HDAC specificity and kinase off-targeting by purine-benzohydroxamate anti-hematological tumor agents.

A series of hybrid inhibitors, combining pharmacophores of known kinase inhibitors bearing anilino-purines (ruxolitinib, ibrutinib) and benzohydroxamate HDAC inhibitors (nexturastat A), were generated in the present study. The compounds have been synthesized and tested against solid and hematological tumor cell lines. Compounds 4d-f were the most promising in cytotoxicity assays (IC50 ≤ 50 nM) vs. hematological cells and displayed moderate activity in solid tumor models (EC50 = 9.3-21.7 µM). Compound 4d potently inhibited multiple kinase targets of interest for anticancer effects, including JAK2, JAK3, HDAC1, and HDAC6. Molecular dynamics simulations showed that 4d has stable interactions with HDAC and members of the JAK family, with differences in the hinge binding energy conferring selectivity for JAK3 and JAK2 over JAK1. The kinase inhibition profile of compounds 4d-f allows selective cytotoxicity, with minimal effects on non-tumorigenic cells. Moreover, these compounds have favorable pharmacokinetic profiles, with high stability in human liver microsomes (e.g., see t1/2: >120 min for 4f), low intrinsic clearance, and lack of significant inhibition of four major CYP450 isoforms.

1,3-Diphenylureido hydroxamate as a promising scaffold for generation of potent antimalarial histone deacetylase inhibitors.

We report a series of 1,3-diphenylureido hydroxamate HDAC inhibitors evaluated against sensitive and drug-resistant P. falciparum strains. Compounds 8a-d show potent antiplasmodial activity, indicating that a phenyl spacer allows improved potency relative to cinnamyl and di-hydrocinnamyl linkers. In vitro, mechanistic studies demonstrated target activity for PfHDAC1 on a recombinant level, which agreed with cell quantification of the acetylated histone levels. Compounds 6c, 7c, and 8c, identified as the most active in phenotypic assays and PfHDAC1 enzymatic inhibition. Compound 8c stands out as a remarkable inhibitor, displaying an impressive 85% inhibition of PfHDAC1, with an IC50 value of 0.74 µM in the phenotypic screening on Pf3D7 and 0.8 µM against multidrug-resistant PfDd2 parasites. Despite its potent inhibition of PfHDAC1, 8c remains the least active on human HDAC1, displaying remarkable selectivity. In silico studies suggest that the phenyl linker has an ideal length in the series for permitting effective interactions of the hydroxamate with PfHDAC1 and that this compound series could bind as well as in HsHDAC1. Taken together, these results highlight the potential of diphenylurea hydroxamates as a privileged scaffold for the generation of potent antimalarial HDAC inhibitors with improved selectivity over human HDACs.

Association between ventilatory ratio and mortality in patients with acute respiratory distress syndrome and COVID 19: A multicenter, retrospective cohort study.

BACKGROUND: Mortality rates in patients with COVID-19 undergoing mechanical ventilation in the intensive care unit are high. The causes of this mortality have been rigorously investigated. The aim of the present study is to establish mortality risk factors related to lung mechanics measured at days 1 and 5 in patients with covid-19 ARDS managed with invasive mechanical ventilation in the intensive care unit. METHODS: A retrospective observational multicenter study including consecutive patients with a confirmed diagnosis of COVID-19-induced ARDS, admitted to three institutions and seven intensive care units in the city of Bogota between May 20, 2020 and May 30, 2022 who required mechanical ventilation for at least five days. Data were collected from the medical records of patients who met the inclusion criteria on day 1 and day 5 of mechanical ventilation. The primary outcome assessed was mortality at day 30. RESULTS: A total of 533 consecutive patients admitted with ARDS with COVID-19 were included. Ventilatory ratio, plateau pressure and driving pressure measured on day 5 were significantly higher in non-survivors (p < 0.05). Overall, 30-day follow-up mortality was 48.8%. The increases between day 1 and day 5 in the ventilatory ratio (OR 1.42, 95%CI 1.03-2.01, p = 0.04), driving pressure (OR 1.56, 95%CI 1.10-2.22, p = 0.01); and finally plateau pressure (OR 1.9, 95%CI 1.34-2.69, p = 0.001) were associated with an increased risk of death. There was no association between deterioration of PaO2/FIO2 index and mortality (OR 1.34, 95%CI 0.96-1.56, p = 0.053). CONCLUSIONS: Ventilatory ratio, plateau pressure, driving pressure, and age were identified as independent risk factors for 30-day mortality in patients with ARDS due to COVID-19 on day 5 of invasive mechanical ventilation.

Structure-Activity Relationship and Biological Investigation of a REV-ERBα-Selective Agonist SR-29065 (34) for Autoimmune Disorders.

Autoimmune diseases affect 50 million Americans, predominantly women, and are thought to be one of the top 10 leading causes of death among women in age groups up to 65 years. A central role for TH17 cells has been highlighted by genome-wide association studies (GWAS) linking genes preferentially expressed in TH17 cells to several human autoimmune diseases. We and others have reported that the nuclear receptors REV-ERBα and ß are cell-intrinsic repressors of TH17 cell development and pathogenicity and might therefore be therapeutic targets for intervention. Herein, we describe detailed SAR studies of a novel REV-ERBα-selective scaffold. Metabolic stability of the ligands was optimized allowing for in vivo interrogation of the receptor in a mouse model of multiple sclerosis (EAE) with a ligand (34). Reduction in frequency and number of T-cells in the CNS as well as key REV-ERB target genes is a measure of target engagement in vivo.

In support of 2D:4D: More data exploring its conflicting results on handedness, sexual orientation and sex differences.

In the last few years, several studies have questioned the value of the second-to-fourth digit ratio (2D:4D) as a measure of exposure to sex hormones before birth. Controversy has also extended to the 2D:4D association with individual features previously related to this exposure such as handedness and sexual orientation. Given that it has been argued that sex differences in 2D:4D could be a consequence of body-size differences, we have tested in a large sample the allometric relationship between finger lengths and body size. Our results show that the association is either allometric or isometric, depending on the analyses performed. In any case, the deviation from isometry is not large enough to explain the typically observed sex difference in this trait. We have also tested the association between sexual orientation and 2D:4D, finding a relationship between 2D:4D and sexual orientation in men but not in women. We attribute this discordance with previously published meta-analysis to differences in genetic background, a variable that has gained relevance in recent years in studies involving 2D:4D. Finally, we did not find any relationship between 2D:4D and handedness, evaluated through self-reported preference and hand performance. Our main conclusion is that 2D:4D shows differences between sexes beyond their disparity in body size. In our opinion, 2D:4D can be used cautiously as an indicator of intrauterine exposure to sex hormones taking into account some considerations, such as analysing a very large sample and taking careful measurements of the ethnicity of the sample.

Structure-based design of bitopic ligands for the µ-opioid receptor.

Mu-opioid receptor (µOR) agonists such as fentanyl have long been used for pain management, but are considered a major public health concern owing to their adverse side effects, including lethal overdose1. Here, in an effort to design safer therapeutic agents, we report an approach targeting a conserved sodium ion-binding site2 found in µOR3 and many other class A G-protein-coupled receptors with bitopic fentanyl derivatives that are functionalized via a linker with a positively charged guanidino group. Cryo-electron microscopy structures of the most potent bitopic ligands in complex with µOR highlight the key interactions between the guanidine of the ligands and the key Asp2.50 residue in the Na+ site. Two bitopics (C5 and C6 guano) maintain nanomolar potency and high efficacy at Gi subtypes and show strongly reduced arrestin recruitment-one (C6 guano) also shows the lowest Gz efficacy among the panel of µOR agonists, including partial and biased morphinan and fentanyl analogues. In mice, C6 guano displayed µOR-dependent antinociception with attenuated adverse effects, supporting the µOR sodium ion-binding site as a potential target for the design of safer analgesics. In general, our study suggests that bitopic ligands that engage the sodium ion-binding pocket in class A G-protein-coupled receptors can be designed to control their efficacy and functional selectivity profiles for Gi, Go and Gz subtypes and arrestins, thus modulating their in vivo pharmacology.

Teratoma de ligamento redondo, reporte de caso y revisión de la bibliografía / Round ligament teratoma, case report and literature review

Resumen ANTECEDENTES: El teratoma es un tumor casi siempre benigno, con una amplia variabilidad en su localización, extremadamente rara, en el ligamento redondo. CASO CLÍNICO: Paciente de 30 años, con antecedente de un embarazo a término. En la revisión ecográfica se reportó una lesión quística paraovárica izquierda de 46 x 35 mm, sin componente sólido, graso ni calcificaciones. En el examen ginecológico se palpó una masa por encima del útero, orientada hacia el lado izquierdo, no dolorosa. El resto del examen físico trascurrió sin otras alteraciones. La impresión diagnóstica inicial fue de teratoma abdominopélvico sustentada en la ecografía transvaginal en la que los ovarios se observaron normales, con una masa de ecogenicidad mixta de 50 x 40 x 46 mm, con áreas ecolúcidas y ecogénicas de intensidad variable hacia la fosa iliaca izquierda superior, sin contacto con el ovario. El ligamento redondo se seccionó a ambos lados de la masa y se extrajo sin complicaciones; el reporte histopatológico fue de: teratoma quístico maduro. CONCLUSIONES: El ligamento redondo es una localización infrecuente de los quistes dermoides que debe considerarse en los diagnósticos diferenciales de las masas pélvicas; es susceptible de tratamiento quirúrgico por vía laparoscópica.

Abstract BACKGROUND: Teratoma is an almost always benign tumor, with a wide variability in its location; its location in the round ligament is extremely rare. CLINICAL CASE: 30-year-old patient, with a history of a full-term pregnancy. On routine ultrasound examination, a 46 x 35 mm left paraovarian cystic lesion was reported, with no solid, fatty component or calcifications. In the gynecological examination a mass was palpated above the uterus, oriented to the left side, non-painful. The rest of the physical examination passed without other alterations. The initial diagnostic impression was of abdomino-pelvic teratoma supported by transvaginal ultrasound in which the ovaries were normal, with a mass of mixed echogenicity of 50 x 40 x 46 mm, with echolucent and echogenic areas of variable intensity towards the left superior iliac fossa, without contact with the ovary. The round ligament was sectioned on both sides of the mass and removed without complications; the histopathologic report was: mature cystic teratoma. CONCLUSIONS: The round ligament is an infrequent location of dermoid cysts that should be considered in the differential diagnoses of pelvic masses; it is amenable to surgical treatment laparoscopically.

Development of a putative Zn2+-chelating but highly selective MMP-13 inhibitor.

Starting from an already known MMP-13 inhibitor, 1, we pursued an SAR-approach focusing on optimizing interactions close to the Zn2+ binding site of the enzyme. We found the oxetane containing compound 32 (MMP-13 IC50 = 42 nM), which exhibited complete inhibition of collagenolysis in in vitro studies and an excellent selectivity profile among the MMP family. Interestingly, docking studies propose that the oxetane ring in 32 is oriented towards the Zn2+ ion for chelating the metal ion. Chelating properties of MMP13-inhibitors are often connected with non-selectivity within the enzyme family. Compound 32 demonstrates a rare example where the selectivity can be explained via combinatorial effects of interactions within the S1' loop and a chelating effect of the oxetane moiety. Furthermore, in vivo pharmacokinetic studies were performed demonstrating a concentration of 1.97 µM of 32 within the synovial fluid of the rat knee joint, which makes the compound a promising lead compound for further optimization and development for osteoarthritis.

Morphing Natural Product Platensimycin via Heck, Sonogashira, and One-Pot Sonogashira/Cycloaddition Reactions to Produce Antibiotics with In Vivo Activity.

Type II fatty acid synthases are promising drug targets against major bacterial pathogens. Platensimycin (PTM) is a potent inhibitor against ß-ketoacyl-[acyl carrier protein] synthase II (FabF) and ß-ketoacyl-[acyl carrier protein] synthase I (FabB), while the poor pharmacokinetics has prevented its further development. In this work, thirty-two PTM derivatives were rapidly prepared via Heck, Sonogashira, and one-pot Sonogashira/cycloaddition cascade reactions based on the Gram-scale synthesis of 6-iodo PTM (4). About half of the synthesized compounds were approximately equipotent to PTM against the tested Staphylococcus aureus strains. Among them, the representative compounds 4, A4, and B8 exhibited different plasma protein binding affinity or stability in the human hepatic microsome assay and showed improved in vivo efficacy over PTM in a mouse peritonitis model. In addition, A4 was also effective in an S. aureus-infected skin mouse model. Our study not only significantly expands the known PTM derivatives with improved antibacterial activities in vivo, but showcased that C-C cross-coupling reactions are useful tools to functionalize natural product drug leads.

Efficacy of Transversus Abdominis Plane Block in the Reduction of Pain and Opioid Requirement in Laparoscopic and Robot-assisted Hysterectomy: A Systematic Review and Meta-analysis.

OBJECTIVE: To summarize the available evidence of TAP Block in efficacy in laparoscopic or robotic hysterectomy. DATA SOURCES: We searched databases and gray literature for randomized controlled trials in which transversus abdominis plane (TAP) block was compared with placebo or with no treatment in patients who underwent laparoscopic or robot-assisted hysterectomy. METHOD OF STUDY SELECTION: Two researchers independently evaluated the eligibility of the selected articles. TABULATION, INTEGRATION, AND RESULTS: Seven studies were selected, involving 518 patients. Early postoperative pain showed a difference in the mean mean difference (MD): - 1.17 (95% confidence interval [CI]: - 1.87-0.46) in pain scale scores (I2 = 68%), which was statistically significant in favor of using TAP block, but without clinical relevance; late postoperative pain: DM 0.001 (95%CI: - 0.43-0.44; I2 = 69%); opioid requirement: DM 0.36 (95%CI: - 0.94-1.68; I2 = 80%); and incidence of nausea and vomiting with a difference of 95%CI = - 0.11 (- 0.215-0.006) in favor of TAP. CONCLUSION: With moderate strength of evidence, due to the high heterogeneity and imbalance in baseline characteristics among studies, the results indicate that TAP block should not be considered as a clinically relevant analgesic technique to improve postoperative pain in laparoscopic or robotic hysterectomy, despite statistical significance in early postoperative pain scale scores. CLINICAL TRIAL NUMBER AND REGISTRY: PROSPERO ID - CRD42018103573.

OBJETIVO: Resumir as evidências disponíveis sobre a eficácia do bloqueio TAP em histerectomia laparoscópica ou robótica. FONTES DE DADOS: Pesquisamos bancos de dados e literatura cinza por ensaios clínicos randomizados nos quais o bloqueio do plano transverso do abdome (TAP na sigla em inglês) foi comparado com placebo ou com nenhum tratamento em pacientes que foram submetidos a histerectomia laparoscópica ou assistida por robô. MéTODOS DE SELEçãO DE ESTUDOS: Dois pesquisadores avaliaram independentemente a elegibilidade dos artigos selecionados. TABULAçãO, INTEGRAçãO E RESULTADOS: Sete estudos foram selecionados envolvendo 518 pacientes. A dor pós-operatória precoce apresentou diferença nas médias (DM) de: -1 17 (intervalo de confiança [IC] de 95%: - 1 87­0 46) nos escores da escala de dor (I2 = 68%) o que foi estatisticamente significativo a favor do uso do bloqueio TAP mas sem relevância clínica; dor pós-operatória tardia: DM 0001 (IC95%: - 043­044; I2 = 69%); necessidade de opioides: DM 0 36 (95%CI: - 0 94­168; I2 = 80%); e incidência de náuseas e vômitos com diferença de 95% CI = - 011 (- 0215­0006) a favor do TAP. CONCLUSãO: Com moderada força de evidência devido à alta heterogeneidade e ao desequilíbrio nas características basais entre os estudos os resultados indicam que o bloqueio do TAP não deve ser considerado como uma técnica analgésica clinicamente relevante para melhorar a dor pós-operatória em histerectomia laparoscópica ou robótica apesar da significância estatística nas pontuações da escala de dor pós-operatória inicial. NúMERO E REGISTRO DO ENSAIO CLíNICO:: PROSPERO ID - CRD42018103573.

Efficacy of Transversus Abdominis Plane Block in the Reduction of Pain and Opioid Requirement in Laparoscopic and Robot-assisted Hysterectomy: A Systematic Review and Meta-analysis / Eficácia do bloqueio transverso do plano abdominal na redução da dor e da necessidade de opioides em histerectomia laparoscópica e assistida por robô: Uma revisão sistemática e metanálise

Abstract Objective To summarize the available evidence of TAP Block in efficacy in laparoscopic or robotic hysterectomy. Data Sources We searched databases and gray literature for randomized controlled trials in which transversus abdominis plane (TAP) block was compared with placebo or with no treatment in patients who underwent laparoscopic or robot-assisted hysterectomy. Method of Study Selection Two researchers independently evaluated the eligibility of the selected articles. Tabulation, Integration, and Results Seven studies were selected, involving 518 patients. Early postoperative pain showed a difference in the mean mean difference (MD): - 1.17 (95% confidence interval [CI]: - 1.87-0.46) in pain scale scores (I2=68%), which was statistically significant in favor of using TAP block, but without clinical relevance; late postoperative pain: DM 0.001 (95%CI: - 0.43-0.44; I2=69%); opioid requirement: DM 0.36 (95%CI: - 0.94-1.68; I2=80%); and incidence of nausea and vomiting with a difference of 95%CI=- 0.11 (- 0.215-0.006) in favor of TAP. Conclusion With moderate strength of evidence, due to the high heterogeneity and imbalance in baseline characteristics among studies, the results indicate that TAP block should not be considered as a clinically relevant analgesic technique to improve postoperative pain in laparoscopic or robotic hysterectomy, despite statistical significance in early postoperative pain scale scores. Clinical Trial Number and Registry: PROSPERO ID - CRD42018103573.

Resumo Objetivo Resumir as evidências disponíveis sobre a eficácia do bloqueio TAP em histerectomia laparoscópica ou robótica. Fontes de Dados Pesquisamos bancos de dados e literatura cinza por ensaios clínicos randomizados nos quais o bloqueio do plano transverso do abdome (TAP na sigla em inglês) foi comparado com placebo ou com nenhum tratamento em pacientes que foram submetidos a histerectomia laparoscópica ou assistida por robô. Métodos de Seleção de Estudos Dois pesquisadores avaliaram independentemente a elegibilidade dos artigos selecionados. Tabulação, Integração e Resultados Sete estudos foram selecionados envolvendo 518 pacientes. A dor pós-operatória precoce apresentou diferença nasmédias (DM) de: -1 17 (intervalo de confiança [IC] de 95%: - 1 87-0 46) nos escores da escala de dor (I2=68%) o que foi estatisticamente significativo a favor do uso do bloqueio TAP mas sem relevância clínica; dor pós-operatória tardia: DM 0001 (IC95%: - 043-044; I2=69%); necessidade de opioides: DM0 36 (95%CI: - 0 94-168; I2=80%); e incidência de náuseas e vômitos com diferença de 95% CI=- 011 (- 0215-0006) a favor do TAP. Conclusão Com moderada força de evidência devido à alta heterogeneidade e ao desequilíbrio nas características basais entre os estudos os resultados indicam que o bloqueio do TAP não deve ser considerado como uma técnica analgésica clinicamente relevante para melhorar a dor pós-operatória em histerectomia laparoscópica ou robótica apesar da significância estatística nas pontuações da escala de dor pósoperatória inicial. Número e Registro do Ensaio Clínico: PROSPERO ID - CRD42018103573.

Alterations in Lysosome Homeostasis in Lipid-Related Disorders: Impact on Metabolic Tissues and Immune Cells.

Lipid-related disorders, which primarily affect metabolic tissues, including adipose tissue and the liver are associated with alterations in lysosome homeostasis. Obesity is one of the more prevalent diseases, which results in energy imbalance within metabolic tissues and lysosome dysfunction. Less frequent diseases include Niemann-Pick type C (NPC) and Gaucher diseases, both of which are known as Lysosomal Storage Diseases (LSDs), where lysosomal dysfunction within metabolic tissues remains to be fully characterized. Adipocytes and hepatocytes share common pathways involved in the lysosome-autophagic axis, which are regulated by the function of cathepsins and CD36, an immuno-metabolic receptor and display alterations in lipid diseases, and thereby impacting metabolic functions. In addition to intrinsic defects observed in metabolic tissues, cells of the immune system, such as B cells can infiltrate adipose and liver tissues, during metabolic imbalance favoring inflammation. Moreover, B cells rely on lysosomes to promote the processing and presentation of extracellular antigens and thus could also present lysosome dysfunction, consequently affecting such functions. On the other hand, growing evidence suggests that cells accumulating lipids display defective inter-organelle membrane contact sites (MCSs) established by lysosomes and other compartments, which contribute to metabolic dysfunctions at the cellular level. Overall, in this review we will discuss recent findings addressing common mechanisms that are involved in lysosome dysregulation in adipocytes and hepatocytes during obesity, NPC, and Gaucher diseases. We will discuss whether these mechanisms may modulate the function of B cells and how inter-organelle contacts, emerging as relevant cellular mechanisms in the control of lipid homeostasis, have an impact on these diseases.

Comparable Outcomes of Matched Sibling Donor and Matched Unrelated Donor Stem Cell Transplantation in Children With Acute Leukemia in Argentina.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an effective mode of consolidation therapy for children with high-risk acute leukemia. In high-income countries, match sibling donor (MSD) and match unrelated donor (MUD) HSCT have similar outcomes, but data are scarce in upper-middle-income countries. Our objective was to compare MSD and MUD HSCT outcomes for children with acute leukemia in Argentina. PATIENTS AND METHODS: This was a single-institution retrospective cohort study. We included children with acute leukemia who underwent HSCT with either MSD or MUD between 2014 and 2019. RESULTS: The study included 45 patients who received MSD (n=27) or MUD (n=18) for acute leukemia. Event-free survival was not significantly different between MSD (62.3±10.7%) versus MUD (54.2±15.0%; P=0.54) at 5 years. Similarly, there was no significant difference in 5-year overall survival between MSD (71.9±9.8%) versus MUD (65.1±13.5%; P=0.38). The cumulative incidence of treatment-related mortality (P=0.31), cumulative incidence of relapse (P=0.99), and proportion with acute-graft-versus-host disease (P=0.76) and chronic-graft-versus-host disease (P=0.68) were also not significantly different. CONCLUSIONS: In Argentina, we did not show significant differences in outcomes between MSD and MUD HSCT for children with high-risk leukemia. Future work should focus on strategies to reduce the relapse risk in children with high-risk leukemia in upper-middle-income countries.

Population genetics of wild and captive Trachemysvenusta (Gray, 1856) (Reptilia: Emydidae) in the Usumacinta river basin in Mexico.

The Mesoamerican slider Trachemysvenusta is endemic to Central America and Southern Mexico. Several human-mediated disturbances, including habitat degradation and illegal hunting for food, have impacted its populations along the Usumacinta river basin. The extent to which these disturbances have affected the genetic diversity and population structure of T. venusta inhabiting the basin remains unresolved. To this end, we analyzed eight microsatellite markers in five wild populations of T. venusta from the middle and lower reaches of the basin as well as one captive population. Our results show high levels of genetic diversity for all analyzed populations, low F ST values, high gene flow and no genetic structure, indicating an absence of genetic differentiation across sites and, thus, a single panmictic population for the basin. Evidence of a genetic bottleneck was observed in two of the wild populations (and the captive one), indicating some impact from disturbances, whether from poaching or habitat fragmentation, despite the seemingly high connectivity of most populations. Results are discussed in terms of the relative importance of genetic parameters for the conservation of T. venusta, particularly in light of the importance of demographic stochasticity in local conditions undergoing rapid changes.

Mercury in soils impacted by alluvial gold mining in the Peruvian Amazon.

Gold mining is the largest source of mercury (Hg) pollution worldwide. The discharge of mercury in the environment bears direct human health risks and is likely to increase cascading effects throughout local food chains. In the Peruvian Amazon the mining process consists of slashing and burning trees, followed by extraction of gold-bearing sediment, amalgamation with Hg and gold recovery, leading each year to the degradation of 6,000-10,000 ha and the release of 180 metric tons of Hg per year to the enviroment. The purpose of this study was to determine soil Hg levels in soils of abandoned alluvial gold mine spoils and undisturbed forest in the Madre de Dios region, the epicenter of alluvial gold mining in Peru. We selected gold mine spoils of the two most important technologies locally applied for gold extraction, i.e., Minimally Mechanized Mining (MMM) and Highly Mechanized Mining (HMM), in the native communities of Laberinto and Kotzimba, respectively. We collected 127 and 35 soil samples (0-20cm depth) from potentially contaminated sites and undisturbed forest, respectively. Physicochemical analysis and determination of Hg levels were determined for all soil samples. None of the samples had Hg concentrations above Peruvian, Canadian and British Environmental Quality Standards for Agricultural Soil (6.6mg/kg). Hg levels in MMM and HMM were not significantly different between the two areas. The main variables explaining variation of soil Hg concentrations were the vegetation cover, soil organic matter, soil pH and clay particle content, which explained up to 80% of data set variation. Surprisingly, highest Hg concentrations were found in untouched old-growth forest bordering the mine spoils, but there was also a trend of increasing Hg concentrations with the regenerating vegetation. Our findings suggest that Hg concentrations in old mine spoils are low and shouldn't stand in the way of efforts to restore soil conditions and develop sustainable land uses. However, it is urgent to end the use of Hg in mining operation to decrease human and environmental risks.

Structure-Activity Relationship and Biological Investigation of SR18292 (16), a Suppressor of Glucagon-Induced Glucose Production.

Despite a myriad of available pharmacotherapies for the treatment of type 2 diabetes (T2D), challenges still exist in achieving glycemic control. Several novel glucose-lowering strategies are currently under clinical investigation, highlighting the need for more robust treatments. Previously, we have shown that suppressing peroxisome proliferator-activated receptor gamma coactivator 1-alpha activity with a small molecule (SR18292, 16) can reduce glucose release from hepatocytes and ameliorate hyperglycemia in diabetic mouse models. Despite structural similarities in 16 to known ß-blockers, detailed structure-activity relationship studies described herein have led to the identification of analogues lacking ß-adrenergic activity that still maintain the ability to suppress glucagon-induced glucose release from hepatocytes and ameliorate hyperglycemia in diabetic mouse models. Hence, these compounds exert their biological effects in a mechanism that does not include adrenergic signaling. These probe molecules may lead to a new therapeutic approach to treat T2D either as a single agent or in combination therapy.

Interaction of Bephratelloides cubensis (Hymenoptera: Eurytomidae) with Annona macroprophyllata fruits in orchards of Chiapas, Mexico / Interacción de Bephratelloides cubensis (Hymenoptera: Eurytomidae) con frutos de Annona macroprophyllata en huertos de Chiapas, México

Introduction: Annona macroprophyllata Donn. Smith. (Annonaceae) (syn. Annona diversifolia Saff.) is a valued fruit tree species known as papausa. In Mexico and Central America, this fruit has become an important crop because of its tasty flavor and high pulp content. Its fruits are frequently damaged by the incidence of wasps of the genus Bephratelloides Girault (Hymenoptera: Eurytomidae), which develop inside the seeds. Objective: To report the interaction of Bephratelloides cubensis Ashmead during its life cycle in fruits of A. macroprophyllata. Methods: We periodically collected fruits in different states of growth recording a) oviposition, b) the moment of evident infection, c) the development of the wasps inside the seeds, and d) their emergence as adults. We also determined the proportion of damaged fruits and seeds. Results: The data indicate that wasps preferred to oviposit on fruits with a diameter of less than 8 cm, oviposition was more frequent between 11:00 am and 03:00 pm., and there was 26 % infestation of fruits, and 9 % of seeds. Conclusion: It is an obligatory interaction for the wasp, the highest proportion of attack on fruits was in the early stages of fruit development and control actions should focus on the protection of these early stages.

Introducción: Annona macroprophyllata Donn. Smith. (Annonaceae) es una especie de árbol frutal, conocida como papausa. En México y América Central, esta fruta se ha convertido en un cultivo importante y valorado debido a su delicioso sabor y la cremosa textura de su pulpa. Sus frutos son frecuentemente dañados por la incidencia de avispas del género Bephratelloides Girault (Hymenoptera: Eurytomidae), que se desarrollan dentro de las semillas. Objetivo: Describir la interacción de Bephratelloides cubensis Ashmead durante su ciclo de vida en frutos de A. macroprophyllata. Método: Recolectamos frutos en diferentes estados de crecimiento registrando a) la ovoposición, b) el momento de la infección evidente, c) el desarrollo de las avispas dentro de las semillas, y d) su emergencia como adultos. También determinamos la proporción de frutas y semillas dañadas. Resultados: Los datos indican que las avispas preferían ovipositar en frutas con un diámetro de menos de 8 cm, la oviposición era más frecuente entre las 11:00 a.m. y las 3:00 p.m., y que había un 26 % de la infestación en las frutas y un 9 % en semillas. Conclusión: Es una interacción obligada para la avispa y la mayor proporción de ataque a los frutos fue en las etapas tempranas de desarrollo de frutos y las acciones de control se deberían enfocar a la protección de estas etapas.

Caracterización de extractos de piel y hojas de Persea americana Mill. y analisis in vitro de sus potenciales propiedades anti-inflamatorias / Characterization of Persea americana Mill. peels and leaves extracts and analysis of its potential in vitro anti-inflammatory properties

Existe una tendencia mundial de incremento en prevalencia de enfermedades no transmisibles, que se caracterizan por un estado pro-inflamatorio crónico. Por lo tanto, es importante estudiar la relación entre alimentos y salud. La palta (Persea americana), sobresale en la industria por su valor nutricional. El procesamiento de la palta genera gran cantidad de subproductos, que contienen bioactivos con propiedades beneficiosas, como polifenoles. El objetivo del presente trabajo fue caracterizar cuatro extractos de palto (acuoso e hidroalcohólico; de hoja y de cáscara) y analizar sus posibles propiedades anti-inflamatorias in vitro. Fueron determinados polifenoles totales (con el método de Folin­Ciocalteau) y capacidad antioxidante (por FRAP y DPPH) de los extractos. Las propiedades anti-inflamatorias de los extractos fueron determinadas por la liberación de NO y de TNF-, y por la expresión génica de TNF-. Los resultados indican que los extractos hidroalcohólicos presentan más polifenoles (p<0,001) y capacidad antioxidante (p<0,001, por FRAP) que los acuosos. Mas aún, observamos que los extractos hidroalcohólicos de hojas presentaron mayores efectos anti-inflamatorios in vitro, especialmente el hidroalcohólico de hoja en liberación de NO (p<0,001, frente a tratamiento con LPS), acuosos e hidroalcohólicos en liberación de TNF- (p<0,05), y solo los hidroalcohólicos en la expresión de TNF- (p<0,01). En conclusión, los extractos hidroalcohólicos de palto, y especialmente el de hoja, presentan propiedades anti-inflamatorias in vitro que pueden ser consideradas para aplicaciones en mejoría de salud humana.

There is a worldwide trend of increasing prevalence of non-communicable diseases characterized by a chronic inflammatory state. Therefore, it is important to study the relationship between food and health. Avocado (Persea americana) stands out in food industry for its nutritional value. Industrials process of avocado generates a large number of by-products, which contain phytochemical compounds with antioxidant properties, such as polyphenols. The objective of the present research was to characterize four aqueous and hydroalcoholic extracts from avocado leaves and peels and analyze it possible anti-inflammatory properties in vitro. Total polyphenol content (with the Folin-Ciocalteau method) and antioxidant capacity (by FRAP and DPPH) were determined. Extracts inflammatory features were measured by NO and TNF- release, and by TNF- gene expression. Our results indicated that hydroalcoholic extracts present higher total polyphenol content (p<0.001) and antioxidant capacity (p<0.001, by FRAP) than the aqueous ones. Furthermore, we report that hydroalcoholic leaves extract presented greater in vitro anti-inflammatory effect, especially the leave hydroalcoholic regarding NO release (p<0.001, against LPS treatment), aqueous and hydroalcoholics regarding TNF- release (p<0.05), and only the hydroalcoholic in the TNF- gene expression (p<0.01). In conclusion, the avocado hydroalcoholic extracts, and especially from leaves, present in vitro anti-inflammatory features that might be considered for human health improvement applications.

Obesidad parental y modificaciones epigenéticas en la descendencia / Parental obesity and epigenetic modifications in offspring

RESUMEN La obesidad es una enfermedad multifactorial definida como acumulación patológica de grasa. Su prevalencia ha aumentado enormemente en el mundo. Chile presenta una de las mayores prevalencias de obesidad de la OCDE. Su casuística simplificada comprende una diferencia sostenida entre gasto e ingesta de energía, manteniendo un delta positivo traducido en mayor acumulación de grasa. No obstante, la etiología completa de esta enfermedad comprende también factores psicológicos, genéticos, ambientales, etc. El ambiente juega un papel clave en la predisposición al consumo de alimentos, a la realización de ejercicio físico, incluso afectando la susceptibilidad genómica, exacerbando o disminuyendo la carga genética. Esta modificación de susceptibilidad genética por el ambiente se conoce como epigenética, que se refiere a una serie de modificaciones por "sobre" la genética que son altamente modificables por factores ambientales. Se ha descrito que algunas de estas modificaciones pueden heredarse de una generación a otra, lo que otorga otro nivel de complejidad al estudio de nuevas terapias complementarias para frenar la tendencia al sobrepeso. En la presente revisión se describe cuales son las modificaciones epigenéticas más frecuentes encontradas, su relación con obesidad y dieta, y finalmente como se relaciona con la transmisión transgeneracional de esta patología.

ABSTRACT Obesity is a multifactorial disease defined by a pathological accumulation of body fat. Its prevalence has increased greatly across the world. Chile has one of the highest prevalence of obesity among OCDE countries. It is caused by a sustained difference between energy expenditure and intake, keeping a positive delta, which drives fat accumulation. However, its etiology is comprised several factors: psychological, genetics, environmental, etc. The environment plays a key role in the predisposition towards food consumption, the adoption of exercise, and genetic susceptibility, increasing or decreasing the genetic load towards obesity. This modification of susceptibility is known as epigenetics, which refers to modifications "over" genetics, which are highly modifiable by environmental factors. Some of these modifications can be inherited from one generation to another, granting a higher complexity level regarding designing novel complementary therapies against obesity. Thus, the present review described which epigenetic modifications are related to obesity and different dietary patterns, and finally how epigenetic modifications can be related to transgenerational transmission of obesity.