A semi-synthetic molecule derived from dehydroleucodine affects the trypanosoma cruzi cell cycle

Trypanosoma cruzi is a parasite causing Chagas disease, which is endemic in Latin America, but in the last 20 years, it has expanded worldwide. The current treatment is restricted to Nifurtimox and Benznidazole, but both are relatively toxic and have limited efficacy on the patients. The development of new effective therapeutic agents is urgently needed. The sesquiterpene lactones (STLs) are natural compounds purified from native plants of Argentina with multiple pharmacological applications. The STL dehydroleucodine (DhL), has an alpha-methylene group that could react with multiple sulfhydryl group-containing proteins, affecting cellular functions such as proliferation, the activity mitochondrial, leading to the cell death/apoptosis. This study is focused on elucidating the action mechanisms of DhL and its derivative DC-X11, obtained by chemical substitution, on T. cruzi epimastigotes (strain Dm28c). We observed that DhL and DC-X11 have antiproliferative and cytostatic effects on the parasites. By morphological and ultrastructural studies, we observed an increase of parasites with multiple cell nuclei, kinetoplasts, or flagella after the treatment with DC-X11, suggesting an effect on late steps of the cell cycle (i.e., cellular division). These results were confirmed with parasites synchronized with hydroxyurea (HU 20 mM) for 24 h, and then they were treated with the compound. We concluded that the derivative DC-X11 inhibits T. cruzi proliferation by delaying the progression of the cell division. Further studies are necessary to identify the molecular targets affected by DC-X11.Fil: Gomez, Jessica Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Histología y Embriología D/mend Dr.m.burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Guarise, C.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; ArgentinaFil: Cifuente, Diego Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; ArgentinaFil: Sosa, Claudia Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Histología y Embriología D/mend Dr.m.burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Barrera, Patricia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Histología y Embriología D/mend Dr.m.burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaXXXVII Reunión Científica Anual de la Sociedad de Biología de CuyoSan LuisArgentinaSociedad Biología de Cuy

Income Elasticities of Food Demand in Africa: A Meta-Analysis

In order to combat malnutrition, economists and policymakers need to understand how food demand will change, as the continent further develops. Especially, a better understanding of, first, the factors underlying the relation between income and food demand, and, second, how this relation is changing according to the income level and/or characteristics of the country under study, may help improve the design and implementation of nutrition policies. There are a number of studies that have estimated the relation between income growth and food demand in Africa, but the resulting estimates are highly heterogeneous. This report provides a systematic review of the existing literature on income elasticities of food demand in Africa. Using a meta-analysis approach, this report identifies the factors determining the relation between food demand and income. Further research could usefully explore in greater detail some of the patterns identified and, in doing so, contribute to the design of policies aimed at addressing malnutrition.JRC.J.4-Agriculture and Life Sciences in the Econom

Sesquiterpene lactones affect the redox system of trypanosoma cruzi

Chagas disease is caused by Trypanosoma cruzi (T. cruzi) and affects millions of people worldwide, mostly in Latin America. Despite its sanitary importance, there are currently only two drugs available for its treatment: benznidazole and nifurtimox, both exhibiting serious adverse effects on patients. In order to complete its life cycle, T. cruzi faces extreme environmental conditions ?i.e. oxidative stress- as it propagates from an insect vector to a mammalian host, driving the transition from non-infective epimastigote to the infective form trypomastigote. It is known that the antioxidant defense system in the trypanosomatids is different from that in mammalian cells since the parasites have exclusive molecules and reducing enzymes. Because of this, the parasite redox machinery is an attractive target for antiparasitic therapies. The sesquiterpene lactone dehydroleucodine (DhL), is a trypanocidal molecule containing an alpha-methylene group that could react with sulfhydryl groups of key redox enzymes. This study was focused on elucidating the DhL mechanism of action and extended to ten DhL derivatives (DC-X1 to DC-X10) obtained by chemical substitutions on the methylene group. We firstly confirmed an antiproliferative effect of DhL and its chemical derivatives, being DC- X6 one of the most active. The effect of DhL and DC-X6 was blocked by reduced glutathione, suggesting that compounds are reactive to sulfhydryl groups of certain molecules. Moreover, parasites overexpressing reducing enzymes, such as Tc-CPX, showed a protective effect against these STLs. Consistent with these results, both STLs increased ROS concentration in the wild type parasites. These results indicate that STLs induce oxidative stress on the parasites, possibly by affecting some crucial enzymes of the redox system.Fil: Gomez, Jessica Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Histología y Embriología D/mend Dr.m.burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales. Departamento de Biología; ArgentinaFil: Guarise, C.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Histología y Embriología D/mend Dr.m.burgos; ArgentinaFil: Tello Faral, P.. Instituto Pasteur de Montevideo; UruguayFil: Robello, Carlos. Instituto Pasteur de Montevideo; UruguayFil: Caballero, P.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Histología y Embriología D/mend Dr.m.burgos; ArgentinaFil: Cifuente, Diego Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; ArgentinaFil: Sosa, M. A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Histología y Embriología D/mend Dr.m.burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Barrera, Patricia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Histología y Embriología D/mend Dr.m.burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; ArgentinaXXXVII Reunión Científica Anual de la Sociedad de Biología de CuyoSan LuisArgentinaSociedad de Biología de Cuy

Response of obesity-resistant BALB/c mice to a ketogenic diet

Introduction. The ketogenic diet (KD) is a high-fat, low-carbohydrate diet in which the body undergoes metabolic adjustments that stimulate ketogenesis, thereby increasing circulating ketone bodies. Loss of body weight is attributed to these adjustments, as well as neuroprotective properties. However, the mechanisms involved are still not fully elucidated. That aim of this work was to evaluate the effect of a ketogenic diet on body composition, feeding behavior and glucose metabolism in mice of the BALB/c strain, a mouse model resistant to obesity. Materials and methods. BALB/c mice of both sexes, 12 weeks old, were divided into KD and control groups, which received a ketogenic diet (Research Diets) or standard chow (LabDiet 5001), respectively, for 23 days. Throughout the experiment, body weight gain, water and food intake were measured, whereas body mass index (BMI), the percentage of interscapular, inguinal, and visceral adipose tissue and blood b-hidroxybutyrate levels were measured at the end of the protocol. In addition, glucose tolerance tests were carried out at the beginning and at the end of the experiment. Results. Similar body weight gain (10%) was observed in males and females on KD compared to the control group (p\u3c0.05). However, a higher BMI was observed only in males. The KD group consumed 50% less food in both sexes, whereas water consumption was diminished 25% in males and 50% in females, compared to the control (p= 0.0001). The estimated energy intake was lower (12 Kcal) in males on ketogenic diet, but not in females. Regarding the metabolic state at day 23, in KD mice levels of b-hidroxybutyrate increased to 0.4 mmol/L in males and 0.7 mmol/L in females. Mice of both sexes on KD showed increased inguinal and visceral fat, when compared to the control group on standard chow. At day 23, the glucose tolerance test showed an increase in the area under the curve, indicating impaired glucose tolerance, in both males and females on KD. Conclusions. In obesity-resistant BALB/c mice, the consumption of a ketogenic diet for a short period induces a state of nutritional ketosis accompanied by weight gain, increased fat tissue, and impaired glucose intolerance

Informing the Plastic Treaty negotiations on science - experiences from the Scientists’ Coalition for an Effective Plastic Treaty

The ongoing international negotiations on a global plastics treaty will have pivotal implications for future efforts to transform the plastic economy. This is essential since the current use of plastic in the economy impacts the environment beyond the planetary carrying capacity. To ensure that the forthcoming Treaty can provide the foundation for this transition, the best available science must be made available in the negotiations, but with no formal scientific mechanism to inform the negotiations process, this is not ensured. The Scientists’ Coalition for an Effective Plastic Treaty serves as an example of how the global scientific community has self-organized and come together to address this task, working with five different categories of science-policy communication. The Scientists’ Coalition’s work is made transparent here with the hope that it can inspire organization of scientific input into other future policy areas

Retention strategies for health disparities preventive trials: findings from the Early Childhood Caries Collaborating Centers

ObjectivesTo identify successful strategies for retention of participants in multiyear, community-based randomized controlled trials (RCTs) aiming to reduce early childhood caries in health disparities populations from diverse racial/ethnic backgrounds and across diverse geographic settings.MethodsFour RCTs conducted by the Early Childhood Caries Collaborating Centers (EC4), an initiative of the National Institute of Dental and Craniofacial Research, systematically collected information on the success of various strategies implemented to promote participant retention in each RCT. The observational findings from this case series of four RCTs were tabulated and the strategies rated by study staff.ResultsParticipant retention at 12 months of follow-up ranged from 52.8 percent to 91.7 percent, and at 24 months ranged from 53.6 percent to 85.9, across the four RCTs. For the three RCTs that had a 36-month follow-up, retention ranged from 53.6 percent to 85.1 percent. Effectiveness of different participant retention strategies varied widely across the RCTs.ConclusionsFindings from this case series study may help to guide the design of future RCTs to maximize retention of study participants and yield needed data on effective interventions to reduce oral health disparities

Linfoma cutáneo de células B tipo centro folicular con infiltración a médula ósea reporte de un caso

Los linfomas cutáneos primarios de células B constituyen cerca del 20-25% de todos los linfomas. Ellinfoma cutáneo primario de células B tipo centro folicular es el subtipo más frecuente y se manifiesta principalmente en pacientes adultos con una edad media de 58 años (1), la diseminación extra-cutánea es muy rara y se presenta con nódulos, tumores o placas solitarios o en grupo usualmente localizados en cabeza o tronco. Presentamos el caso de una paciente con un linfoma primario cutáneo tipo centro folicular con infiltración a médula ósea

Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment

This is the peer reviewed version of the following article: Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment. Gut 64.12 (2015): 1921-1935 and which has been published in final form at http://dx.doi.org/10.1136/gutjnl-2014-308935OBJECTIVES: The tumour stroma/microenvironment not only provides structural support for tumour development, but more importantly it provides cues to cancer stem cells (CSCs) that regulate their self-renewal and metastatic potential. This is certainly true for pancreatic ductal adenocarcinomas (PDAC), where tumour-associated fibroblasts, pancreatic stellate cells and immune cells create an abundant paracrine niche for CSCs via microenvironment-secreted factors. Thus understanding the role that tumour stroma cells play in PDAC development and CSC biology is of utmost importance. DESIGN: Microarray analyses, tumour microarray immunohistochemical assays, in vitro co-culture experiments, recombinant protein treatment approaches and in vivo intervention studies were performed to understand the role that the immunomodulatory cationic antimicrobial peptide 18/LL-37 (hCAP-18/LL-37) plays in PDAC biology. RESULTS: We found that hCAP-18/LL-37 was strongly expressed in the stroma of advanced primary and secondary PDAC tumours and is secreted by immune cells of the stroma (eg, tumour-associated macrophages) in response to tumour growth factor-β1 and particularly CSC-secreted Nodal/ActivinA. Treatment of pancreatic CSCs with recombinant LL-37 increased pluripotency-associated gene expression, self-renewal, invasion and tumourigenicity via formyl peptide receptor 2 (FPR2)- and P2X purinoceptor 7 receptor (P2X7R)-dependent mechanisms, which could be reversed by inhibiting these receptors. Importantly, in a genetically engineered mouse model of K-Ras-driven pancreatic tumourigenesis, we also showed that tumour formation was inhibited by either reconstituting these mice with bone marrow from cathelicidin-related antimicrobial peptide (ie, murine homologue of hCAP-18/LL-37) knockout mice or by pharmacologically inhibiting FPR2 and P2X7R. CONCLUSIONS: Thus, hCAP-18/LL-37 represents a previously unrecognised PDAC microenvironment factor that plays a critical role in pancreatic CSC-mediated tumourigenesis.CH: ERC Advanced Investigator Grant (Pa-CSC 233460), European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 256974 (EPC-TM-NET) and n° 602783 (CAM-PaC), the Subdirección General de Evaluación y Fomento de la Investigación, Fondo de Investigación Sanitaria (PS09/02129 & PI12/02643) and the Programa Nacional de Internacionalización de la I+D, Subprogramma: FCCI 2009 (PLE2009-0105; both Ministerio de Economía y Competitividad (es), Spain), BSJr: Rámon y Cajal Merit Award from the Ministerio de Economía y Competitividad, Spain and Clinic and Laboratory Integration Program (CLIP) grant from the Cancer Research Institute, NY, NY. MC: La Caixa Predoctoral Fellowshi

Aging- And Alcohol-Associated Spatial Transcriptomic Signature in Mouse Acute Pancreatitis Reveals Heterogeneity of Inflammation and Potential Pathogenic Factors

The rapidly aging population is consuming more alcohol, leading to increased alcohol-associated acute pancreatitis (AAP) with high mortality. However, the mechanisms remain undefined, and currently there are no effective therapies available. This study aims to elucidate aging- and alcohol-associated spatial transcriptomic signature by establishing an aging AAP mouse model and applying Visium spatial transcriptomics for understanding of the mechanisms in the context of the pancreatic tissue. Upon alcohol diet feeding and caerulein treatment, aging mice (18 months) developed significantly more severe AAP with 5.0-fold increase of injury score and 2.4-fold increase of amylase compared to young mice (3 months). Via Visium spatial transcriptomics, eight distinct tissue clusters were revealed from aggregated transcriptomes of aging and young AAP mice: five acinar, two stromal, and one islet, which were then merged into three clusters: acinar, stromal, and islet for the comparative analysis. Compared to young AAP mice, \u3e 1300 differentially expressed genes (DEGs) and approximately 3000 differentially regulated pathways were identified in aging AAP mice. The top five DEGs upregulated in aging AAP mice include Mmp8, Ppbp, Serpina3m, Cxcl13, and Hamp with heterogeneous distributions among the clusters. Taken together, this study demonstrates spatial heterogeneity of inflammatory processes in aging AAP mice, offering novel insights into the mechanisms and potential drivers for AAP development

Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance

Thyroid hormones (THs) act in the brain to modulate energy balance. We show that central triiodothyronine (T3) regulates de novo lipogenesis in liver and lipid oxidation in brown adipose tissue (BAT) through the parasympathetic (PSNS) and sympathetic nervous system (SNS), respectively. Central T3 promotes hepatic lipogenesis with parallel stimulation of the thermogenic program in BAT. The action of T3 depends on AMP-activated protein kinase (AMPK)-induced regulation of two signaling pathways in the ventromedial nucleus of the hypothalamus (VMH): decreased ceramide-induced endoplasmic reticulum(ER) stress, which promotes BAT thermogenesis, and increased c-Jun N-terminal kinase (JNK) activation, which controls hepatic lipid metabolism. Of note, ablation of AMPK alpha 1 in steroidogenic factor 1 (SF1) neurons of the VMH fully recapitulated the effect of central T3, pointing to this population in mediating the effect of central THs on metabolism. Overall, these findings uncover the underlying pathways through which central T3 modulates peripheral metabolism.Peer reviewe