15 research outputs found
Kinetic evidence for interaction of TMPyP4 with two different G-quadruplex conformations of human telomeric DNA
Background: Stabilization of G-quadruplex helices by small ligands has attracted growing attention because they
inhibit the activity of the enzyme telomerase, which is overexpressed in> 80% cancer cells. TMPyP4, one of the
most studied G-quadruplex ligands, is used as a model to show that the ligands can exhibit different binding
features with different conformations of a human telomeric specific sequence.
Methods: UVâVis, FRET melting Assay, Isothermal Titration Calorimetry, Time-resolved Fluorescence lifetime,
T-Jump and Molecular Dynamics.
Results: TMPyP4 yields two different complexes with two Tel22 telomeric conformations in the presence of Na+
or K+. T-Jump kinetic experiments show that the rates of formation and dissociation of these complexes in the
ms time scale differ by one order of magnitude. MD simulations reveal that, in K+ buffer, âhybrid 1â conformation
yields kinetic constants on interaction with TMPyP4 one order lower than âhybrid 2â. The binding
involves ÏâÏ stacking with external loop bases.
Conclusions: For the first time we show that for a particular buffer TMPyP4 interacts in a kinetically different
way with the two Tel22 conformations even if the complexes formed are thermodynamically indistinguishable.
General significance: G-quadruplexes, endowed with technological applications and potential impact on regulation
mechanisms, define a new research field. The possibility of building different conformations from same
sequence is a complex issue that confers G-quadruplexes very interesting features. The obtaining of reliable
kinetic data constitutes an efficient tool to determine reaction mechanisms between conformations and small
molecules.âla
Caixaâ Foundation (project OSLC-2012-007), MINECO, (CTQ2014-
58812-C2-2-R) and Junta de Castilla y LeĂłn, (BU042U16), FEDER
Funds Spai
ÎČ-Alanine Supplementation in Combat Sports: Evaluation of Sports Performance, Perception, and Anthropometric Parameters and Biochemical MarkersâA Systematic Review of Clinical Trials
[EN] ÎČ-alanine does not have an ergogenic effect by itself, but it does as a precursor for the
synthesis of carnosine in human skeletal muscle. ÎČ-alanine and carnosine together help improve
the musclesâ functionality, especially in high-intensity exercises such as combat sports. Therefore,
ÎČ-alanine could be considered a nutritional ergogenic aid to improve sports performance in combat
athletes. We aimed to critically review clinical trial evidence on the impact of ÎČ-alanine supplementation on sports performance, perception, and anthropometric parameters, as well as circulating
biochemical markers in combat athletes. This systematic review was conducted following the specific
methodological guidelines of the Preferred Report Items for Systematic Reviews and Meta-Analyses
guidelines (PRISMA), the PICOS question model, the Critical Review Form of McMaster, and the
PEDro scale. Furthermore, the Cochrane risk-of-bias assessment tool was used. The search was
carried out in the SCOPUS, Web of Science (WOS), and Medline (PubMed) databases for studies
published from the beginning of the database until July 31, 2023. Of the 41 registers identified, only
7 met the established criteria and were included in this systematic review. Overall, performance
parameters related to strength, power, total exercise work capacity, and combat-specific parameters
were significantly improved (p 0.05).
Regarding biochemical parameters, carnosine increased significantly (p 0.05), and the results for blood bicarbonate and blood lactate were heterogeneous.
Finally, there was a non-significant (p > 0.05) improvement in the anthropometric parameters of lean
mass and fat mass. ÎČ-alanine supplementation appears to be safe and could be a suitable nutritional
ergogenic aid for combat athletes.S
Synthesis of water-soluble hemicoronenediimides by photocyclization of perylenediimides: Turn-on fluorescent probes in water by complexation with Cucurbit[7]uril or binding to G-quadruplex Motifs
A new series of perylene and hemicoronene diimides, obtained by visible light photocyclization, are presented,
between them some remarkable examples that are soluble in only water, and give nanoparticles by selfassociation. Those compounds work as new fluorescent materials in water by complexation with cucurbit[7]
uril, as well as selective G-quadruplex binding ligands with remarkable cytotoxic activity when the interaction
with G4 was sufficiently strong.We acknowledge the Ministerio de Ciencia, InnovaciĂłn y Universidades-FEDER (Grants PID2019-111215RB-100 and RTI2018- 102040-B-100), the Junta de Castilla y LeĂłn, ConsejerĂa de EducaciĂłn y Cultura y Fondo Social Europeo (Grants BU263P18 and BU305P18), âla Caixaâ Foundation (LCF/PR/PR12/11070003) for financial support. A. R.C. thanks SecretarĂa General de Universidades for a FPU18/03225 Grant. This research has made use of the high-performance computing resources of the Castilla y LeĂłn Supercomputing Center (SCAYLE, htt ps://www.scayle.es), financed by FEDER (Fondo Europeo de Desarrollo Regional). We thank Ms. Ma del Pilar Castroviejo-FernĂĄndez, from PCT, UBU, for assistance in AFM studies and Mr. Javier Gutierrez-Reguera from LTI, UVA, for assistance in DLS studies
Targets, Mechanisms and Cytotoxicity of Half-Sandwich Ir(III) Complexes Are Modulated by Structural Modifications on the Benzazole Ancillary Ligand
Cancers are driven by multiple genetic mutations but evolve to evade treatments targeting
specific mutations. Nonetheless, cancers cannot evade a treatment that targets mitochondria, which
are essential for tumor progression. Iridium complexes have shown anticancer properties, but
they lack specificity for their intracellular targets, leading to undesirable side effects. Herein we
present a systematic study on structure-activity relationships of eight arylbenzazole-based Iridium(III)
complexes of type [IrCl(Cp*)], that have revealed the role of each atom of the ancillary ligand in the
physical chemistry properties, cytotoxicity and mechanism of biological action. Neutral complexes,
especially those bearing phenylbenzimidazole (HL1 and HL2), restrict the binding to DNA and
albumin. One of them, complex 1[C,NH-Cl], is the most selective one, does not bind DNA, targets
exclusively the mitochondria, disturbs the mitochondria membrane permeability inducing proton
leak and increases ROS levels, triggering the molecular machinery of regulated cell death. In
mice with orthotopic lung tumors, the administration of complex 1[C,NH-Cl] reduced the tumor
burden. Cancers are more vulnerable than normal tissues to a treatment that harnesses mitochondrial
dysfunction. Thus, complex 1[C,NH-Cl] characterization opens the way to the development of new
compounds to exploit this vulnerabilityWe acknowledge the âla Caixaâ Foundation (LCF/PR/PR12/11070003), Ministerio de Ciencia InnovaciĂłn y Universidades-FEDER (RTI2018-102040-B-100) and Junta de Castilla y LeĂłn-FEDER (BU305P18) for financial support. Networking support by COST Action CA18202 (NECTAR) is also acknowledged
Biological activity and photocatalytic properties of a naphthyl-imidazo phenanthroline (HNAIP) ligand and its [Ir(ppy)2(HNAIP)]Cl and [Rh(ppy)2(HNAIP)]Cl complexes
The synthesized 2-(hydroxy-1-naphtyl)imidazo-[4,5-f][1,10]phenanthroline (HNAIP) ligand and its new iridium ([Ir(ppy)2(HNAIP)]Cl) and rhodium ([Rh(ppy)2(HNAIP)]Cl) complexes, being ppy = 2-phenylpiridinate, show cytotoxic effects in SW480 (colon adenocarcinoma) and A549 (epithelial lung adenocarcinoma) cells. They all are cytotoxic in the tested cell lines. HNAIP and [Rh(ppy)2(HNAIP)]+ are the most cytotoxic, whereas [Ir(ppy)2(HNAIP)]+ displays negligible cytotoxicity towards A549 cells and moderate activity towards SW480. The interaction of all three compounds with Bovine Serum Albumin (BSA), l-glutathione reduced (GSH), nicotinamide adenine dinucleotide (NADH) and DNA was studied to explain the differences found in terms of cytotoxicity. None of them are able to interact with BSA, thus excluding bioavailability due to plasma protein interaction as the possible differentiating factor in their biological activity. By contrast, small differences have been observed regarding DNA interaction. In addition, taking advantage of the emission properties of these molecules, they have been visualized in the cytoplasmic region of A549 cells. Inductively coupled plasma mass spectrometry (ICP-MS) experiments show, in turn, that the internalization ability follow the sequence [Rh(ppy)2(HNAIP)]+âŻ>âŻ[Ir(ppy)2(HNAIP)]+âŻ>âŻcisplatin. Therefore, it seems clear that the cellular uptake by tumour cells is the key factor affecting the different cytotoxicity of the metal complexes and that this cellular uptake is influenced by the hydrophobicity of the studied complexes. On the other hand, preliminary catalytic experiments performed on the photo-oxidation of GSH and some amino acids such as l-methionine (Met), l-cysteine (Cys) and l-tryptophan (Trp) provide evidence for the photocatalytic activity of the Ir(III) complex in this type of reactions.âla Caixaâ Banking Foundation (LCF/PR/PR12/11070003), Ministerio de Ciencia, InnovaciĂłn y Universidades (RTI2018-102040-B-100 and RTI2018-100709-B-C21), Junta de Castilla y LeĂłn (BU305P18, FEDER Funds
Self-Assembly Hydrosoluble Coronenes: A Rich Source of Supramolecular Turn-On Fluorogenic Sensing Materials in Aqueous Media
Water-soluble coronenes, that form nanoparticles by self-association, work as new fluorescent materials by complexation with cucurbit[7]uril, as well as selective turn-on fluorogenic sensors for nitroaromatic explosives with remarkable selectivity, by using only water as solvent.NATO Science for Peace and Security Programme (SPS G5536), Ministerio de Ciencia, InnovaciĂłn y Universidades-FEDER (PID2019-111215RB-100 and RTI2018-102040-B-100), Junta de Castilla y LeĂłn, ConsejerĂa de EducaciĂłn y Cultura y Fondo Social Europeo (BU263P18) and âla Caixaâ Foundation (LCF/PR/PR12/11070003) for financial support. A.R.C. thanks SecretarĂa General de Universidades (FPU18/03225)
Role of Seroalbumin in the Cytotoxicity of cis-Dichloro Pt(II) Complexes with (N^N)-Donor Ligands Bearing Functionalized Tails
Given the potent anticancer properties of cisdiamminedichloroplatinum(
II) and knowing its mode of action, we
synthesized four new cis-[PtCl2(N^N)] organoplatinum complexes, two
with N-substituted pbi ligands (pbiR = 1-R-2-(2-pyridyl)benzimidazole)
(namely, 1 and 2) and two more with 4,4âČ-disubstituted bpy ligands (bpy =
2,2âČ-bipyridine) (namely, 3 and 4). We explored their cytotoxicity and
ability to bind to deoxyguanosine monophosphate (dGMP), DNA, and
albumin models. By 1H NMR and UVâvis spectroscopies, circular
dichroism, agarose gel electrophoresis, differential scanning calorimetry
measurements, and density functional theory calculations, we verified that
only 3 can form aquacomplex species after dimethyl sulfoxide solvation;
surprisingly, 1, 2, and 3 can bind covalently to DNA, whereas 4 can form a noncovalent complex. Interestingly, only complexes 1
and 4 exhibit good cytotoxicity against human ovarian carcinoma (HeLa) cell line, whereas 2 and 3 are inactive. Although lung
carcinoma (A549) cells are more resistant to the four platinum complexes than HeLa cells, when the protein concentration in the
extracellular media is lower, the cytotoxicity becomes substantially enhanced. By native electrophoresis of bovine seroalbumin
(BSA) and inductively coupled plasma mass spectrometry uptake studies we bear out, on one hand, that 2 and 3 can interact
strongly with BSA and its cellular uptake is negligible and, on the other hand, that 1 and 4 can interact with BSA only weakly, its
cellular uptake being higher by several orders. These results point up the important role of the protein binding features on their
biological activity and cellular uptake of cis-âPtCl2â derivatives. Our results are valuable in the future rational design of new
platinum complexes with improved biological properties, as they expose the importance not only of their DNA binding abilities
but also of additional factors such as protein binding.La
Caixa Foundation (LCF/PR/PR12/11070003), Ministerio de
EconomiÌa
y Competitividad-FEDER (CTQ2014-58812-C2-2-
R, CTQ2014-58812-C2-1-R, and CTQ2015-70371-REDT),
ConsejeriÌa
de EducacioÌnâJunta de Castilla y LeoÌn-FEDER
(BU042U16), Spain
Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries
Abstract
Background
Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres.
Methods
This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and lowâmiddle-income countries.
Results
In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of âsingle-useâ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for lowâmiddle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia.
Conclusion
This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both highâ and lowâmiddleâincome countries
Alcian blue pyridine variant interaction with DNA and RNA polynucleotides and G-quadruplexes: changes in the binding features for different biosubstrates
This work concerns an analysis of the binding mechanism of a copper phthalocyanine (Alcian Blue-tetrakis(methylpyridinium) chloride, ABTP) to natural calf thymus DNA, G-quadruplexes (G4) and synthetic RNA polynucleotides in the form of double polyriboadenylic·polyribouridylic acid (poly(A)·poly(U)) or triple strands polyriboadenylic·2polyribouridylic acid (poly(A)·2poly(U)). ABTP is a well know dye that might undergo novel applications, but its interaction with DNA is scarcely studied and we lack information on possible RNA or G4 binding. This might be related to system complexity due to the presence of supramolecular dye-dye aggregates. Despite this, we show here that apparent parameters can be calculated, which provide information on the binding mechanism. Absorbance titrations in the presence of biosubstrate excess, melting and circular dichroism experiments show that ABTP binds to both RNAs and DNA. External/groove binding is the main feature for RNAs, whereas partial intercalation is the major binging mode for DNA. ABTP externally binds to both hybrid, parallel and anti-parallel G4s but seem to show a slightly different binding mode and a preference for anti-parallel structures. The thermodynamic features of the different systems are also discussed in the frame of the enthalpy-entropy compensation phenomenon.la Caixaâ Foundation (LCF/PR/PR12/11070003), Ministerio de Ciencia, InnovaciĂłn y Universidades-FEDER (RTI2018- 102040-B-100) and Junta de Castilla y LeĂłn-FEDER (BU305P18
Screening the biological properties of transition metal carbamates reveals gold(I) and silver(I) complexes as potent cytotoxic and antimicrobial agents
We report a screening study aimed to assess for the first time the air- and water-stability and the biological potential of simple metal-carbamates. These molecular metallic species are based on elements belonging to the groups 4â5, 7â9 and 11, and tin, and are easily available from inexpensive reagents. Complexes [Ag(O2CNEt2)] (13-Ag) and [Au(O2CNMe2)(PPh3)] (14-Au) resulted substantially stable in aqueous media and exhibited a potent in vitro cytotoxicity. Especially 13-Ag revealed a significant selectivity against the A549 lung adenocarcinoma and the A2780 ovarian cancer cell lines with respect to the noncancerous HEK293 cell line. Generation of ROS (reactive oxygen species) and mitochondrial membrane depolarization were recognized for 13-Ag and 14-Au; notwithstanding, the cell death mechanism is different in the two cases: apoptosis and cell cycle arrest in G0/G1 phase for 13-Ag; necroptosis and cell cycle arrest in S phase for 14-Au. Both 13-Ag and 14-Au are endowed with antibacterial activity, which is relatively stronger for 13-Ag towards Gram negative and for 14-Au towards Gram positive strains, respectively.La Caixa Foundation (LCF/PR/PR12/11070003), ConsejerĂa de EducaciĂłn-Junta de Castilla y LeĂłn-FEDER Funds (BU305P18), Ministerio de Ciencia, InnovaciĂłn y Universidades (RTI2018-102040-B-100) and the University of Pisa (PRA_2020_39)