The clinical applicability of G-quadruplexes (G4s) as anticancer drugs is currently being evaluated. Several G4 ligands and aptamers are undergoing clinical trials following the notable examples of ...quarfloxin and AS1411, respectively. In this review, we summarize the latest achievements and breakthroughs in the use of G4 nucleic acids as both therapeutic tools (‘friends’, as healing anticancer drugs) and targets (‘foes’, within the harmful cancer cell), particularly using aptamers and quadruplex-targeted ligands, respectively. We explore the recent research on synthetic G4 ligands toward the discovery of anticancer therapeutics and their mechanism of action. Additionally, we highlight recent advances in chemical and structural biology that enable the design of specific G4 aptamers to be used as novel anticancer agents.
Guanine-rich sequences with the potential to form stable G4 structures are nonrandomly distributed throughout the human genome, being over-represented in key regions, such as telomeres, gene promoters, and RNA molecules.Current evidence points to the clinical relevance of G4s, particularly in anticancer drug design. Small compounds able to bind and stabilize these structures have been synthesized and their potential to interfere with telomeric functions and/or oncogene expression has been demonstrated.G4s constitute a motif frequently found in aptamers (i.e., synthetic nucleic acids resulting from an in vitro selection process against a target, such as nucleolin). Several aptamers are guanine-rich G4-forming sequences that target proteins with remarkable biological effects.
•Phenolic acids are representative molecules in the diet.•After absorption, they are extensively metabolized in the organism.•Glucuronidation, methylation and sulfation reactions occur in their ...metabolism.•Glucuronated metabolites exert antioxidant action in vivo.•Methylated and glucuronated derivatives increase antimicrobial and antitumor activities.
Phenolic acids are present in our diet in different foods, for example mushrooms. Due to their bioactive properties, phenolic acids are extensively studied and there is evidence of their role in disease prevention. Nevertheless, in vivo, these compounds are metabolized and circulate in the organism as glucuronated, sulphated and methylated metabolites, displaying higher or lower bioactivities. To clarify the importance of the metabolism of phenolic acids, knowledge about the bioactivity of metabolites is extremely important.
In this review, chemical features, biosynthesis and bioavailability of phenolic acids are discussed, as well as the chemical and enzymatic synthesis of their metabolites. Finally, metabolite bioactive properties are compared with that of the corresponding parental compounds.
In the context of recombinant DNA technology, the development of feasible and high-yielding plasmid DNA production processes has regained attention as more evidence for its efficacy as vectors for ...gene therapy and DNA vaccination arise. When producing plasmid DNA in Escherichia coli, a number of biological restraints, triggered by plasmid maintenance and replication as well as culture conditions are responsible for limiting final biomass and product yields. This termed “metabolic burden” can also cause detrimental effects on plasmid stability and quality, since the cell machinery is no longer capable of maintaining an active metabolism towards plasmid synthesis and the stress responses elicited by plasmid maintenance can also cause increased plasmid instability. The optimization of plasmid DNA production bioprocesses is still hindered by the lack of information on the host metabolic responses as well as information on plasmid instability. Therefore, systematic and on-line approaches are required not only to characterise this “metabolic burden” and plasmid stability but also for the design of appropriate metabolic engineering and culture strategies. The monitoring tools described to date rapidly evolve from laborious, off-line and at-line monitoring to online monitoring, at a time-scale that enables researchers to solve these bioprocessing problems as they occur. This review highlights major E. coli biological alterations caused by plasmid maintenance and replication, possible causes for plasmid instability and discusses the ability of currently employed bioprocess monitoring techniques to provide information in order to circumvent metabolic burden and plasmid instability, pointing out the possible evolution of these methods towards online bioprocess monitoring.
Mobile phone usage has been rapidly increasing worldwide. mHealth could efficiently deliver high-quality health care, but the evidence supporting its current effectiveness is still mixed.
We ...performed a systematic review of systematic reviews to assess the impact or effectiveness of mobile health (mHealth) interventions in different health conditions and in the processes of health care service delivery.
We used a common search strategy of five major scientific databases, restricting the search by publication date, language, and parameters in methodology and content. Methodological quality was evaluated using the Measurement Tool to Assess Systematic Reviews (AMSTAR) checklist.
The searches resulted in a total of 10,689 articles. Of these, 23 systematic reviews (371 studies; more than 79,665 patients) were included. Seventeen reviews included studies performed in low- and middle-income countries. The studies used diverse mHealth interventions, most frequently text messaging (short message service, SMS) applied to different purposes (reminder, alert, education, motivation, prevention). Ten reviews were rated as low quality (AMSTAR score 0-4), seven were rated as moderate quality (AMSTAR score 5-8), and six were categorized as high quality (AMSTAR score 9-11). A beneficial impact of mHealth was observed in chronic disease management, showing improvement in symptoms and peak flow variability in asthma patients, reducing hospitalizations and improving forced expiratory volume in 1 second; improving chronic pulmonary diseases symptoms; improving heart failure symptoms, reducing deaths and hospitalization; improving glycemic control in diabetes patients; improving blood pressure in hypertensive patients; and reducing weight in overweight and obese patients. Studies also showed a positive impact of SMS reminders in improving attendance rates, with a similar impact to phone call reminders at reduced cost, and improved adherence to tuberculosis and human immunodeficiency virus therapy in some scenarios, with evidence of decrease of viral load.
Although mHealth is growing in popularity, the evidence for efficacy is still limited. In general, the methodological quality of the studies included in the systematic reviews is low. For some fields, its impact is not evident, the results are mixed, or no long-term studies exist. Exceptions include the moderate quality evidence of improvement in asthma patients, attendance rates, and increased smoking abstinence rates. Most studies were performed in high-income countries, implying that mHealth is still at an early stage of development in low-income countries.
Circular dichroism (CD) has emerged as one of the standard biophysical techniques for the study of guanine-quadruplex (G4) folding, cation effect, and ligand binding. The utility of this technique is ...based on its robustness, ease of use, and requirement of only small quantities of nucleic acid. This experiment is also extendable to the classroom and adaptable to students from graduate school in a multidisciplinary area, bridging chemistry, biochemistry, and medicinal chemistry. Specifically, students employ a solution of a nucleic acid that can adopt a G4 conformation, anneal it in the presence of a metal cation, and assess the folding and topology by the characteristic CD signatures. During the class experiment, it was also possible to interconvert the G4 topology by changing the cation type, and to determine the melting temperature of the G4 structure in the absence and presence of molecules called G4 ligands. The current experiment used the commercially available porphyrin TMPyP4 as a G4 ligand and human telomeric 22AG and mutated oncogene promoter c-MYC G4 structures to illustrate the CD applicability in a context that can be explored or adapted to a student’s course level and topic.
•Human papillomavirus (HPV) has a primordial role in the development of cervical cancer.•Therapies currently available for cervical cancer treatment are reviewed.•The relevance of nucleic-acid-based ...therapies targeting HPV functions is discussed.•HPV oncoprotein silencing is a promising path to explore in cervical cancer treatment.
Novel nucleic acid-based therapeutic approaches as a promising non-invasive solution for the treatment of cervical cancer caused by Human Papillomavirus.
Cervical cancer is the fourth most common cancer among women worldwide and its development is mainly associated with human papillomavirus infection, a highly sexually transmissible virus. The expression of E6 and E7 viral oncoproteins deregulates cell repairing mechanisms through impairment of tumor suppressor protein functions, such as p53 or retinoblastoma protein. Although the implementation of new preventive vaccines has decreased the infection rate and cervical cancer progression, there are still many women who are affected by this pathology. Nowadays, the main treatment often requires the use of invasive techniques. From well-established strategies, like DNA vaccines and gene therapy, to innovative gene silencing technologies; different methodologies are currently under scrutiny that target the E6 and E7 oncoproteins and/or their modes of action.
The aim of this work was to study the antibacterial effect of coriander (Coriandrum sativum) essential oil against Gram-positive and Gram-negative bacteria. Antibacterial susceptibility was evaluated ...using classical microbiological techniques concomitantly with the use of flow cytometry for the evaluation of cellular physiology. Our results showed that coriander oil has an effective antimicrobial activity against all bacteria tested. Also, coriander oil exhibited bactericidal activity against almost all bacteria tested, with the exception of Bacillus cereus and Enterococcus faecalis. Propidium iodide incorporation and concomitant loss of all other cellular functions such as efflux activity, respiratory activity and membrane potential seem to suggest that the primary mechanism of action of coriander oil is membrane damage, which leads to cell death. The results obtained herein further encourage the use of coriander oil in antibacterial formulations due to the fact that coriander oil effectively kills pathogenic bacteria related to foodborne diseases and hospital infections.
Arcobacter genus currently comprises 18 recognized species, among which Arcobacter butzleri, Arcobacter cryaerophilus and Arcobacter skirrowii have been associated with human and animal disease. ...Although these organisms, with special emphasis A. butzleri, are emerging as clinical pathogens, several aspects of their epidemiology and virulence are only starting to be clarified. In vitro human and animal cell culture assays have been used to show that several Arcobacter species can adhere to and invade eukaryotic cells, induce an immune response and produce toxins that damage host cells. In addition, data from genome sequencing highlighted several potential markers that may be helpful candidates for the study and understanding of these mechanisms; however, more work is necessary to clarify the molecular mechanisms involved in Arcobacter virulence. Arcobacter can be considered a relatively robust organism showing to be able to survive in adverse conditions, as the ones imposed by food processing and storage. Moreover, these bacteria have shown increased antibiotic resistance, along with high multidrug resistance. In this review, we seek to update the state-of-the-art concerning Arcobacter distribution, its interaction with the host, the trends of antibiotic resistance, its ability to survive, and finally the use of natural antimicrobials for control of Arcobacter.
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The synthesis and biological evaluation of novel 1-aryl-3-2-, 3- or 4-(thieno3,2-bpyridin-7-ylthio)phenylureas 3, 4 and 5 as VEGFR-2 tyrosine kinase inhibitors, are reported. The ...1-aryl-3-3-(thieno3,2-bpyridin-7-ylthio)phenylureas 4a–4h, with the arylurea in the meta position to the thioether, showed the lowest IC50 values in enzymatic assays (10–206nM), the most potent compounds 4d–4h (IC50 10–28nM) bearing hydrophobic groups (Me, F, CF3 and Cl) in the terminal phenyl ring. A convincing rationalization was achieved for the highest potent compounds 4 as type II VEGFR-2 inhibitors, based on the simultaneous presence of: (1) the thioether linker and (2) the arylurea moiety in the meta position. For compounds 4, significant inhibition of Human Umbilical Vein Endothelial Cells (HUVECs) proliferation (BrdU assay), migration (wound-healing assay) and tube formation were observed at low concentrations. These compounds have also shown to increase apoptosis using the TUNEL assay. Immunostaining for total and phosphorylated (active) VEGFR-2 was performed by Western blotting. The phosphorylation of the receptor was significantly inhibited at 1.0 and 2.5μM for the most promising compounds. Altogether, these findings point to an antiangiogenic effect in HUVECs.
•Protected glucuronide derivatives of p-hydroxybenzoic and cinnamic acids were synthesized.•The compounds revealed higher antimicrobial activity than commercial standards.•The compounds revealed ...higher antimicrobial activity than G. lucidum extract.•The extract was the only one with demelanizing activity against A. niger.•The acetylated glucuronide derivatives could be deprotected to obtain glucuronide metabolites.
Mushroom extracts or isolated compounds may be useful in the search of new potent antimicrobial agents. Herein, it is described the synthesis of protected (acetylated) glucuronide derivatives of p-hydroxybenzoic and cinnamic acids, two compounds identified in the medicinal mushroom Ganoderma lucidum. Their antimicrobial and demelanizing activities were evaluated and compared to the parent acids and G. lucidum extract. p-Hydroxybenzoic and cinnamic acids, as also their protected glucuronide derivatives revealed high antimicrobial (antibacterial and antifungal) activity, even better than the one showed by commercial standards. Despite the variation in the order of parent acids and the protected glucuronide derivatives, their antimicrobial activity was always higher than the one revealed by the extract. Nevertheless, the extract was the only one with demelanizing activity against Aspergillus niger. The acetylated glucuronide derivatives could be deprotected to obtain glucuronide metabolites, which circulate in the human organism as products of the metabolism of the parent compounds.
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