Antileishmanial activity of terpenylquinones on Leishmania infantum and their effects on Leishmania topoisomerase IB

[EN] Leishmania is the aethiological agent responsible for the visceral leishmaniasis, a serious parasite-borne disease widely spread all over the World. The emergence of resistant strains makes classical treatments less effective; therefore, new and better drugs are necessary. Naphthoquinones are interesting compounds for which many pharmacological properties have been described, including leishmanicidal activity. This work shows the antileishmanial effect of two series of terpenyl-1,4-naphthoquinones (NQ) and 1,4-anthraquinones (AQ) obtained from natural terpenoids, such as myrcene and myrceocommunic acid. They were evaluated both in vitro and ex vivo against the transgenic iRFP-Leishmania infantum strain and also tested on liver HepG2 cells to determine their selectivity indexes. The results indicated that NQ derivatives showed better antileishmanial activity than AQ analogues, and among them, compounds with a diacetylated hydroquinone moiety provided better results than their corresponding quinones. Regarding the terpenic precursor, compounds obtained from the monoterpenoid myrcene displayed good antiparasitic efficiency and low cytotoxicity for mammalian cells, whereas those derived from the diterpenoid showed better antileishmanial activity without selectivity. In order to explore their mechanism of action, all the compounds have been tested as potential inhibitors of Leishmania type IB DNA topoisomerases, but only some compounds that displayed the quinone ring were able to inhibit the recombinant enzyme in vitro. This fact together with the docking studies performed on LTopIB suggested the existence of another mechanism of action, alternative or complementary to LTopIB inhibition. In silico druglikeness and ADME evaluation of the best leishmanicidal compounds has shown good predictable druggabilitySIFinancial support came from Spanish MINECO (CTQ2015-68175-R, AGL2016-79813-C2-1-R, AGL2016-79813-C2-2-R and SAF2017-83575-R), ISCIII-RICET Network (RD12/0018/0002) and Consejería de Educación de la Junta de Castilla y León (LE020P17) co-financed by the Fondo Social Europeo of the European Union (FEDER-EU). P. G. J. acknowledges funding by Fundación Salamanca Ciudad de Cultura y Saberes (’‘Programme for attracting scientific talent to Salamanca’‘

New oxidized ent-kaurane and ent-norkaurane derivatives from kaurenoic acid

New oxidized ent-kaurane and ent-norkaurane derivatives were synthezised starting from kaurenoic acid. The spectroscopic characterization of all compounds is reported

Novel compound shows in vivo anthelmintic activity in gerbils and sheep infected by Haemonchus contortus

8 páginas, 2 figuras, 2 tablas.The control of gastrointestinal nematodes in livestock is becoming increasingly difficult due to the limited number of available drugs and the rapid development of anthelmintic resistance. Therefore, it is imperative to develop new anthelmintics that are effective against nematodes. Under this context, we tested the potential toxicity of three compounds in mice and their potential anthelmintic efficacy in Mongolian gerbils infected with Haemonchus contortus. The compounds were selected from previous in vitro experiments: two diamine (AAD-1 and AAD-2) and one benzimidazole (2aBZ) derivatives. 2aBZ was also selected to test its efficacy in sheep. In Mongolian gerbils, the benzimidazole reduced the percentage of pre-adults present in the stomach of gerbils by 95% at a dose of 200 mg/kg. In sheep, there was a 99% reduction in the number of eggs shed in faeces after 7 days at a dose of 120 mg/kg and a 95% reduction in the number of worm adults present in the abomasum. In conclusion, 2aBZ could be considered a promising candidate for the treatment of helminth infections in small ruminants. © 2022, The Author(s).Financial support came from MINECO: RETOS (AGL2016-79813-C2-1R/2R) and MICINN/AEI (PID2020- 119035RB-100). EVG was funded by FPU17/00627, FPU17/05346; VCGA, MAB, MCP and LGP are recipients of Junta de Castilla y León (JCyL) (LE082-18, LE051-18, LE135-19, LE096-20, respectively) and MMV by the Spanish “Ramon y Cajal” Programme (Ministerio de Economía y competitividad; MMV, RYC-2015-18368).Peer reviewe

Country-Specific vs. Common Birthweight-for-Gestational Age References to Identify Small for Gestational Age Infants Born at 24-28 weeks: An International Study

BACKGROUND Controversy exists as to whether birthweight-for-gestational age references used to classify infants as small for gestational age (SGA) should be country specific or based on an international (common) standard. We examined whether different birthweight-for-gestational age references affected the association of SGA with adverse outcomes among very preterm neonates. METHODS Singleton infants (n = 23 788) of 24(0) -28(6) weeks' gestational age in nine high-resource countries were classified as SGA (<10th centile) using common and country-specific references based on birthweight and estimated fetal weight (EFW). For each reference, the adjusted relative risk (aRR) for the association of SGA with composite outcome of mortality or major morbidity was estimated. RESULTS The percentage of infants classified as SGA differed slightly for common compared with country specific for birthweight references [9.9% (95% CI 9.5, 10.2) vs. 11.1% (95% CI 10.7, 11.5)] and for EFW references [28.6% (95% CI 28.0, 29.2) vs. 24.6% (95% CI 24.1, 25.2)]. The association of SGA with the composite outcome was similar when using common or country-specific references for the total sample for birthweight [aRRs 1.47 (95% CI 1.43, 1.51) and 1.48 (95% CI 1.44, 1.53) respectively] and for EFW references [aRRs 1.35 (95% CI 1.31, 1.38) and 1.39 (95% CI 1.35, 1.43) respectively]. CONCLUSION Small for gestational age is associated with higher mortality and morbidity in infants born <29 weeks' gestational age. Although common and country-specific birthweight/EFW references identified slightly different proportions of SGA infants, the risk of the composite outcome was comparable

Preventive strategies and factors associated with surgically treated necrotising enterocolitis in extremely preterm infants: an international unit survey linked with retrospective cohort data analysis

Objectives To compare necrotising enterocolitis (NEC) prevention practices and NEC associated factors between units from eight countries of the International Network for Evaluation of Outcomes of Neonates, and to assess their association with surgical NEC rates.Design Prospective unit-level survey combined with retrospective cohort study.Setting Neonatal intensive care units in Australia/New Zealand, Canada, Finland, Israel, Spain, Sweden, Switzerland and Tuscany (Italy).Patients Extremely preterm infants born between 240 to 286 weeks’ gestation, with birth weightsExposures NEC prevention practices (probiotics, feeding, donor milk) using responses of an on-line pre-piloted questionnaire containing 10 questions and factors associated with NEC in literature (antenatal steroids, c-section, indomethacin treated patent ductus arteriosus and sepsis) using cohort data.Outcome measures Surgical NEC rates and death following NEC using cohort data.Results The survey response rate was 91% (153 units). Both probiotic provision and donor milk availability varied between 0%–100% among networks whereas feeding initiation and advancement rates were similar in most networks. The 9792 infants included in the cohort study to link survey results and cohort outcomes, revealed similar baseline characteristics but considerable differences in factors associated with NEC between networks. 397 (4.1%) neonates underwent NEC surgery, ranging from 2.4%–8.4% between networks. Standardised ratios for surgical NEC were lower for Australia/New Zealand, higher for Spain, and comparable for the remaining six networks.Conclusions The variation in implementation of NEC prevention practices and in factors associated with NEC in literature could not be associated with the variation in surgical NEC incidence. This corroborates the current lack of consensus surrounding the use of preventive strategies for NEC and emphasises the need for research

Anthelmintic activity of aminoalcohol and diamine derivatives against the gastrointestinal nematode Teladorsagia circumcincta

11 páginas, 5 figuras, 4 tablas.Gastrointestinal nematodes (GIN) infections are a serious problem in livestock production due to the great economic losses they cause. Their control is increasingly difficult because of the rapid development of drug resistance and the limited number of available drugs. Therefore, this study evaluated 18 aminoalcohol and 16 diamine derivatives against eggs, first and third stage larvae from a susceptible and a resistant isolate of Tela-dorsagia circumcincta collected from sheep. The effectiveness of the in vitro anthelmintic activity of the com-pounds was evaluated using three different procedures: Egg Hatch Test (EHT), Larval Mortality Test (LMT) and Larval Migration Inhibition Test (LMIT). Those compounds with activities higher than 90 % in the initial screening at 50 μM were selected to determine their half maximal effective concentration (EC50). In parallel, cytotoxicity assays were conducted on Caco2 and HepG2 cell lines to calculate Selectivity Indexes (SI) for each compound. The diamine 30 presented the best results in preventing egg hatching, displaying the lowest EC50 value (1.01 ±0.04 μM) of all compounds tested and the highest SI (21.21 vs. Caco-2 cells). For the LMIT, the diamine 34 showed the highest efficacy, with EC50 values of 2.67 ±0.08 and 3.02 ±0.09 μM on the susceptible and resistant isolate of the parasite, respectively.We are grateful to Dave Bartley, from Moredun Research Institute for providing the triple-resistant isolate of T. circumcincta. RE thank the RICET contract (E07D401988BR) EC Programs. Financial support came from MINECO: RETOS (AGL2016-79813-C2-1R/2R) and Junta de Castilla y León (JCyL) co-financed by FEDER, UE (LE020P17). EVG was funded by FPU16/03536; JV, VCGA and MAB are recipients of Junta de Castilla y Leon and European Social Found (ESF)’s Fellowships Scheme for Doctoral Training Programs. (JCYL-USAL35B, LE082-18, LE051-18, respectively) and MMV by the Spanish “Ramon y Cajal” Programme (Ministerio de Economía y Competitividad; RYC-2015-18368).Peer reviewe

Preventive strategies and factors associated with surgically treated necrotising enterocolitis in extremely preterm infants: an international unit survey linked with retrospective cohort data analysis

OBJECTIVES To compare necrotising enterocolitis (NEC) prevention practices and NEC associated factors between units from eight countries of the International Network for Evaluation of Outcomes of Neonates, and to assess their association with surgical NEC rates. DESIGN Prospective unit-level survey combined with retrospective cohort study. SETTING Neonatal intensive care units in Australia/New Zealand, Canada, Finland, Israel, Spain, Sweden, Switzerland and Tuscany (Italy). PATIENTS Extremely preterm infants born between 24$^{0}$ to 28$^{6}$ weeks' gestation, with birth weights<1500 g, and admitted between 2014-2015. EXPOSURES NEC prevention practices (probiotics, feeding, donor milk) using responses of an on-line pre-piloted questionnaire containing 10 questions and factors associated with NEC in literature (antenatal steroids, c-section, indomethacin treated patent ductus arteriosus and sepsis) using cohort data. OUTCOME MEASURES Surgical NEC rates and death following NEC using cohort data. RESULTS The survey response rate was 91% (153 units). Both probiotic provision and donor milk availability varied between 0%-100% among networks whereas feeding initiation and advancement rates were similar in most networks. The 9792 infants included in the cohort study to link survey results and cohort outcomes, revealed similar baseline characteristics but considerable differences in factors associated with NEC between networks. 397 (4.1%) neonates underwent NEC surgery, ranging from 2.4%-8.4% between networks. Standardised ratios for surgical NEC were lower for Australia/New Zealand, higher for Spain, and comparable for the remaining six networks. CONCLUSIONS The variation in implementation of NEC prevention practices and in factors associated with NEC in literature could not be associated with the variation in surgical NEC incidence. This corroborates the current lack of consensus surrounding the use of preventive strategies for NEC and emphasises the need for research

The nature and fate of natural resins in the geosphere. XII. Investigation of C-ring aromatic diterpenoids in Raritan amber by pyrolysis-GC-matrix isolation FTIR-MS

Upper Cretaceous amber from the Raritan Formation (Sayerville, New Jersey) has been investigated by Pyrolysis-GC-MS and Pyrolysis-GC-matrix isolation FTIR-MS. Results establish the existence of two distinct forms of amber in this deposit. Both forms are Class Ib ambers, but they are unambiguously differentiated on the basis of their (intact) diterpenoid composition. The presence of callitrisate in both forms, and cupraene in samples designated form 1, strongly suggest that both derive from related-but-distinct species within the Cupressaceae. In addition to callitrisate, dehydroabietate and analogous 17-nor-, 16,17-dinor- and 15,16,17-trinor- analogues of these compounds are also observed. The distributions of these products in multiple samples suggest that they are the result of biological emplacement, rather than diagenetic modification of the parent compounds. This indicates that the distributions of diterpenes observed in these samples are representative of the original bioterpenoids and, hence, are useful for chemotaxonomic analyses

Variations in Oxygen Saturation Targeting, and Retinopathy of Prematurity Screening and Treatment Criteria in Neonatal Intensive Care Units: An International Survey

BACKGROUND Rates of retinopathy of prematurity (ROP) and ROP treatment vary between neonatal intensive care units (NICUs). Neonatal care practices, including oxygen saturation (SpO2) targets and criteria for the screening and treatment of ROP, are potential contributing factors to the variations. OBJECTIVES To survey variations in SpO2 targets in 2015 (and whether there had been recent changes) and criteria for ROP screening and treatment across the networks of the International Network for Evaluating Outcomes in Neonates (iNeo). METHODS Online prepiloted questionnaires on treatment practices for preterm infants were sent to the directors of 390 NICUs in 10 collaborating iNeo networks. Nine questions were asked and the results were summarized and compared. RESULTS Overall, 329/390 (84%) NICUs responded, and a majority (60%) recently made changes in upper and lower SpO2 target limits, with the median set higher than previously by 2-3% in 8 of 10 networks. After the changes, fewer NICUs (15 vs. 28%) set an upper SpO2 target limit > 95% and fewer (3 vs. 5%) a lower limit < 85%. There were variations in ROP screening criteria, and only in the Swedish network did all NICUs follow a single guideline. The initial retinal examination was carried out by an ophthalmologist in all but 6 NICUs, and retinal photography was used in 20% but most commonly as an adjunct to indirect ophthalmoscopy. CONCLUSIONS There is considerable variation in SpO2 targets and ROP screening and treatment criteria, both within networks and between countries

Personality Traits of an Entrepreneur, Determinants of Successful Microenterprise in Ireland

Why do certain individuals become entrepreneur and are successful, whereas others do not? The researchers in the entrepreneurship field attempt to answer that question by studying the personality traits of entrepreneurs for decades. Many confirm that the personality traits have a positive correlation with entrepreneurial intention and performance. Various studies suggest that the main entrepreneurial characteristics are risk attitudes, need for achievement, internal locus of control, innovativeness, and self-efficacy. However, debate exist if the personality traits are born or inherited and if the entrepreneurs’ actions are influenced by factors such as family, culture, education and market conditions. Although these aspects will be reviewed the focus of this study is on entrepreneurs’ personality traits only. Consequently, the aim of this study is to identify which of the personality traits, and whether there are traits, that are associated with operating successful microenterprise, from a perspective of an owner-manager of an established business in Ireland. The findings of this research revealed that the participants perceive themselves as individuals who possess indirectly four out of five most cited traits in the literature, which are need for achievement, locus of control, innovativeness and self-efficacy. In addition, they mentioned ability to relate to others, being organized and perform a quality work as the most important characteristics of a successful business owner. Also, other factors of environment influenced the participants’ decision to become an entrepreneur and Ireland was perceived as an attractive country to set up a business. Still, most of the participants do not perceive themselves as a successful entrepreneur. In summary, the inconclusiveness of this study generate more questions than it provide answers, coupled with this study limitations it is suggested that additional and more extensive research is desired