was administered to P. yoelii-infected mice at 35 mg/kg for 4 days, it significantly reduced parasitemia. RHW was also assayed in combination with the ornithine decarboxylase inhibitor difluoromethylornithine, and the two drugs were found not to have synergistic antimalarial activity. Furthermore, these inhibitors led to decreased cellular spermidine and spermine levels in P. falciparum, suggesting that they exert their antimalarial activities by inhibition of spermidine synthase

Lysine harvesting is an antioxidant strategy and triggers underground polyamine metabolism

Both single and multicellular organisms depend on anti-stress mechanisms that enable them to deal with sudden changes in the environment, including exposure to heat and oxidants. Central to the stress response are dynamic changes in metabolism, such as the transition from the glycolysis to the pentose phosphate pathway—a conserved first-line response to oxidative insults1,2. Here we report a second metabolic adaptation that protects microbial cells in stress situations. The role of the yeast polyamine transporter Tpo1p3,4,5 in maintaining oxidant resistance is unknown6. However, a proteomic time-course experiment suggests a link to lysine metabolism. We reveal a connection between polyamine and lysine metabolism during stress situations, in the form of a promiscuous enzymatic reaction in which the first enzyme of the polyamine pathway, Spe1p, decarboxylates lysine and forms an alternative polyamine, cadaverine. The reaction proceeds in the presence of extracellular lysine, which is taken up by cells to reach concentrations up to one hundred times higher than those required for growth. Such extensive harvest is not observed for the other amino acids, is dependent on the polyamine pathway and triggers a reprogramming of redox metabolism. As a result, NADPH—which would otherwise be required for lysine biosynthesis—is channelled into glutathione metabolism, leading to a large increase in glutathione concentrations, lower levels of reactive oxygen species and increased oxidant tolerance. Our results show that nutrient uptake occurs not only to enable cell growth, but when the nutrient availability is favourable it also enables cells to reconfigure their metabolism to preventatively mount stress protection

Structural Studies of Polyamine Biosynthesis Enzymes: Potential Targets for Drugs against Tropical Parasites

Two enzymes involved in the biosynthesis of polyamines, ornithine decarboxylase (ODC, from human and Leishmania donovani) and spermidine synthase (SPDS, from Plasmodium falciparum and Caenorhabditis elegans) were studied using biochemical methods, homology modelling and X-ray crystallography. ODC catalyses the first and committed step in polyamine biosynthesis, the decarboxylation of ornithine to putrescine. Kinetic parameters were different between L. donovani and human ODC. 3-aminooxy-1-aminopropane (APA) was a potent inhibitor of both human and L. donovani ODC with a Ki value of around 1.0 nM. The structure of human ODC in complex with its inhibitor, APA, revealed the binding mode of APA with no oxime formed between APA and pyridoxal 5'-phosphate. SPDS catalyses the transfer of an aminopropyl group from decarboxylated S-adenosylmethionine, (dcAdoMet) to putrescine, forming spermidine. Analysis of the crystal structure of C. elegans SPDS confirmed a homo-dimeric organisation of the nematode enzyme and revealed a high degree of conservation of the overall fold when compared to the structure of other SPDSs. Furthermore, a nematode-specific insertion that has been identified close to the N-terminus of the C. elegans and other nematode SPDSs was found to be located in close proximity to the substrate binding site. The structure of the apo-enzyme as well as the structures with the substrate dcAdoMet and the inhibitors, S-adenosyl-1,8-diamino-3-thio-octane (AdoDATO) and trans-4-methylcyclohexylamine (4MCHA) of P. falciparum SPDS were determined. Comparison of the apo- and dcAdoMet structures suggests that the binding of dcAdoMet is necessary for the binding of the second substrate, putrescine. AdoDATO and 4MCHA bind such that the proximal negatively charged putrescine binding pocket is not occupied. The complex with 4MCHA clearly demonstrates why it is a better inhibitor of P. falciparum than cyclohexylamine and suggests a way for the development of new inhibitors of higher potency

Contextual modifiers of healthspan, lifespan, and epigenome in mice under chronic social stress

: Sustained life stress and low socioeconomic status are among the major causes of aging-related diseases and decreased life expectancy. Experimental rodent models can help to identify the underlying mechanisms, yet very few studies address the long-term consequences of social stress on aging. We conducted a randomized study involving more than 300 male mice of commonly used laboratory strains (C57BL/6J, CD1, and Sv129Ev) chosen for the spontaneous aggression gradient and stress-vulnerability. Mice were exposed to a lifelong chronic psychosocial stress protocol to model social gradients in aging and disease vulnerability. Low social rank, inferred based on a discretized aggression index, was found to negatively impact lifespan in our study population. However, social rank interacted with genetic background in that low-ranking C57BL/6J, high-ranking Sv129Ev, and middle-ranking CD1 mice had lower survival, respectively, implying a cost of maintaining a given social rank that varies across strains. Machine learning linear discriminant analysis identified baseline fat-free mass as the most important predictor of mouse genetic background and social rank in the present dataset. Finally, strain and social rank differences were significantly associated with epigenetic changes, most significantly in Sv129Ev mice and in high-ranking compared to lower ranking subjects. Overall, we identified genetic background and social rank as critical contextual modifiers of aging and lifespan in an ethologically relevant rodent model of social stress, thereby providing a preclinical experimental paradigm to study the impact of social determinants of health disparities and accelerated aging

Crystal structure of Plasmodium falciparum spermidine synthase in complex with the substrate decarboxylated S-adenosylmethionine and the potent inhibitors 4MCHA and AdoDATO

Plasmodium falciparum is the causative agent of the most severe type of malaria, a life-threatening disease affecting the lives of over three billion people. Factors like widespread resistance against available drugs and absence of an effective vaccine are seriously compounding control of the malaria parasite. Thus, there is an urgent need for the identification and validation of new drug targets. The enzymes of the polyamine biosynthesis pathway have been suggested as possible targets for the treatment of malaria. One of these enzymes is spermidine synthase (SPDS, putrescine aminopropyltransferase), which catalyzes the transfer of an aminopropyl moiety from decarboxylated S-adenosylmethionine (dcAdoMet) to putrescine, leading to the formation of spermidine and 5 '-methylthioadenosine. Here we present the three-dimensional structure of P falciparum spermidine synthase (pfSPDS) in apo form, in complex with dcAdoMet and two inhibitors, S-adenosyl-1,8-diamino-3-thio-octane (AdoDATO) and trans-4-methylcyclohexylamine (4MCHA). The results show that binding of dcAdoMet to pfSPDS stabilizes the conformation of the flexible gatekeeper loop of the enzyme and affects the conformation of the active-site amino acid residues, preparing the protein for binding of the second substrate. The complexes of AdoDATO and 4MCHA with pfSPDS reveal the mode of interactions of these compounds with the enzyme. While AdoDATO essentially fills the entire active-site pocket, 4MCHA only occupies part of it, which suggests that simple modifications of this compound may yield more potent inhibitors of pfSPDS. (C) 2007 Elsevier Ltd. All rights reserved

A structural insight into the inhibition of human and Leishmania donovani ornithine decarboxylases by 1-amino-oxy-3-aminopropane

The critical role of polyamines in key processes such as cell growth, differentiation and macromolecular synthesis makes the enzymes involved in their synthesis potential targets in the treatment of certain types of cancer and parasitic diseases. Here we present a study on the inhibition of human and Leishmania donovani ODC (ornithine decarboxylase), the first committed enzyme in the polyamine biosynthesis pathway, by APA (1-amino-oxy-3-aminopropane). The present study shows APA to be a potent inhibitor of both human and L. donovani ODC with a Ki value of around 1.0 nM. We also show that L. donovani ODC binds the substrate, the co-enzyme pyridoxal 5′-phosphate and the irreversible inhibitor α-difluoromethylornithine (a curative agent of West African sleeping sickness) with less affinity than human ODC. We have also determined the three-dimensional structure of human ODC in complex with APA, which revealed the mode of the inhibitor binding to the enzyme. In contrast with earlier reports, the structure showed no indication of oxime formation between APA and PLP (pyridoxal 5′-phosphate). Homology modelling suggests a similar mode of binding of APA to L. donovani ODC. A comparison of the ODC–APA–PLP structure with earlier ODC structures also shows that the protease-sensitive loop (residues 158–168) undergoes a large conformational change and covers the active site of the protein. The understanding of the structural mode of APA binding may constitute the basis for the development of more specific inhibitors of L. donovani ODC

The structures of human dihydroorotate dehydrogenase with and without inhibitor reveal conformational flexibility in the inhibitor and substrate binding sites.

Inhibitors of dihydroorotate dehydrogenase (DHODH) have been suggested for the treatment of rheumatoid arthritis, psoriasis, autoimmune diseases, Plasmodium, and bacterial and fungal infections. Here we present the structures of N-terminally truncated (residues Met30-Arg396) DHODH in complex with two inhibitors: a brequinar analogue (6) and a novel inhibitor (a fenamic acid derivative) (7), as well as the first structure of the enzyme to be characterized without any bound inhibitor. It is shown that 7 uses the "standard" brequinar binding mode and, in addition, interacts with Tyr356, a residue conserved in most class 2 DHODH proteins. Compared to the inhibitor-free structure, some of the amino acid side chains in the tunnel in which brequinar binds and which was suggested to be the binding site of ubiquinone undergo changes in conformation upon inhibitor binding. Using our data, the loop regions of residues Leu68-Arg72 and Asn212-Leu224, which were disordered in previously studied human DHODH structures, could be built into the electron density. The first of these loops, which is located at the entrance to the inhibitor-binding pocket, shows different conformations in the three structures, suggesting that it may interfere with inhibitor/cofactor binding. The second loop has been suggested to control the access of dihydroorotate to the active site of the enzyme and may be an important player in the enzymatic reaction. These observations provide new insights into the dynamic features of the DHODH reaction and suggest new approaches to the design of inhibitors against DHODH