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Caracterización molecular del redirigimiento metabólico inducido por la vitamina C en tumores gastrointestinales con mutación en KRAS: mecanismo para mejorar la respuesta terapéutica
No full textTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 20-06-2024Esta tesis tiene embargado el acceso al texto completo hasta el 20-12-2025Gastrointestinal cancers, which include colorectal (CCR) and pancreatic (PDAC) cancer encompass a diverse group of tumors, leading cancer-related deaths globally. Colorectal cancer (CCR) is Spain's most prevalent diagnosed cancer, while Pancreatic Ductal Adenocarcinoma (PDAC) stands out for its aggressiveness with a mere 8% 5-year survival rate. KRAS mutations, found in 30-50% of CCR and nearly 100% of PDAC cases, contribute to therapy resistance.
Since 2011, metabolic rewiring in tumor cells has been recognized as a hallmark of cancer, also linked to therapy resistance. KRAS mutations, along with Hypoxia Inducible Factor 1 alpha (Hif1α) stabilization, activate this aberrant metabolism.
This study reveals that pharmacological doses of ascorbic acid induce hydroxylation and degradation of Hif1α, leading to the downregulation Glucose Transporter 1 (GLUT1) and Lactate Dehydrogenase 1A (LDHA). LDHA downregulation reduces lactate production, impacting extracellular acidification in both, KRAS mutant CCR and PDAC either in cells and in Patient Derived Xenograft (PDX) tumors. Ascorbic acid also downregulates Pyruvate Dehydrogenase kinase 1 (PDK1) expression, enhancing pyruvate dehydrogenase (PDH) activity and enabling glucose oxidation through the Tricarboxylic Acid (TCA) cycle. Surprisingly, glucose oxidation in the (TCA) cycle decreases with ascorbate treatment as augmented Reactive Oxygen Species (ROS) generation inhibits citrate synthase (CS) and reduces glucose-derived citrate levels. Moreover, vitamin C disrupts citrate metabolism towards lipogenesis by downregulating ATP citrate lyase (ACLY) and Fatty Acid Synthase (FASN) through AKT/SREBP1 axis. Despite these changes, compensatory mechanisms such as enhanced glutamine-derived oxidative phosphorylation may be considered
Notably, the metabolic change induced by vitamin C synergizes with gemcitabine in a PDAC PDX model as well as remarkably reduces tumor growth in a KRAS mutant CCR model. This highlights the potential of vitamin C as a metabolic modulator in KRAS mutant gastrointestinal tumors, suggesting relevance for future medical approachesLos cánceres gastrointestinales, incluyendo el colorrectal (CCR) y el adenocarcinoma ductal pancreático (PDAC), representan un grupo diverso de tumores con altas tasas de mortalidad a nivel mundial. El CCR es el más prevalente en España, mientras que el PDAC destaca por su agresividad, con una baja tasa de supervivencia del 8% a 5 años. Las mutaciones en KRAS, presentes en el 30-50% de los casos de CCR y casi el 100% de los de PDAC, contribuyen a la resistencia a las terapias.
Desde 2011, se reconoce la glicólisis aeróbica como un rasgo distintivo del cáncer vinculado a la resistencia terapéutica, activada por mutaciones de KRAS y la estabilización de Factor Inducible de Hipoxia 1 alpha (Hif1α)
Este estudio revela que altas dosis de ácido ascórbico inducen la degradación de Hif1α, afectando la desregulación de Transportador de Glucosa 1 (GLUT1) y Lactato deshidrogenasa A (LDHA). Esto reduce la producción de lactato, afectando la acidificación extracelular en células y tumores de xenoinjerto derivado de pacientes (PDX) de CCR y PDAC. Además, el ácido ascórbico afecta la expresión de piruvato deshidrogenasa quinasa 1 (PDK1), aumentando la actividad de la piruvato deshidrogenasa (PDH) y permitiendo la oxidación de glucosa a través del ciclo del ácido tricarboxílico (TCA). Sorprendentemente, la oxidación de la glucosa por TCA disminuye con el tratamiento, ya que el aumento de especies reactivas de oxígeno (ROS) inhibe la citrato sintasa (CS). La vitamina C también altera el metabolismo del citrato hacia la lipogénesis mediante la reducción de la ATP citrato liasa (ACLY) y la sintasa de ácidos grasos (FASN) a través del eje AKT/SREBP1. A pesar de estos cambios, se deben considerar mecanismos compensatorios como el aumento de la fosforilación oxidativa derivada de la glutamina.
Cabe destacar que el cambio metabólico inducido por la vitamina C sinergiza con la actividad antitumoral de la gemcitabina (Gemzar®) en un modelo animal de tumor xenoinjertado de paciente (PDX) de PDAC, así como reduce notablemente el crecimiento tumoral en un modelo de CCR mutante KRAS. Esto pone de relieve el potencial de la vitamina C como modulador metabólico en tumores gastrointestinales mutantes de KRAS, lo que sugiere su relevancia para futuros enfoques médico
The role of floods in urban environments
No full textFloods are the natural hazard that affects the largest population in the World. In addition, the demographic evolution moves from a population majority located in rural areas to an urbanization and change towards the city. Many of the main European cities are located in fluvial plains of more or less mighty rivers (Paris, Barcelona, Vienna, Budapest, etc.), which is why floods are evolving towards a more punctual affectation and not necessarily related to the river discharge, but by the pairing between the flow that is generated after torrential rainfall and the sealing of the soil creating greater runoff. This means that the potential risk for loss of life is much higher than it was just a few decades ago. In this chapter we analyze the evolution of urban flooding, and how the effects of large river floods have changed and which mitigation measures have been taking place, together with the demographic increase that has occurred in these populations in recent centuriesThis research has received funding, in the case of CSG from the European Union-Next Generation EU, the Spanish Ministry of Universities under the Horizon 2020 research and innovation program through Margarita Salas fellowship (ref. MARSALAS21-22). CSG belongs to the FluVAlps Research Group (PID2020-113664RB-I00) supported by the Spanish Ministry of Science and Innovatio
Are phlebotomine sand flies (Diptera: Psychodidae) really attracted to UV-light sources?
No full textThis manuscript version is made available under the CC-BY-NC-ND 4.0 licence http://creativecommons.org/licenses/by-nc-nd/4.0/Phlebotomine sand flies are the sole confirmed vector of leishmaniosis, a group of endemic and re-emerging diseases in southern European countries such as Spain. Light traps are the major surveillance method currently being employed. Nevertheless, color light attraction by sand flies remains mostly unknown. Following prior research, the effect of UV-LED light sources, and its synergic effect with different color lights has been evaluated employing a modified Flebocollect (FC) light trap model. Results suggest that female Phlebotomus perniciosus sand flies are more attracted to a FC trap lured with the combination of blue and UV LED light sources than commercial CDC (Center for Disease Control and prevention) traps (Bonferroni post-hoc test; p < 0.08; blue/UV mean = 0.50; CDC mean = 0.13), while the combination of red and UV modified-traps excel in capturing Sergentomyia minuta sand flies (Bonferroni post-hoc test; p < 0.04; blue/UV mean = 1.19; CDC mean = 0.66). However, based on our prior studies, incorporating UV light sources into sand fly traps does not seem to enhance their attractiveness, as it has not resulted in higher capture rates. These findings contribute to understanding how sand flies’ vision and light color detection is. Further research is recommended to standardize trap construction procedures and explore variations in different endemic regions according to different sand fly specie
Argentina
No full textThis chapter examines the integration of international law within the Argentine legal framework, highlighting its constitutional acceptance since the 19th century and the substantial deepening occurred with democratization after 1983 and the constitutional reform of 1994. Through both doctrinal and empirical analysis of treaty practices and judicial applications, it illustrates Argentina’s respect for and application of international norms, especially in international human rights law, countering traditional dualist and monist theories. The study contributes to understanding domestic implementation of international law and the dynamics of such law in Argentina’s legal system, signaling some features of a distinctive Argentine foreign relations la
Universally Adaptable Multiscale Molecular Dynamics (UAMMD). A native-GPU software ecosystem for complex fluids, soft matter, and beyond
Get PDFWe introduce UAMMD (Universally Adaptable Multiscale Molecular Dynamics), a novel software infrastructure tailored for mesoscale complex fluid simulations on GPUs. The UAMMD library encompasses a comprehensive range of computational schemes optimized for the GPU, spanning from molecular dynamics to immersed boundary fluctuating-hydrodynamics. Developed in CUDA/C++14, this header-only open-source software serves both as a simulation engine and as a library with a modular architecture, offering a vast array of independent modules, categorized as interactors (neighbor search, bonded, non-bonded and electrostatic interactions, etc.) and integrators (molecular dynamics, dissipative particle dynamics, smooth particle hydrodynamics, Brownian hydrodynamics and a rather complete array of Immersed Boundary -IB- schemes). UAMMD excels in schemes that couple particle-based elastic structures with continuum fields in different regions of the mesoscale. To that end, thermal fluctuations can be added in physically consistent ways, and fast modes can be eliminated to adapt UAMMD to different regimes (compressible or incompressible flow, inertial or Stokesian dynamics, etc.). Thus, UAMMD is extremely useful for coarse-grained simulations of nanoparticles, and soft and biological matter (from proteins to viruses and micro-swimmers). Importantly, all UAMMD developments are hand-to-hand validated against experimental techniques, and it has proven to quantitatively reproduce experimental signals from quartz-crystal microbalance, atomic force microscopy, magnetic sensors, optic-matter interaction and ultrasound. Program summary: Program Title: UAMMD CPC Library link to program files: https://doi.org/10.17632/srrt2y5s4m.1 Developer's repository link: https://github.com/RaulPPelaez/UAMMD/ Licensing provisions: GPLv3 Programming language: C++/CUDA Nature of problem: The key problem addressed in computational physics is simulating the behavior of matter at various scales, encompassing both discrete (particle-based) and continuum (field-based) approaches. The challenge lies in accurately and efficiently modeling interactions at different spatio-temporal scales, ranging from atomic (microscopic) to fluid dynamics (macroscopic). This complexity is further amplified in mesoscale regions, where different physics domains intersect, necessitating advanced computational techniques to capture the nuanced dynamics of systems such as colloids, polymers, and biological structures. Solution method: The present solution consists in the creation of UAMMD (Universally Adaptable Multiscale Molecular Dynamics), a CUDA/C++14 library designed for GPU-accelerated complex fluid simulations. UAMMD offers a flexible platform that integrates discrete particle dynamics with continuum fluid dynamics. It supports a variety of computational schemes, each tailored for specific spatio-temporal regimes. The library's modular architecture allows for the seamless introduction of new algorithms and easy integration into existing codebases. Additional comments including restrictions and unusual features: UAMMD's design emphasizes modularity and GPU-native architecture, optimizing computational efficiency and flexibility. However, its focus on GPU acceleration and low level nature means it requires compatible hardware and familiarity with CUDA programming. While UAMMD is versatile in handling various physical regimes, it currently lacks certain standard force field potentials and multi-GPU support. Nonetheless, its ongoing development and open-source nature promise continual enhancementsAcknowledgment is made to the Donors of the American Chemical Society Petroleum Research Fund (PRF# 54312-ND9) for support of this research. Also, to Spanish MINECO Projects FIS2013-47350-C05-1-R and FIS2017-86007-C3-1-P. We also acknowledge funding from \u201CRetos\u201D Grants PID2020-117080RB-C51 and Prueba de Concepto Project PDC2021-121441-C21 both funded by the Ministerio de Ciencia, Innovaci\u00F3n y Universidades (MICIU) and Agencia Estatal de Investigaci\u00F3n (AEI) of Spain and through the \u201CMar\u00EDa de Maeztu\u201D Programme for Units of Excellence in R&D (CEX2023-001316-M)
Exploring the conformational landscape through rotational spectroscopy and computational modelling: The tunneling dynamics in 2,6-diethylphenol
Get PDFPhenol and some of its derivatives exhibit interesting tunneling motions consisting of two groups of transitions separated by a few hundred MHz. Recently, one of its derivatives, 2,6-di-tert-butylphenol, has shown additional hyperfine tunneling components, the origin of which remains unclear. In this work, another member of the family, 2,6-diethylphenol, has been investigated through its rotational spectrum. The jet-cooled broadband chirped-pulse Fourier transform microwave spectra in the 2–8 GHz frequency region revealed the presence of two conformers. The comparison with the equilibrium structure obtained by computational calculations at the B3LYP-D3(BJ)/Def2-TZVP level validates the structural determination and the orientation of the lateral ethyl groups. Additional observation of all the singly-substituted 13C isotopologues for the most stable ones allowed the determination of the substitution structure by means of the Kraitchman equations. Both conformers exhibited tunneling that was reproduced using an advanced 1D model, which provides an estimate of the barrier height for both conformersWe acknowledge funding from the Spanish Ministerio de Ciencia e Innovaci\u00F3n and the European Regional Development Fund (MICINN\u2013ERDF, Grant No. PID2021-125015NBI00) and the Junta de Castilla y Le\u00F3n (Grant No. INFRARED IR2021-UVa13). M. J. thanks the University of Valladolid for a \u201CMargarita Salas\u201D postdoc contract. W.L. thanks the China Scholarship Council for a research scholarship. We acknowledge the CINECA award under the ISCRA initiative, for the availability of high-performance computing resources and support. This work was supported by University of Bologna (RFO). L.P. and A.P. acknowledge the Spanish Ministry of Science, Innovation and Universities & the State Research Agency through grants refs. PID2021-126560NB-I00 and CNS2022-135803 (MCIU/AEI/FEDER, UE), and the \u201CMar\u00EDa de Maeztu\u201D Programme for Units of Excellence in R&D (CEX2023-001316-M), and FASLIGHT network (RED2022-134391-T), and computer resources and assistance provided by Centro de Computaci\u00F3n Cient\u00EDfica de la Universidad Aut\u00F3noma de Madrid and Barcelona Supercomputing Center (FI-2023-1-0035 and FI-2023-2-0012)
Analysis of the steady-state concentrations of reactive species and their role in contaminant degradation by the iron-biochar/persulfate advanced oxidation process: Comparison of probe compound and quenching agent methods
Get PDFReactive species, including hydroxyl radicals ([rad]OH), sulfate radicals (SO4[rad]−), singlet oxygen (1O2), superoxide radicals (O2[rad]−), and Fe(IV), are generated by the iron-biochar activated persulfate (Fe-BC/PS) process. These reactive species can be leveraged for treatment of micropollutants, such as the sulfamethoxazole antibiotic. In this study, the steady-state concentrations and contributions of [rad]OH, SO4[rad]−, 1O2, O2[rad]−, and Fe(IV) to sulfamethoxazole degradation were calculated for different operating conditions in the iron-biochar/persulfate (Fe-BC/PS advanced oxidation process. Electron paramagnetic resonance was employed to confirm the production of each reactive species. The nitrobenzene, benzoic acid, furfuryl alcohol, p-chlorobenzoic acid or p-benzoquinone, and phenyl methyl sulfoxide probe compounds were added to experimental solutions in isolation, as mixtures, and at different concentrations to calculate the steady-state concentrations of [rad]OH, SO4[rad]−, 1O2, O2[rad]−, and Fe(IV) and determine their contributions to sulfamethoxazole degradation at variable pH conditions. The results not only informed the primary mechanisms of sulfamethoxazole degradation by the Fe-BC/PS system, but also highlighted best practices for the use of probe compounds and quenching agents in persulfate-based advanced oxidation processes. In particular, the initial concentration of the probe compounds should be as low as possible to avoid impacts on target contaminant degradation and misinterpretation of the role of each reactive species. Furthermore, quenching-based approaches to determination of the key reactive species were less consistent than evaluation by probe compounds. The overall outcomes of this work inform sulfamethoxazole treatment by the Fe-BC/PS system and emphasize the need for internal validation of kinetics results using a multi-pronged approachThis work was supported by the Natural Scientific Fund of Chongqing (Grant No. CSTB2023NSCQ-MSX0205), the Graduate Education and Teaching Reform Research of Southwest University (Grant No. SWUYJS226106), the Beijing Natural Science Foundation (Grant No. 8222046), the Excellent Youth Science Foundation of BAAFS (Grant No. YXQN202201), and the Yibin City Silkworm Industry Efficient Production Technology Innovation and Integration Demonstration (Grant No. XNDX2022020015)
Plant and animal protein intake and transitions from multimorbidity to frailty and mortality in older adults
Get PDFBackground: Multimorbidity is the most common chronic condition experienced among older adults. It is unknown which amount and source of protein influences the development of frailty and mortality in patients with multimorbidity. We aimed to examine the association of plant and animal sources of protein intake with frailty and mortality among this type of patients. Methods: This longitudinal study included 1868 participants aged ≥ 60 years from the Seniors-ENRICA cohort in Spain with multimorbidity, defined as having 2 or more clinician-diagnosed chronic diseases. Habitual diet was assessed at baseline (2008–2010) with a validated computerized diet history. Participants underwent repeated physical examinations (in 2013, 2015 and 2017) for assessment of frailty (≥ 3 criteria from the frailty phenotype: low physical activity, slow walking speed, muscle weak-ness, weight loss and exhaustion). All-cause mortality was assessed up to January 2022. Analyses were conducted using Cox proportional hazard models and multistate models adjusted for sociodemographic, lifestyle and other dietary factors. Results: Mean consumption of protein was 90.2 (standard deviation [SD]: 26.8) g/day, which represents 18.7% of the total energy intake and 1.23 (0.39) g per kg of body weight per day. Plant protein represented 6.16% of the energy intake, while animal protein represented 12.5%. During a median follow-up of 12.9 (range: 11.7–13.9) years, we documented 196 incident cases of frailty and 490 deaths; of these mortality cases, 83 individuals died after a frailty diagnosis. Higher intake of total protein was associated with decreased risk of frailty (hazard ratio [HR] for tertile 3 vs. tertile 1: 0.66; 95% confidence interval [CI]: 0.45, 0.96; p trend: 0.03). In multistate models, higher fish protein intake decreased the risk in the progression from multimorbidity to frailty (HR per 1- SD increment: 0.81 [95% CI: 0.68, 0.97]), and higher plant protein decreased the risk of progressing from multimorbidity to mortality (0.86 [0.75, 0.98]). In the progression from frailty to mortality, estimates for total, plant and animal protein showed increased risk (HR for 1 SD increment in total protein: 1.38 [1.05, 1.81]; HR for plant protein: 1.29 [1.01, 1.67]; HR for animal protein: 1.41 [1.04, 1.92]). No significant associations were found between meat pro-tein and dairy protein in any transitionThis work was supported by grants from the Instituto de Salud Carlos III, State Secretary of R+D+I of Spain ERDF/ESF (European Regional Development Fund/European Social Fund) (FIS 20/1040, 23/272). A.V.-F. holds a ‘Training of university professors – FPU’ grant (FPU20/06456) from the Spanish Ministry of Universities. E.A.S. holds a Ramon y Cajal contract (RYC2021-031146-I) from the Spanish Ministry of Science and Innovation. The funding agencies had no role in study design, data analysis, interpretation of results, manuscript preparation or in the decision to submit this manuscript for publicatio
Untargeted Metabolomics and Chemometrics Elucidate Dynamic Plasma Profile Changes Induced by Cocoa Shell in Female Rats
Get PDFThis study aimed to explore the effects of cocoa shell extract (CSE) supplementation on the plasma metabolome of female rats. Methods: Female rats were
supplemented with CSE (250 mg/kg/day) over seven days, and plasma samples were collected
at baseline, day 4, and day 7 for untargeted metabolomic profiling using LC-ESIQTOF.
Results: A total of 244 plasma metabolites were identified, while 180 were detected
in the CSE. Among these, only 21 compounds were consistently detected in both the CSE
and the plasma at baseline and day 7. Notably, just three compounds, caffeine, theobromine,
and N-isovaleroylglycine, were bioavailable, detected only in plasma after supplementation on day 7, confirming their absorption and systemic distribution. Pathways related to caffeine metabolism, glycerophospholipid biosynthesis, nicotinate, and nicotinamide metabolism were significantly upregulated, indicating enhanced lipid metabolism
and energy homeostasis. Conversely, reductions were observed in pathways involving tryptophan, glutathione, arginine, and proline, pointing to shifts in amino acid metabolism and antioxidant defense mechanisms. Network analysis revealed significant changes
in the cholinergic synapse, retrograde endocannabinoid signaling, and glutamatergic synapse
pathways, which are crucial for cellular communication and neurotransmission.
Conclusions: The observed metabolic reconfiguration demonstrates CSE’s rapid modulation of the metabolome, highlighting the bioavailability of its key components. These findings suggest potential mechanisms for CSE as a functional food ingredient with health-promoting effects, potentially supporting cognitive function and metabolic health through energy metabolism, neurotransmission, and lipid signaling pathwaysThis research was funded by the COCARDIOLAC project from the Spanish Ministry of Science and Innovation (RTI 2018–097504–B–I00) and the Excellence Line for University Teaching Staff within the Multiannual Agreement between the Community of Madrid and the UAM (2019–2023). M. Rebollo-Hernanz received funding from the program of the Ministry of Universities for the requalification of the Spanish university system (CA1/RSUE/2021–00656
A new antibiotic-loaded sol-gel can prevent bacterial prosthetic joint infection: from in vitro studies to an in vivo model
Get PDFThe aim of this study was to evaluate the effect of a moxifloxacin-loaded organic-inorganic sol-gel with different antibiotic concentration in the in vitro biofilm development and treatment against Staphylococcus aureus, S. epidermidis, and Escherichia coli, cytotoxicity and cell proliferation of MC3T3-E1 osteoblasts; and its efficacy in preventing the prosthetic joint infection (PJI) caused by clinical strains of S. aureus and E. coli using an in vivo murine model. Three bacterial strains, S. epidermidis ATCC 35984, S. aureus 15981, and, E. coli ATCC 25922, were used for microbiological studies. Biofilm formation was induced using tryptic-soy supplemented with glucose for 24 h, and then, adhered and planktonic bacteria were estimated using drop plate method and absorbance, respectively. A 24-h-mature biofilm of each species growth in a 96-well plate was treated for 24 h using a MBECTM biofilm Incubator lid with pegs coated with the different types of sol-gel, after incubation, biofilm viability was estimated using alamrBlue. MC3T3-E1 cellular cytotoxicity and proliferation were evaluated using CytoTox 96 Non-Radioactive Cytotoxicity Assay and alamarBlue, respectively. The microbiological studies showed that sol-gel coatings inhibited the biofilm development and treated to a mature biofilm of three evaluated bacterial species. The cell studies showed that the sol-gel both with and without moxifloxacin were non-cytotoxic and that cell proliferation was inversely proportional to the antibiotic concentration containing by sol-gel. In the in vivo study, mice weight increased over time, except in the E. coli-infected group without coating. The most frequent symptoms associated with infection were limping and piloerection; these symptoms were more frequent in infected groups with non-coated implants than infected groups with coated implants. The response of moxifloxacin-loaded sol-gel to infection was either total or completely absent. No differences in bone mineral density were observed between groups with coated and non-coated implants and macrophage presence lightly increased in the bone grown directly in contact with the antibiotic-loaded sol-gel. In conclusion, moxifloxacin-loaded sol-gel coating is capable of preventing PJI caused by both Gram-positive and Gram-negative specie