Gold(I) complexes based on nonsteroidal anti-inflammatory derivatives as multi-target drugs against colon cancer

Targeting inflammation and the molecules involved in the inflammatory process could be an effective cancer prevention and therapy strategy. Therefore, the use of anti-inflammatory strategies, such as NSAIDs and metal-based drugs, has become a promising approach for preventing and treating cancer by targeting multiple pathways involved in tumor progression. The present work describes new phosphane gold(I) complexes derived from nonsteroidal anti-inflammatory drugs as multitarget drugs against colon cancer. The antiproliferative effect of the most active complexes, [Au(L3)(JohnPhos)] (3b), [Au(L4)(CyJohnPhos)] (4a) and [Au(L4)(JohnPhos)] (4b) against colon cancer cells (Caco2-/TC7) seems to be mediated by the inhibition of the enzyme cyclooxygenase-1/2, modulation of reactive oxygen species levels by targeting thioredoxin reductase (TrxR) activity, and induction of apoptosis in cancer cells. Additionally, the three complexes exhibit high selectivity index values toward noncancerous cells. The research highlights the importance of maintaining cellular redox balance and the role of TrxR in cancer cell survival

Light signals generated by vegetation shade facilitate acclimation to low light in shade-avoider plants

[EN] When growing in search for light, plants can experience continuous or occasional shading by other plants. Plant proximity causes a decrease in the ratio of R to far-red light (low R:FR) due to the preferential absorbance of R light and reflection of FR light by photosynthetic tissues of neighboring plants. This signal is often perceived before actual shading causes a reduction in photo-synthetically active radiation (low PAR). Here, we investigated how several Brassicaceae species from different habitats respond to low R:FR and low PAR in terms of elongation, photosynthesis, and photoacclimation. Shade-tolerant plants such as hairy bittercress (Cardamine hirsuta) displayed a good adaptation to low PAR but a poor or null response to low R:FR exposure. In contrast, shade-avoider species, such as Arabidopsis (Arabidopsis thaliana), showed a weak photosynthetic performance under low PAR but they strongly elongated when exposed to low R:FR. These responses could be genetically uncoupled. Most interestingly, exposure to low R:FR of shade-avoider (but not shade-tolerant) plants improved their photoacclimation to low PAR by triggering changes in photosynthesis-related gene expression, pigment accumulation, and chloroplast ultrastructure. These results indicate that low R:FR signaling unleashes molecular, metabolic, and developmental responses that allow shade-avoider plants (including most crops) to adjust their photosynthetic capacity in anticipation of eventual shading by nearby plants.L.M. received a predoctoral fellowships from La Caixa Foundation (INPhINIT fellowship LCF/BQ/IN18/11660004). W.Q. is a recipient of a predoctoral Chinese Scholarship Council (CSC) fellowship. A.I.-S. is supported by a predoctoral fellowship from MICINN (PRE2018-083610). I.F.-S. has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement no. 753301. Our research is supported by grants from MICINN-FEDER (BIO2017-85316-R, and BIO2017-84041-P) and AGAUR (2017-SGR1211, 2017-SGR710 and Xarba) to J.F.M.-G. and M.R.-C. We also acknowledge the support of the MINECO for the "Centro de Excelencia Severo Ochoa 2016-2019" award SEV-2015-0533 and by the CERCA Programme/Generalitat de Catalunya.Morelli, L.; Paulisic, S.; Qin, W.; Iglesias-Sanchez; Roig-Villanova, I.; Florez-Sarasa, I.; Rodriguez Concepción, M.... (2021). Light signals generated by vegetation shade facilitate acclimation to low light in shade-avoider plants. Plant Physiology (Online). 186(4):2137-2151. https://doi.org/10.1093/plphys/kiab20621372151186

In vivo study of the bioavailability and metabolic profile of (poly)phenols after sous-vide artichoke consumption

Artichokes are a rich source of (poly)phenols, mainly caffeoylquinic acids, but little is known about their bioavailability from this source. This study investigated the absorption, metabolism and excretion of (poly)phenols after sous-vide artichoke consumption (5776 µmol of (poly)phenols) by healthy volunteers. Seventy-six (poly)phenol metabolites were identified by UHPLC-MS/MS using authentic standards, including acyl-quinic acids plus C6–C3, C6–C1, C6–C2, C6–C1–N, C6–C0 metabolites, and their phase-II conjugates. The major metabolites were 3ʹ-methoxy-4ʹ-hydroxycinnamic acid, 3ʹ-methoxycinnamic acid-4ʹ-sulfate, and 4ʹ-hydroxycinnamic acid-3ʹ-sulfate, which appeared early in plasma (Tmax 6 h). The 24 h urinary recovery averaged 8.9% (molar basis) of the (poly)phenols consumed. Hepatic beta-oxidation of 3ʹ,4ʹ-dihydroxycinnamic acid and methylated conjugates occurred, but was limited (<0.04%). 3ʹ-Methylation exceeded 4ʹ-methylation and interindividual variability was high, especially for gut microbial metabolites (up to 168-fold)

Effectiveness of Exercise on Fatigue and Sleep Quality in Fibromyalgia: A Systematic Review and Meta-analysis of Randomized Trials

Objectives: To determine the effects of exercise on fatigue and sleep quality in fibromyalgia (primary aim) and to identify which type of exercise is the most effective in achieving these outcomes (secondary aim). Data Sources: PubMed and Web of Science were searched from inception until October 18, 2018. Study Selection: Eligible studies contained information on population (fibromyalgia), intervention (exercise), and outcomes (fatigue or sleep). Randomized controlled trials (RCT) testing the effectiveness of exercise compared with usual care and randomized trials (RT) comparing the effectiveness of 2 different exercise interventions were included for the primary and secondary aims of the present review, respectively. Two independent researchers performed the search, screening, and final eligibility of the articles. Of 696 studies identified, 17 RCTs (nZ1003) were included for fatigue and 12 RCTs (nZ731) for sleep. Furthermore, 21 RTs compared the effectiveness of different exercise interventions (nZ1254). Data Extraction: Two independent researchers extracted the key information from each eligible study. Data Synthesis: Separate random-effect meta-analyses were performed to examine the effects from RCTs and from RTs (primary and secondary aims). Standardized mean differences (SMD) effect sizes were calculated using Hedges’ adjusted g. Effect sizes of 0.2, 0.4, and 0.8 were considered small, moderate, and large. Compared with usual care, exercise had moderate effects on fatigue and a small effect on sleep quality (SMD, e0.47; 95% confidence interval [CI], e0.67 to e0.27; P<.001 and SMD, e0.17; 95% CI, e0.32 to e0.01; PZ.04). RTs in which fatigue was the primary outcome were the most beneficial for lowering fatigue. Additionally, meditative exercise programs were the most effective for improving sleep quality. Conclusions: Exercise is moderately effective for lowering fatigue and has small effects on enhancing sleep quality in fibromyalgia. Meditative exercise programs may be considered for improving sleep quality in fibromyalgi

Evolutionary diversification and characterization of the eubacterial gene family encoding DXR type II, an alternative isoprenoid biosynthetic enzyme

[EN] Background: Isoprenoids constitute a vast family of natural compounds performing diverse and essential functions in all domains of life. In most eubacteria, isoprenoids are synthesized through the methylerythritol 4-phosphate (MEP) pathway. The production of MEP is usually catalyzed by deoxyxylulose 5-phosphate reductoisomerase (DXR-I) but a few organisms use an alternative DXR-like enzyme (DXR-II). Results: Searches through 1498 bacterial complete proteomes detected 130 sequences with similarity to DXR-II. Phylogenetic analysis identified three well-resolved clades: the DXR-II family (clustering 53 sequences including eleven experimentally verified as functional enzymes able to produce MEP), and two previously uncharacterized NAD(P)-dependent oxidoreductase families (designated DLO1 and DLO2 for DXR-II-like oxidoreductases 1 and 2). Our analyses identified amino acid changes critical for the acquisition of DXR-II biochemical function through type-I functional divergence, two of them mapping onto key residues for DXR-II activity. DXR-II showed a markedly discontinuous distribution, which was verified at several levels: taxonomic (being predominantly found in Alphaproteobacteria and Firmicutes), metabolic (being mostly found in bacteria with complete functional MEP pathways with or without DXR-I), and phenotypic (as no biological/phenotypic property was found to be preferentially distributed among DXR-II-containing strains, apart from pathogenicity in animals). By performing a thorough comparative sequence analysis of GC content, 3: 1 dinucleotide frequencies, codon usage and codon adaptation indexes (CAI) between DXR-II sequences and their corresponding genomes, we examined the role of horizontal gene transfer (HGT), as opposed to an scenario of massive gene loss, in the evolutionary origin and diversification of the DXR-II subfamily in bacteria. Conclusions: Our analyses support a single origin of the DXR-II family through functional divergence, in which constitutes an exceptional model of acquisition and maintenance of redundant gene functions between nonhomologous genes as a result of convergent evolution. Subsequently, although old episodic events of HGT could not be excluded, the results supported a prevalent role of gene loss in explaining the distribution of DXR-II in specific pathogenic eubacteria. Our results highlight the importance of the functional characterization of evolutionary shortcuts in isoprenoid biosynthesis for screening specific antibacterial drugs and for regulating the production of isoprenoids of human interest.We thank all our laboratory members for stimulating discussions and suggestions. We thank Derek Taylor and Mario A Fares for critical reading of the manuscript and helpful comments. Financial support for this research was provided by the Spanish Ministerio de Ciencia e Innovacion (grants BIO2011-23680 to MRC and BFU2011-25658 to FJS) and Generalitat de Catalunya (2009SGR-26 and XRB) to MRC.Carretero Paulet, L.; Lipska, A.; Perez-Gil, J.; Sangari, J.; Albert, V.; Rodriguez-Concepción, M. (2013). Evolutionary diversification and characterization of the eubacterial gene family encoding DXR type II, an alternative isoprenoid biosynthetic enzyme. BMC Evolutionary Biology. 13(180):1-18. https://doi.org/10.1186/1471-2148-13-180S1181318

Tissue damage during acute Trypanosoma cruzi infection is associated with reduced reparative regulatory T cell response and can be attenuated by early interleukin-33 administration

Fil: Boccardo, Santiago. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica, Argentina.Fil: Boccardo, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Argentina.Fil: Rodriguez, Constanza. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica, Argentina.Fil: Rodriguez, Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Argentina.Fil: Araujo Furlan, Cintia L. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica, Argentina.Fil: Araujo Furlan, Cintia L. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Argentina.Fil: Abrate, Carolina P. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica, Argentina.Fil: Abrate, Carolina P. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Argentina.Fil: Almada, Laura. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica, Argentina.Fil: Almada, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Argentina.Fil: Giménez, Camila M. S. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica, Argentina.Fil: Giménez, Camila M. S. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Argentina.Fil: Saldivia Concepción, Manuel A. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica, Argentina.Fil: Saldivia Concepción, Manuel A. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Argentina.Fil: Skewes-Cox Peter. BioMedical Research, Novartis, Emeryville, California, United States.Fil: Rao, Srinivasa P. S. BioMedical Research, Novartis, Emeryville, California, United States.Fil: Montes, Carolina L. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica, Argentina.Fil: Montes, Carolina L. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Argentina.Fil: Gruppi, Adriana. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica, Argentina.Fil: Gruppi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Argentina.Fil: Acosta Rodríguez, Eva V. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica, Argentina.Fil: Acosta Rodríguez, Eva V. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Argentina.This article is a preprint and has not been certified by peer review.Tissue-repair regulatory T cells (trTregs) constitute a specialized regulatory subset renowned for orchestrating tissue homeostasis and repair. While extensively investigated in sterile injury models, their role in infection-induced tissue damage and the regulation of protective antimicrobial immunity remains largely unexplored. This investigation examines trTregs dynamics during acute Trypanosoma cruzi infection, a unique scenario combining extensive tissue damage with robust antiparasitic CD8+ immunity. Contrary to conventional models of sterile injury, our findings reveal a pronounced reduction of trTregs in secondary lymphoid organs and tissues during acute T. cruzi infection. This unexpected decline correlates with systemic as well local tissue damage, as evidenced by histological alterations and downregulation of repair-associated genes in skeletal muscle. Remarkably, a parallel decrease in systemic levels of IL-33, a crucial factor for trTregs survival and expansion, was detected. We found that early treatment with systemic recombinant IL-33 during infection induces a notable surge in trTregs, accompanied by an expansion of type 2 innate lymphoid cells and parasite-specific CD8+ cells. This intervention results in a mitigated tissue damage profile and reduced parasite burden in infected mice. These findings shed light on trTregs biology during infection-induced injury and demonstrate the feasibility of enhancing a specialized Tregs response without impairing the magnitude of effector immune mechanisms, ultimately benefiting the host. Furthermore, this study settles groundwork of relevance for potential therapeutic strategies in Chagas’ disease and other infections.info:eu-repo/semantics/publishedVersionFil: Boccardo, Santiago. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica, Argentina.Fil: Boccardo, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Argentina.Fil: Rodriguez, Constanza. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica, Argentina.Fil: Rodriguez, Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Argentina.Fil: Araujo Furlan, Cintia L. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica, Argentina.Fil: Araujo Furlan, Cintia L. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Argentina.Fil: Abrate, Carolina P. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica, Argentina.Fil: Abrate, Carolina P. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Argentina.Fil: Almada, Laura. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica, Argentina.Fil: Almada, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Argentina.Fil: Giménez, Camila M. S. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica, Argentina.Fil: Giménez, Camila M. S. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Argentina.Fil: Saldivia Concepción, Manuel A. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica, Argentina.Fil: Saldivia Concepción, Manuel A. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Argentina.Fil: Skewes-Cox Peter. BioMedical Research, Novartis, Emeryville, California, United States.Fil: Rao, Srinivasa P. S. BioMedical Research, Novartis, Emeryville, California, United States.Fil: Montes, Carolina L. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica, Argentina.Fil: Montes, Carolina L. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Argentina.Fil: Gruppi, Adriana. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica, Argentina.Fil: Gruppi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Argentina.Fil: Acosta Rodríguez, Eva V. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica, Argentina.Fil: Acosta Rodríguez, Eva V. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Argentina.This article is a preprint and has not been certified by peer review

Influence of the LILRA3 Deletion on Multiple Sclerosis Risk : Original Data and Meta-Analysis

Altres ajuts: Junta de Andalucía (JA)- Fondos Europeos de Desarrollo Regional (FEDER) (grant number CTS2704 to FM).Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease of the central nervous system. Genome-wide association studies (GWAS) have identified over hundred polymorphisms with modest individual effects in MS susceptibility and they have confirmed the main individual effect of the Major Histocompatibility Complex. Additional risk loci with immunologically relevant genes were found significantly overrepresented. Nonetheless, it is accepted that most of the genetic architecture underlying susceptibility to the disease remains to be defined. Candidate association studies of the leukocyte immunoglobulin-like receptor LILRA3 gene in MS have been repeatedly reported with inconsistent results. In an attempt to shed some light on these controversial findings, a combined analysis was performed including the previously published datasets and three newly genotyped cohorts. Both wild-type and deleted LILRA3 alleles were discriminated in a single-tube PCR amplification and the resulting products were visualized by their different electrophoretic mobilities. Overall, this meta-analysis involved 3200 MS patients and 3069 matched healthy controls and it did not evidence significant association of the LILRA3 deletion [carriers of LILRA3 deletion: p = 0.25, OR (95% CI) = 1.07 (0.95-1.19)], even after stratification by gender and the HLA-DRB1*15 : 01 risk allele

Imported cysticercosis in Spain: A retrospective case series from the +REDIVI Collaborative Network

Neurocysticercosis (NCC) is the most common parasitic neurological disease worldwide and a major cause of epilepsy. Spain is the country reporting the highest number of NCC imported cases in Europe. Retrospective case series of NCC patients registered in the +REDIVI Network from October 1, 2009 to July 2018. A specific questionnaire, including clinical and diagnostic characteristics, was created and sent to the collaborator centers. 46 cases were included in the analysis. 55% were male, mean age of 40 years. 95.6% were migrants. The median duration since migration from an endemic area was 10 years. Predominant nationalities were Ecuadorians (50%) and Bolivians (30.4%). Frequent locations were parenchymal (87%), subarachnoid (26.1%) and intraventricular cysts (10.9%). Serological analysis was performed in 91.3%, being 54.8% positive. Most prevalent clinical manifestations were persistent headache (60.9%), epilepsy (43.5%) and visual changes (13%). Patients were mainly treated with albendazole (76.1%), corticosteroids (67.4%), and anticonvulsionants (52.2%). 82.5% had a favorable clinical outcome. Most NCC cases were long-standing migrants. Few clinical differences were observed depending on the cysticerci location. The treatment was often not according to current recommendations, and no uniform criteria were followed when it came to the therapeutic regimen. NCC case management in Spain (including clinician awareness and laboratory capacity improvements) needs to be strengthened.We would thanks María Jesús Perteguer from the National Center of Microbiology for the information and update on NCC lab techniques currently performed in Spain. The corresponding author’s affiliation centre belongs to the ISCIII-Sub. Gral. Redes- Network Biomedical Research on Tropical Diseases (RICET in Spanish) grant RD16CIII/0003/0001, RD16/0027/0020, RD16CIII/0003/0001 and the European Regional Development Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S

Burden of multimorbidity, socioeconomic status and use of health services across stages of life in urban areas: a cross-sectional study

BACKGROUND: The burden of chronic conditions and multimorbidity is a growing health problem in developed countries. The study aimed to determine the estimated prevalence and patterns of multimorbidity in urban areas of Catalonia, stratified by sex and adult age groups, and to assess whether socioeconomic status and use of primary health care services were associated with multimorbidity. METHODS: A cross-sectional study was conducted in Catalonia. Participants were adults (19+ years) living in urban areas, assigned to 251 primary care teams. Main outcome: multimorbidity (≥2 chronic conditions). Other variables: sex (male/female), age (19–24; 25–44; 45–64; 65–79; 80+ years), socioeconomic status (quintiles), number of health care visits during the study. RESULTS: We included 1,356,761 patients; mean age, 47.4 years (SD: 17.8), 51.0% women. Multimorbidity was present in 47.6% (95% CI 47.5-47.7) of the sample, increasing with age in both sexes but significantly higher in women (53.3%) than in men (41.7%). Prevalence of multimorbidity in each quintile of the deprivation index was higher in women than in men (except oldest group). In women, multimorbidity prevalence increased with quintile of the deprivation index. Overall, the median (interquartile range) number of primary care visits was 8 (4–14) in multimorbidity vs 1 (0–4) in non-multimorbidity patients. The most prevalent multimorbidity pattern beyond 45 years of age was uncomplicated hypertension and lipid disorder. Compared with the least deprived group, women in other quintiles of the deprivation index were more likely to have multimorbidity than men until 65 years of age. The odds of multimorbidity increased with number of visits in all strata. CONCLUSIONS: When all chronic conditions were included in the analysis, almost 50% of the adult urban population had multimorbidity. The prevalence of multimorbidity differed by sex, age group and socioeconomic status. Multimorbidity patterns varied by life-stage and sex; however, circulatory-endocrine-metabolic patterns were the most prevalent multimorbidity pattern after 45 years of age. Women younger than 80 years had greater prevalence of multimorbidity than men, and women’s multimorbidity prevalence increased as socioeconomic status declined in all age groups. Identifying multimorbidity patterns associated with specific age-related life-stages allows health systems to prioritize and to adapt clinical management efforts by age group