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Dengue is a disease caused by a flavivirus (DENV) and transmitted by the bite of a mosquito, primarily the Aedes aegypti and Aedes albopictus species. Previous studies have demonstrated a relationship between the host gut microbiota and the evolution of dengue. It seems to be a bidirectional relationship, in which the DENV can affect the microbiota by inducing alterations related to intestinal permeability, leading to the release of molecules from microbiota dysbiosis that can influence the evolution of dengue. The role of angiotensin II (Ang II) in the microbiota/dengue relationship is not well understood, but it is known that the renin-angiotensin system (RAS) is present in the intestinal tract and interacts with the gut microbiota. The possible effect of Ang II on the microbiota/Ang II/dengue relationship can be summarised as follows: the presence of Ang II induced hypertension, the increase in angiotensinogen, chymase, and microRNAs during the disease, the induction of vascular dysfunction, the production of trimethylamine N-oxide and the brain/microbiota relationship, all of which are elements present in dengue that could be part of the microbiota/Ang II/dengue interactions. These findings suggest the potential use of Ang II synthesis blockers and the use of AT1 receptor antagonists as therapeutic drugs in dengue.
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Dengue , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/efeitos dos fármacos , Dengue/virologia , Animais , Disbiose/microbiologia , Angiotensina II/metabolismo , Vírus da Dengue/fisiologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Aedes/microbiologia , Aedes/virologiaRESUMO
ConspectusGold nanorods (Au NRs) are an exceptionally promising tool in nanotechnology due to three key factors: (i) their strong interaction with electromagnetic radiation, stemming from their plasmonic nature, (ii) the ease with which the resonance frequency of their longitudinal plasmon mode can be tuned from the visible to the near-infrared region of the electromagnetic spectrum based on their aspect ratio, and (iii) their simple and cost-effective preparation through seed-mediated chemical growth. In this synthetic method, surfactants play a critical role in controlling the size, shape, and colloidal stability of Au NRs. For example, surfactants can stabilize specific crystallographic facets during the formation of Au NRs, leading to the formation of NRs with specific morphologies.The process of surfactant adsorption onto the NR surface may result in various assemblies of surfactant molecules, such as spherical micelles, elongated micelles, or bilayers. Again, the assembly mode is critical toward determining the further availability of the Au NR surface to the surrounding medium. Despite its importance and a great deal of research effort, the interaction between Au NPs and surfactants remains insufficiently understood, because the assembly process is influenced by numerous factors, including the chemical nature of the surfactant, the surface morphology of Au NPs, and solution parameters. Therefore, gaining a more comprehensive understanding of these interactions is essential to unlock the full potential of the seed-mediated growth method and the applications of plasmonic NPs. A plethora of characterization techniques have been applied to reach such an understanding, but many open questions remain.In this Account, we review the current knowledge on the interactions between surfactants and Au NRs. We briefly introduce the state-of-the-art methods for synthesizing Au NRs and highlight the crucial role of cationic surfactants during this process. The self-assembly and organization of surfactants on the Au NR surface is then discussed to better understand their role in seed-mediated growth. Subsequently, we provide examples and elucidate how chemical additives can be used to modulate micellar assemblies, in turn allowing for a finer control over the growth of Au NRs, including chiral NRs. Next, we review the main experimental characterization and computational modeling techniques that have been applied to shed light on the arrangement of surfactants on Au NRs and summarize the advantages and disadvantages for each technique. The Account ends with a "Conclusions and Outlook" section, outlining promising future research directions and developments that we consider are still required, mostly related to the application of electron microscopy in liquid and in 3D. Finally, we remark on the potential of exploiting machine learning techniques to predict synthetic routes for NPs with predefined structures and properties.
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Previous studies have demonstrated the relevance of several soluble molecules in the pathogenesis of dengue. In this regard, a possible role for angiotensin II (Ang II) in the pathophysiology of dengue has been suggested by the observation of a blockade of Ang II in patients with dengue, increased expression of molecules related to Ang II production in the plasma of dengue patients, increased expression of circulating cytokines and soluble molecules related to the action of Ang II, and an apparent relationship between DENV, Ang II effects, and miRNAs. In addition, in ex vivo experiments, the blockade of Ang II AT1 receptor and ACE-1 (angiotensin converting enzyme 1), both of which are involved in Ang II production and its function, inhibits infection of macrophages by DENV, suggesting a role of Ang II in viral entry or in intracellular viral replication of the virus. Here, we discuss the possible mechanisms of Ang II in the entry and replication of DENV. Ang II has the functions of increasing the expression of DENV entry receptors, creation of clathrin-coated vesicles, and increasing phagocytosis, all of which are involved in DENV entry. This hormone also modulates the expression of the Rab5 and Rab7 proteins, which are important in the endosomal processing of DENV during viral replication. This review summarizes the data related to the possible involvement of Ang II in the entry of DENV into cells and its replication.
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Angiotensina II , Vírus da Dengue , Internalização do Vírus , Replicação Viral , Angiotensina II/metabolismo , Humanos , Vírus da Dengue/fisiologia , Vírus da Dengue/genética , Animais , Dengue/virologia , Dengue/metabolismoRESUMO
The bottom-up production of chiral gold nanomaterials holds great potential for the advancement of biosensing and nano-optics, among other applications. Reproducible preparations of colloidal nanomaterials with chiral morphology have been reported, using cosurfactants or chiral inducers such as thiolated amino acids. However, the underlying growth mechanisms for these nanomaterials remain insufficiently understood. We introduce herein a purposely devised chiral inducer, a cysteine modified with a hydrophobic chain, as a versatile chiral inducer. The amphiphilic and chiral features of this molecule provide control over the chiral morphology and the chiroptical signature of the obtained nanoparticles by simply varying the concentration of chiral inducer. These results are supported by circular dichroism and electromagnetic modeling as well as electron tomography to analyze structural evolution at the facet scale. Our observations suggest complex roles for the factors involved in chiral synthesis: the chemical nature of the chiral inducers and the influence of cosurfactants.
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Solubility is an essential concept in chemistry that describes the ability of a substance to dissolve in a particular solvent. Despite its importance in many fields of science, understanding the basic principles of solubility is challenging for many undergraduate students. Notably, students often encounter difficulties in comprehending the role of counterions when dealing with charged molecules. Here, we bring the opportunity to assimilate the key concepts of solubility regarding the role of counterions by developing a straightforward, cheap, and visually appealing experiment that focuses on the strategic use of counterions to control solubility. A student questionnaire delivered encouraging results with most of students giving positive feedback in both interest and training their hands-on skills. Hence, our experiment offers a proficient understanding of the solubility concept, thus preparing undergraduate students for advanced courses in the various subject areas of chemistry.
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Cardiovascular complications are the main cause of mortality and morbidity in the diabetic patients, in whom changes in myocardial structure and function have been described. Numerous molecular mechanisms have been proposed that could contribute to the development of a cardiac damage. In this regard, angiotensin II (Ang II), a proinflammatory peptide that constitutes the main effector of the renin-angiotensin system (RAS) has taken a relevant role. The aim of this review was to analyze the role of Ang II in the different biochemical pathways that could be involved in the development of cardiovascular damage during diabetes. We performed an exhaustive review in the main databases, using the following terms: angiotensin II, cardiovascular damage, renin angiotensin system, inflammation, and diabetes mellitus. Classically, the RAS has been defined as a complex system of enzymes, receptors, and peptides that help control the blood pressure and the fluid homeostasis. However, in recent years, this concept has undergone substantial changes. Although this system has been known for decades, recent discoveries in cellular and molecular biology, as well as cardiovascular physiology, have introduced a better understanding of its function and relationship to the development of the diabetic cardiomyopathy.
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Diabetes Mellitus , Cardiomiopatias Diabéticas , Traumatismos Cardíacos , Angiotensina II/metabolismo , Coração , Humanos , Sistema Renina-Angiotensina/fisiologiaRESUMO
DNA is the molecule responsible for the storage and transmission of the genetic information in living organisms. The expression of this information is highly regulated. In eukaryotes, it is achieved mainly at the transcription level thanks to specialized proteins called transcription factors (TFs) that recognize specific DNA sequences, thereby promoting or inhibiting the transcription of particular genes. In many cases, TFs are present in the cell in an inactive form but become active in response to an external signal, which might modify their localization and DNA binding properties or modulate their interactions with the rest of the transcriptional machinery. As a result of the crucial role of TFs, the design of synthetic peptides or miniproteins that can emulate their DNA binding properties and eventually respond to external stimuli is of obvious interest. On the other hand, although the B-form double helix is the most common DNA secondary structure, it is not the only one with an essential biological function. Guanine quadruplexes (GQs) have received considerable attention due to their critical role in the regulation of gene expression, which is usually associated with a change in the GQ conformation. Thus, the development of GQ probes whose properties can be controlled using external signals is also of significant relevance.In this Account, we present a summary of the recent efforts toward the development of stimuli-responsive synthetic DNA binders with a particular emphasis on our own contributions. We first introduce the structure of B and GQ DNAs, and some of the main factors underlying their selective recognition. We then discuss some of the different approaches used for the design of stimulus-mediated DNA binders. We have organized our discussion according to whether the interaction takes place with duplex or guanine quadruplex DNAs, and each section is divided according to the nature of the stimulus (i.e., physical or chemical). Regarding physical stimuli, light (through the incorporation of photolabile protecting groups or photoisomerizable agents) is the most common input for the activation/deactivation of DNA binding events. With respect to chemical signals, the use of metals (through the incorporation of metal-coordinating groups in the DNA binding agent) has allowed the development of a wide range of stimuli-responsive DNA binders. More recently, redox-based systems have also been used to control DNA interactions.This Account ends with a "Conclusions and Outlook" section highlighting some of the general lessons that have been learned and future directions toward further advancing the field.
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DNA/metabolismo , Dicroísmo Circular , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , DNA/química , Quadruplex G , Isomerismo , Metais/química , Metais/metabolismo , Oxirredução , Ligação Proteica , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Raios UltravioletaRESUMO
The use of supramolecular polymers to construct functional biomaterials is gaining more attention due to the tunable dynamic behavior and fibrous structures of supramolecular polymers, which resemble those found in natural systems, such as the extracellular matrix. Nevertheless, to obtain a biomaterial capable of mimicking native systems, complex biomolecules should be incorporated, as they allow one to achieve essential biological processes. In this study, supramolecular polymers based on water-soluble benzene-1,3,5-tricarboxamides (BTAs) were assembled in the presence of hyaluronic acid (HA) both in solution and hydrogel states. The coassembly of BTAs bearing tetra(ethylene glycol) at the periphery (BTA-OEG4) and HA at different ratios showed strong interactions between the two components that led to the formation of short fibers and heterogeneous hydrogels. BTAs were further covalently linked to HA (HA-BTA), resulting in a polymer that was unable to assemble into fibers or form hydrogels due to the high hydrophilicity of HA. However, coassembly of HA-BTA with BTA-OEG4 resulted in the formation of long fibers, similar to those formed by BTA-OEG4 alone, and hydrogels were produced with tunable stiffness ranging from 250 to 700 Pa, which is 10-fold higher than that of hydrogels assembled with only BTA-OEG4. Further coassembly of BTA-OEG4 fibers with other polysaccharides showed that except for dextran, all polysaccharides studied interacted with BTA-OEG4 fibers. The possibility of incorporating polysaccharides into BTA-based materials paves the way for the creation of dynamic complex biomaterials.
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Ácido Hialurônico , Hidrogéis , Materiais Biocompatíveis , Matriz Extracelular , PolímerosRESUMO
The primary function of the cell membrane is to protect cells from their surroundings. This entails a strict regulation on controlling the exchange of matter between the cell and its environment. A key factor when considering potential biological applications of a particular chemical structure has to do with its ability to internalize into cells. Molecules that can readily cross cell membranes are frequently needed in biological research and medicine, since most therapeutic entities are designed to modulate intracellular components. However, the design of molecules that do not penetrate cells is also relevant toward, for example, extracellular contrast agents, which are most widely used in clinical diagnosis. Small molecules have occupied the forefront of biomedical research until recently, but the past few decades have seen an increasing use of larger chemical structures, such as proteins or nanoparticles, leading to unprecedented and often unexpectedly novel research. Great achievements have been made toward understanding the rules that govern cellular uptake, which show that cell internalization of molecules is largely affected by their size. For example, macromolecules such as proteins and nucleic acids are usually unable to internalize cells. Intriguingly, in the case of nanoparticles, larger sizes seem to facilitate internalization via endocytic pathways, through which the particles remain trapped in lysosomes and endosomes. In this Account, we aimed at presenting our personal view of how different chemical structures behave in terms of cell internalization due to their size, ranging from small drugs to large nanoparticles. We first introduce the properties of cell membranes and the main mechanisms involved in cellular uptake. We then discuss the cellular internalization of molecules, distinguishing between those with molecular weights below 1 kDa and biological macromolecules such as proteins and nucleic acids. In the last section, we review the biological behavior of nanoparticles, with a special emphasis on plasmonic nanoparticles, which feature a high potential in the biomedical field. For each group of chemical structures, we discuss the parameters affecting their cellular internalization but also strategies that can be applied to achieve the desired intracellular delivery. Particular attention is paid to approaches that allow conditional regulation of the cell internalization process using external triggers, such as activable cell penetrating peptides, due to the impact that these systems may have in drug delivery and sensing applications. The Account ends with a "Conclusions and Outlook" section, where general lessons and future directions toward further advancements are briefly presented.
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Membrana Celular/metabolismo , Peptídeos Penetradores de Células/metabolismo , Proteínas Imobilizadas/metabolismo , Nanopartículas Metálicas/química , Ácidos Nucleicos/metabolismo , Transporte Biológico , Portadores de Fármacos/química , Endocitose , Endossomos/fisiologia , Humanos , Proteínas Imobilizadas/química , Tamanho da PartículaRESUMO
Size-selective hydroformylation of terminal alkenes was attained upon embedding a rhodium bisphosphine complex in a supramolecular metal-organic cage that was formed by subcomponent self-assembly. The catalyst was bound in the cage by a ligand-template approach, in which pyridyl-zinc(II) porphyrin interactions led to high association constants (>105 m-1 ) for the binding of the ligands and the corresponding rhodium complex. DFT calculations confirm that the second coordination sphere forces the encapsulated active species to adopt the ee coordination geometry (i.e., both phosphine ligands in equatorial positions), in line with in situ high-pressure IR studies of the host-guest complex. The window aperture of the cage decreases slightly upon binding the catalyst. As a result, the diffusion of larger substrates into the cage is slower compared to that of smaller substrates. Consequently, the encapsulated rhodium catalyst displays substrate selectivity, converting smaller substrates faster to the corresponding aldehydes. This selectivity bears a resemblance to an effect observed in nature, where enzymes are able to discriminate between substrates based on shape and size by embedding the active site deep inside the hydrophobic pocket of a bulky protein structure.
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Chemical separations technologies are energetically costly; lowering this cost through the development of new molecular separation methods would thus enable significant energy savings. Molecules could, for example, be selectively encapsulated and separated using coordination cages, which can be designed with cavities of tailored sizes and geometries. Before cages can be used to perform industrially relevant separations, however, the experimental and theoretical foundations for this technology must be established. Using hydrophobic and hydrophilic anions as stimuli, we show that cages can reversibly transfer many times between mutually immiscible liquid phases, thus transporting their molecular cargoes over macroscopic distances. Furthermore, when two cages are dissolved together, sequential phase transfer of individual cage species results in the separation of their molecular cargoes. We present a thermodynamic model that describes the transfer profiles of these cages, both individually and in the presence of other cage species. This model provides a new analytical tool to quantify the hydrophobicity of cages.
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We describe an approach to regulate the cellular uptake of small gold nanoparticles using supramolecular chemistry. The strategy relies on the functionalization of AuNPs with negatively charged pyranines, which largely hamper their penetration in cells. Cellular uptake can be activated in situ through the addition of cationic covalent cages that specifically recognize the fluorescent pyranine dyes and counterbalance the negative charges. The high selectivity and reversibility of the host-guest recognition activates cellular uptake, even in protein-rich biological media, as well as its regulation by rational addition of either cage or pyranine.
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Selective anion extraction is useful for the recovery and purification of valuable chemicals, and in the removal of pollutants from the environment. Here we report that FeII4 L4 cage 1 is able to extract an equimolar amount of ReO4- , a high-value anion and a nonradioactive surrogate of TcO4- , from water into nitromethane. Importantly, the extraction was efficiently performed even in the presence of 10 other common anions in water, highlighting the high selectivity of 1 for ReO4- . The extracted guest could be released into water as the cage disassembled in ethyl acetate, and then 1 could be recycled by switching the solvent to acetonitrile. The versatile solubility of the cage also enabled complete extraction of ReO4- (as the tetrabutylammonium salt) from an organic phase into water by using the sulfate salt of 1 as the extractant.
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Anion-templated aqueous self-assembly resulted in the formation of an endohedrally functionalized FeII4L4 tetrahedron from azaphosphatrane-based subcomponents. This new water-soluble cage is flexible and able to encapsulate anions with volumes ranging from 35 to 219 Å3 via hydrogen bonding and electrostatic interactions. It structurally adapts in response to the size and shape of the template anions, dynamically adopting a conformation either where all four azaphosphatrane +P-H vectors point inward, or else where one points outward and the other three inward. The two cage isomers can coexist in solution and interconvert. A shape memory phenomenon was observed during guest displacement because guest exchange occurs more rapidly than structural reconfiguration.
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The cell internalization of designed oligoarginine peptides equipped with six glutamic acid residues and an anionic pyranine at the N-terminus is triggered upon addition of a supramolecular host. This host binds specifically to the pyranine moiety, enabling the complex to traverse the cell membrane. Interestingly, none of the components, neither the host nor the guest, are able to cross the cell membrane on their own.
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Membrana Celular/química , Substâncias Macromoleculares/química , Animais , Ânions/química , Chlorocebus aethiops , Estrutura Molecular , Células VeroRESUMO
Control over the solubility properties of container molecules is a central challenge in host-guest chemistry. Herein we present a simple anion-exchange protocol that allows the dissolution in water of various hydrophobic metal-organic container molecules prepared by iron(II)-templated subcomponent self-assembly. Our process involved the exchange of less hydrophilic trifluoromethanesulfonate anions for hydrophilic sulfate; the resulting water-soluble cages could be rendered water-insoluble through reverse anion exchange. Notably, this strategy allowed cargoes within capsules, including polycyclic aromatic compounds and complex organic drugs, to be brought into water. Hydrophobic effects appeared to enhance binding, as many of these cargoes were not bound in non-aqueous media. Studies of the scope of this method revealed that cages containing tetratopic and tritopic ligands were more stable in water, whereas cages with ditopic ligands disassembled.
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A flexible tris-formylpyridine subcomponent A was observed to produce three distinct products following Cd(II)-templated self-assembly with different anilines. Two of the products were Cd(II)4L4 tetrahedra, one with ligands puckered inward, and the other outward. The third product was a Cd(II)8L8 structure having all mer stereochemistry, contrasting with the fac stereochemistry of the tetrahedra. These three complexes were observed to coexist in solution. The equilibrium between them could be influenced through guest binding and specific interactions between aniline subcomponents, allowing a selected one of the three to predominate under defined conditions.
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C-reactive protein (CRP) is an acute-phase reactant that increases in the circulation in response to a variety of inflammatory stimuli. Elevated levels in serum during several infectious diseases have been reported. In this study, a highly sensitive CRP enzyme immunoassay was used to evaluate serum CRP values in patients with viral and atypical bacterial infections. Patients (n = 139) with different viral or atypical bacterial infections (systemic or respiratory) and healthy controls (n = 40) were tested for circulating CRP values. High levels of IgM antibodies against several viruses: Dengue virus (n = 36), Cytomegalovirus (n = 9), Epstein Barr virus (n = 17), Parvovirus B19 (n = 26), Herpes simplex 1 and 2 virus (n = 3) and Influenza A and B (n = 8) and against atypical bacteria: Legionella pneumophila (n = 15), Mycoplasma pneumoniae (n = 21) and Coxiella burnetii (n = 4) were found. High values of CRP in infected patients compared with controls (P < 0.001) were found; however, no significant differences between viral and atypical bacterial infections were found. Low levels of CRP in respiratory and Coxiella burnetii infections compared with exanthematic viral and other atypical bacterial infections were found. This study suggests that CRP values are useful to define viral and atypical bacterial infections compared with normal values, but, it is not useful to define type of infection.
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Infecções Bacterianas/diagnóstico , Infecções Bacterianas/patologia , Biomarcadores/análise , Proteína C-Reativa/análise , Viroses/diagnóstico , Viroses/patologia , Adolescente , Adulto , Diagnóstico Diferencial , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Soro/química , Adulto JovemRESUMO
We describe the synthesis of designed peptidic modules that self-assemble in specific DNA sequences of 12 base pairs in the presence of Ni(II) salts. The modules consist of modified fragments of transcription factors that have been appropriately engineered to include metal-chelating His and bipyridine ligands.
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DNA/química , Níquel/química , Peptídeos/química , Sequência de Bases , Sítios de Ligação , Complexos de Coordenação/química , Ligantes , Conformação de Ácido Nucleico , Fatores de Transcrição/químicaRESUMO
Guanine quadruplexes (GQs) are compact four-stranded DNA structures that play a key role in the control of a variety of biological processes, including gene transcription. Bulky ruthenium complexes featuring a bipyridine, a terpyridine, and one exchangeable ligand ([Ru(terpy)(bpy)X]n+ ) are able to metalate exposed guanines present in the GQ of the c-MYC promoter region that are not involved in quadruplex base pairing. qRT-PCR and western-blot experiments indicated that the complexes promote a remarkable increase in the expression of this oncogene. We also show that exchangeable thioether ligands (X=RSR', Met) allow regulation of the metalating activity of the complex with visible light.