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DNA chains with sequential guanine (G) repeats can lead to the formation of G-quadruplexes (G4), which are found in functional DNA and RNA regions like telomeres and oncogene promoters. The development of molecules with adequate structural features to selectively stabilize G4 structures can counteract cell immortality, highly described for cancer cells, and also downregulate transcription events underlying cell apoptosis and/or senescence processes. We describe here, the efficiency of four highly charged porphyrins-phosphonium conjugates to act as G4 stabilizing agents. The spectrophotometric results allowed to select the conjugates P2-PPh3 and P3-PPh3 as the most promising ones to stabilize selectively G4 structures. Molecular dynamics simulation experiments were performed and support the preferential binding of P2-PPh3 namely to MYC and of P3-PPh3 to KRAS. The ability of both ligands to block the activity of Taq polymerase was confirmed and also their higher cytotoxicity against the two melanoma cell lines A375 and SK-MEL-28 than to immortalized skin keratinocytes. Both ligands present efficient cellular uptake, nuclear co-localization and high ability to generate 1O2 namely when interacting with G4 structure. The obtained data points the synthesized porphyrins as promising ligands to be used in a dual approach that can combine G4 stabilization and Photodynamic therapy (PDT).
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Alzheimer's disease is characterized by a progressive deterioration of cognitive function and memory loss, and it is closely associated with the dysregulation of cholinergic neurotransmission. Since acetylcholinesterase (AChE) is a critical enzyme in the nervous system, responsible for breaking down the neurotransmitter acetylcholine, its inhibition holds a significant interest in the treatment of various neurological disorders. Therefore, it is crucial to develop efficient AChE inhibitors capable of increasing acetylcholine levels, ultimately leading to improved cholinergic neurotransmission. The results reported here represent a step forward in the development of novel thiazoloindazole-based compounds that have the potential to serve as effective AChE inhibitors. Molecular docking studies revealed that certain of the evaluated nitroindazole-based compounds outperformed donepezil, a well-known AChE inhibitor used in Alzheimer's disease treatment. Sustained by these findings, two series of compounds were synthesized. One series included a triazole moiety (Tl45a-c), while the other incorporated a carbazole moiety (Tl58a-c). These compounds were isolated in yields ranging from 66 to 87% through nucleophilic substitution and Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reactions. Among the synthesized compounds, the thiazoloindazole-based 6b core derivatives emerged as selective AChE inhibitors, exhibiting remarkable IC50 values of less than 1.0 µM. Notably, derivative Tl45b displays superior performance as an AChE inhibitor, boasting the lowest IC50 (0.071 ± 0.014 µM). Structure-activity relationship (SAR) analysis indicated that derivatives containing the bis(trifluoromethyl)phenyl-triazolyl group demonstrated the most promising activity against AChE, when compared to more rigid substituents such as carbazolyl moiety. The combination of molecular docking and experimental synthesis provides a suitable and promising strategy for the development of new efficient thiazoloindazole-based AChE inhibitors.
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Acetilcolinesterasa , Inhibidores de la Colinesterasa , Indazoles , Simulación del Acoplamiento Molecular , Tiazoles , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/síntesis química , Simulación del Acoplamiento Molecular/métodos , Indazoles/farmacología , Indazoles/química , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/efectos de los fármacos , Humanos , Tiazoles/farmacología , Tiazoles/química , Diseño de Fármacos , Relación Estructura-ActividadRESUMEN
Antimicrobial photodynamic treatment (aPDT) offers an alternative option for combating microbial pathogens, and in this way, addressing the challenges of growing antimicrobial resistance. In this promising and effective approach, cationic porphyrins and related macrocycles have emerged as leading photosensitizers (PS) for aPDT. In general, their preparation occurs via N-alkylation of nitrogen-based moieties with alkyl halides, which limits the ability to fine-tune the features of porphyrin-based PS. Herein, is reported that the conjugation of porphyrin macrocycles with triphenylphosphonium units created a series of effective cationic porphyrin-based PS for aPDT. The presence of positive charges at both the porphyrin macrocycle and triphenylphosphonium moieties significantly enhances the photodynamic activity of porphyrin-based PS against both Gram-positive and Gram-negative bacterial strains. Moreover, bacterial photoinactivation is achieved with a notable reduction in irradiation time, exceeding 50%, compared to 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphyrin (TMPyP), used as the reference and known as good PS. The improved capability of the porphyrin macrocycle to generate singlet oxygen combined with the enhanced membrane interaction promoted by the presence of triphenylphosphonium moieties represents a promising approach to developing porphyrin-based PS with enhanced photosensitizing activity.
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Research has demonstrated the presence of viruses in wastewater (WW), which can remain viable for a long period, posing potential health risks. Conventional WW treatment methods involving UV light, chlorine and ozone efficiently reduce microbial concentrations, however, they produce hazardous byproducts and microbial resistance that are detrimental to human health and the ecosystem. Hence, there is a need for novel disinfection techniques. Antimicrobial Photodynamic Inactivation (PDI) emerges as a promising strategy, utilizing photosensitizers (PS), light, and dioxygen to inactivate viruses. This study aims to assess the efficacy of PDI by testing methylene blue (MB) and the cationic porphyrin TMPyP as PSs, along a low energy consuming white light source (LED) at an irradiance of 50 mW/cm2, for the inactivation of bacteriophage Phi6. Phi6 serves as an enveloped RNA-viruses surrogate model in WW. PDI experiments were conducted in a buffer solution (PBS) and real WW matrices (filtered and non-filtered). Considering the environmental release of the treated effluents, this research also evaluated the ecotoxicity of the resulting solution (post-PDI treatment effluent) on the model organism Daphnia magna, following the Organisation for Economic Cooperation and Development (OECD) immobilization technical 202 guideline. Daphnids were exposed to WW containing the tested PS at different concentrations and dilutions (accounting for the dilution factor during WW release into receiving waters) over 48 h. The results indicate that PDI with MB efficiently inactivated the model virus in the different aqueous matrices, achieving reductions superior to 8 log10 PFU/mL, after treatments of 5 min in PBS and of ca. 90 min in WW. Daphnids survival increased when subjected to the PDI-treated WW with MB, considering the dilution factor. Overall, the effectiveness of PDI in eliminating viruses in WW, the fading of the toxic effects on daphnids after MB' irradiation and the rapid dilution effect upon WW release in the environment highlight the possibility of using MB in WW PDI-disinfection.
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Daphnia , Desinfección , Azul de Metileno , Fármacos Fotosensibilizantes , Aguas Residuales , Aguas Residuales/química , Desinfección/métodos , Daphnia/efectos de los fármacos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Animales , Azul de Metileno/farmacología , Azul de Metileno/química , Porfirinas/química , Porfirinas/farmacología , Bacteriófagos/efectos de los fármacos , Eliminación de Residuos Líquidos/métodos , Purificación del Agua/métodos , EcotoxicologíaRESUMEN
In vivo, cells interact with the extracellular matrix (ECM), which provides a multitude of biophysical and biochemical signals that modulate cellular behavior. Inspired by this, we explored a new methodology to develop a more physiomimetic polysaccharide-based matrix for 3D cell culture. Maleimide-modified alginate (AlgM) derivatives were successfully synthesized using DMTMM to activate carboxylic groups. Thiol-terminated cell-adhesion peptides were tethered to the hydrogel network to promote integrin binding. Rapid and efficient in situ hydrogel formation was promoted by thiol-Michael addition "click" chemistry via maleimide reaction with thiol-flanked protease-sensitive peptides. Alginate derivatives were further ionically crosslinked by divalent ions present in the medium, which led to greater stability and allowed longer cell culture periods. By tailoring alginate's biofunctionality we improved cell-cell and cell-matrix interactions, providing an ECM-like 3D microenvironment. We were able to systematically and independently vary biochemical and biophysical parameters to elicit specific cell responses, creating custom-made 3D matrices. DMTMM-mediated maleimide incorporation is a promising approach to synthesizing AlgM derivatives that can be leveraged to produce ECM-like matrices for a broad range of applications, from in vitro tissue modeling to tissue regeneration.
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Alginatos , Química Clic , Matriz Extracelular , Hidrogeles , Maleimidas , Compuestos de Sulfhidrilo , Humanos , Alginatos/química , Adhesión Celular/efectos de los fármacos , Reactivos de Enlaces Cruzados/química , Matriz Extracelular/metabolismo , Matriz Extracelular/química , Hidrogeles/química , Hidrogeles/síntesis química , Maleimidas/química , Compuestos de Sulfhidrilo/químicaRESUMEN
BACKGROUND AND PURPOSE: Cerebral amyloid angiopathy is characterized by amyloid ß deposition in leptomeningeal and superficial cortical vessels. Cognitive impairment is common and may occur independent of concomitant Alzheimer disease neuropathology. It is still unknown which neuroimaging findings are associated with dementia in cerebral amyloid angiopathy and whether they are modulated by sex. This study compared MR imaging markers in patients with cerebral amyloid angiopathy with dementia or mild cognitive impairment or who are cognitively unimpaired and explored sex-specific differences. MATERIALS AND METHODS: We studied 58 patients with cerebral amyloid angiopathy selected from the cerebrovascular and memory outpatient clinics. Clinical characteristics were collected from clinical records. Cerebral amyloid angiopathy was diagnosed on MR imaging on the basis of the Boston criteria. Visual rating scores for atrophy and other imaging features were independently assessed by 2 senior neuroradiologists. RESULTS: Medial temporal lobe atrophy was higher for those with cerebral amyloid angiopathy with dementia versus those cognitively unimpaired (P = .015), but not for those with mild cognitive impairment. This effect was mainly driven by higher atrophy in men with dementia, compared with women with and without dementia (P = .034, P = .012; respectively) and with men without dementia (P = .012). Enlarged perivascular spaces in the centrum semiovale were more frequent in women with dementia versus men with and without dementia (P = .021, P = .011; respectively) and women without dementia (P = .011). CONCLUSIONS: Medial temporal lobe atrophy was more prominent in men with dementia, whereas women showed a higher number of enlarged perivascular spaces in the centrum semiovale. Overall, this finding suggests differential pathophysiologic mechanisms with sex-specific neuroimaging patterns in cerebral amyloid angiopathy.
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Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Masculino , Humanos , Femenino , Péptidos beta-Amiloides , Angiopatía Amiloide Cerebral/complicaciones , Angiopatía Amiloide Cerebral/diagnóstico por imagen , Angiopatía Amiloide Cerebral/patología , Enfermedad de Alzheimer/patología , Imagen por Resonancia Magnética , Atrofia/complicacionesRESUMEN
The implementation of CRISPR technology in large animals requires further improvements in embryo manipulation and transfer to be applied with commercial purposes. In this study we report (a) developmental competence of CRISPR/Cas microinjected zygotes subjected to in vitro culture in large scale programs in sheep; (b) pregnancy outcomes after early-stage (2-8-cell) embryo transfer into the oviduct or the uterine horn; and (c) embryo survival and birth rate after vitrification/warming of CRISPR/Cas microinjected zygotes. Experiment 1 consisted of a retrospective analysis to evaluate embryo developmental rate of in vitro produced zygotes subjected to CRISPR/Cas microinjection (n = 7,819) compared with a subset of non-microinjected zygotes (n = 701). Development rates to blastocyst on Day 6 were 20.0% for microinjected zygotes and 44.9% for non-injected zygotes (P < 0.05). In Experiment 2, CRISPR/Cas microinjected zygotes were transferred on Day 2 after in vitro fertilization (2-8 cell embryos) into the oviductal ampulla (n = 262) or into the uterine horn (n = 276) in synchronized recipient ewes at prefixed time (i.e., approximately two days after ovulation). Pregnant/transferred recipients (24.0% vs. 25.0%), embryo survival/transferred embryos (6.9% vs. 6.2%), and born lambs/pregnant embryos (72.2% vs. 100.0%) did not differ significantly in the two groups. In Experiment 3, CRISPR/Cas microinjected zygotes were maintained under in vitro culture until blastocyst stage (Day 6), and subjected to vitrification/warming via the Cryotop method (n = 474), while a subset of embryos were left fresh as control group (n = 75). Embryos were transferred into the uterine horn of recipient females at prefixed time 8.5 days after the estrous synchronization treatment (i.e., approximately six days after ovulation). Pregnancy rate (30.8% vs. 48.0%), embryo survival rate (14.8% vs. 21.3%), and birth rate (85.7% vs. 75.0%) were not different (PNS) between vitrified and fresh embryos, respectively. In conclusion, the current study in sheep embryos reports (a) suitable developmental rate after CRISPR/Cas microinjection (i.e., 20%), even though it was lower than non-microinjected zygotes; (b) similar outcomes when Day 2-embryos were placed into the uterine horn instead of the oviduct, avoiding both time-consuming and invasive oviduct manipulation, and extended in vitro culture during one week; (c) promising pregnancy and birth rates obtained with vitrification of CRISPR/Cas microinjected embryos. This knowledge on in vitro embryo development, timing of embryo transfer, and cryopreservation of CRISPR/Cas microinjected zygotes have practical implications for the implementation of genome editing technology in large animals.
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Embrión de Mamíferos , Ganado , Embarazo , Animales , Ovinos , Femenino , Estudios Retrospectivos , Cigoto , Blastocisto , Criopreservación/veterinaria , VitrificaciónRESUMEN
Starch is a biodegradable and biocompatible carbohydrate that, when combined with bioactive molecules, can be processed as biomimetic platforms with enhanced performance, allowing its use as active wound dressing materials. Porphyrinoid photosensitizers can tune the physicochemical/functional profile of biomacromolecules, allowing their use in anti-infective strategies. In this work, the feasibility of using the cationic 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphyrin tetraiodide (TMPyP) to enhance the physicochemical, mechanical, antimicrobial performance, and wound healing ability of casted starch-based films was studied. TMPyP conferred a reddish coloration to the films, maintaining their pristine transparency. It increased by 87 % the films hydrophobicity and, depending on the TMPyP used, conferred mobility to the starch polymeric chains. Starch/TMPyP-based films effectively photoinactivated Escherichia coli (>99.99 %) and favored the wound healing process, even in the absence of light. Therefore, the incorporation of TMPyP into starch-based formulations revealed to be a promising strategy to tune the films compaction degree while giving rise to water tolerant and photosensitive biomaterials that can act as multitarget antimicrobial medical dressings and glycocarriers of active compounds relevant for effective skin wound healing.
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Antiinfecciosos , Fármacos Fotosensibilizantes , Fármacos Fotosensibilizantes/farmacología , Almidón/química , Antiinfecciosos/química , Vendajes , Escherichia coli , Cicatrización de HeridasRESUMEN
Hookworm disease is a major global public health concern, annually affecting 500-700 million of the world's poorest people. The World Health Organization is targeting the elimination of hookworm as a public health problem by 2030 using a strategy of mass drug administration (MDA) to at-risk human populations. However, in Southeast Asia and the Pacific the zoonotic hookworm species, Ancylostoma ceylanicum, is endemic in dogs and commonly infects people. This presents a potential impediment to the effectiveness of MDA that targets only humans. Here, we develop a novel multi-host (dog and human) transmission model of A. ceylanicum and compare the effectiveness of human-only and "One Health" (human plus dog) MDA strategies under a range of eco-epidemiological assumptions. We show that One Health interventions-targeting both dogs and humans-could suppress prevalence in humans to ≤ 1% by the end of 2030, even with only modest coverage (25-50%) of the animal reservoir. With increasing coverage, One Health interventions may even interrupt transmission. We discuss key unresolved questions on the eco-epidemiology of A. ceylanicum, the challenges of delivering MDA to animal reservoirs, and the growing importance of One Health interventions to human public health.
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This study investigated the effect of age and follicle stimulating hormone (FSH) treatment on the estradiol (E2) plasma concentration, ovarian follicle development, endometrial histomorphometry, and ultrasonographic parameters of the ovaries and uterus in prepubertal gilts. Thirty-five prepubertal gilts were grouped according to age (140 or 160 d), and within each age, gilts were allotted to receive 100 mg of FSH (treated; G140 + FSH [n = 10] and G160 + FSH [n = 7]) or saline solution (control; G140 + control [n = 10] and G160 + control [n = 8]). The total dose of FSH was divided into 6 similar doses administered every 8 h (days 0-2). Before and after FSH treatment, blood sample was collected, and transabdominal scanning of the ovaries and uterus was performed. Twenty-four hours after the last FSH injection, the gilts were slaughtered and their ovaries and uterus were processed for histological and histomorphometric analysis. The histomorphometric parameters of the uterus differed (P < 0.05) between prepubertal gilts at 160 d and 140 d of age. Moreover, changes (P < 0.05) in uterine and ovarian ultrasound images occurred between 140 and 160 d of age. Age and FSH treatment did not affect (P > 0.05) E2 plasma concentrations. Follicle stimulating hormone treatment did not affect (P > 0.05) the early stage of folliculogenesis in the prepubertal gilts; however, the number of early atretic follicles decreased (P < 0.05) after the FSH treatment. Follicle stimulating hormone administration increased (P < 0.05) the number of medium follicles and decreased (P < 0.05) the number of small follicles in 140 and 160 d old gilts. In the endometrium, luminal/glandular epithelium height and glandular diameter increased (P < 0.05) after FSH treatment. Thus, injections of 100 mg of FSH stimulate the endometrium epithelium and induce follicular growth to a medium follicle size without affecting the preantral stages in prepubertal gilts; also, the uterine macroscopic morphometry does not change from 140 to 160 d of age.
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Hormona Folículo Estimulante , Ovario , Femenino , Porcinos , Animales , Hormona Luteinizante , Folículo Ovárico/fisiología , Estradiol/farmacología , Sus scrofa , Hormona Folículo Estimulante Humana , ÚteroRESUMEN
Safety assessment of carbon nanomaterials is of paramount importance since they are on the frontline for applications in sensing, bioimaging and drug delivery. The biocompatibility and safety of functionalized nanodiamonds (NDs) are here addressed through the study of the pro-inflammatory response of RAW-264.7 macrophages exposed to new nanodiamonds@corrole hybrids. The corrole unit selected is as a prototype for a hydrophobic organic molecule that can function as a NIR fluorophore reporter, an optical sensor, a photodynamic therapy agent or a photocatalyst. The new functional nanohybrids containing detonated nanodiamonds (NDs) were obtained through esterification using carboxylated NDs and glycol corroles. The success of the covalent functionalization via carbodiimide activation was confirmed through X-ray photoelectron spectroscopy (XPS), Raman and Fourier transform infrared (FTIR) spectroscopy. The UV-vis absorption and emission spectra of the hybrids are additive with respect to the corrole features. The cellular uptake, localization, cell viability and effects on immune cell activation of the new hybrids and of the precursors were carefully investigated using RAW-264.7 macrophages. Overall results showed that the ND@corrole hybrids had no pro-inflammatory effects on the RAW-264.7 macrophage cell line, making them an ideal candidate for a wide range of biomedical applications.
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Nanodiamantes , Porfirinas , Nanodiamantes/química , Sistemas de Liberación de Medicamentos , Porfirinas/farmacología , MacrófagosRESUMEN
This paper aimed to assess the impact of the intensive use of biological control on the technical efficiency of the Brazilian agricultural sector. The study also considered the influence of factors such as technical assistance, rural financing, and membership in cooperatives or class entities on efficiency measures. It was estimated stochastic production frontiers for regions intensively using and not using biological control, considering potential selection bias. Results demonstrate that areas with intensive use of biological pest management have a 0.863 technical efficiency score, while this score is 0.823 for nonintensive areas. This means that the intensive regions would be closer to their efficiency frontiers. Additionally, technical assistance and membership in cooperative or class entities increase efficiency by 6 and 2.5%, respectively. It can be concluded that the intensive adoption of biological control can raise the productive performance of the Brazilian agricultural sector. Therefore, it must be highlighted the importance of formulating joint policies (e.g., credit+rural extension) for the adoption of biological control to be a feasible option to promote the sustainable development of the Brazilian agricultural sector.
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With the increasing data rate requirements on short-reach links, the recent standardization of unamplified coherent optical systems is paving the way for a cost and power-effective solution, targeting a massive deployment in the near future. However, unamplified systems are introducing new challenges. Particularly, the performance is highly dependent on the peak-to-average power ratio (PAPR) of the transmitted signal, which puts at question the use of the typical constellation formats. In this work, we use an end-to-end deep learning framework to optimize the geometry of different constellation sizes, ranging from 8- to 128-ary constellations. In general, it is shown that the performance of these systems is maximized with constellations whose outer symbols are disposed in a square shape, owing to the minimization of the real-valued PAPR. Following this premise, we experimentally demonstrate that odd-bit constellations can be significantly optimized for unamplified coherent links, achieving power budget gains in the range of 0.5-3 dB through the geometric optimization of 8-, 32- and 128-ary constellations.
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The World Health Organization's revised NTD Roadmap and the newly launched Guidelines target elimination of schistosomiasis as a public health problem in all endemic areas by 2030. Key to meeting this goal is elucidating how selective pressures imposed by interventions shape parasite populations. Our aim was to identify any differential impact of a unique cluster-randomized tri-armed elimination intervention (biannual mass drug administration (MDA) applied alone or in association with either mollusciciding (snail control) or behavioural change interventions) across two Zanzibarian islands (Pemba and Unguja) on the population genetic composition of Schistosoma haematobium over space and time. Fifteen microsatellite loci were used to analyse individual miracidia collected from infected individuals across islands and intervention arms at the start (2012 baseline: 1,522 miracidia from 176 children; 303 from 43 adults; age-range 6-75, mean 12.7 years) and at year 5 (2016: 1,486 miracidia from 146 children; 214 from 25 adults; age-range 9-46, mean 12.4 years). Measures of genetic diversity included allelic richness (Ar), Expected (He) and Observed heterozygosity (Ho), inbreeding coefficient (FST), parentage analysis, estimated worm burden, worm fecundity, and genetic sub-structuring. There was little evidence of differential selective pressures on population genetic diversity, inbreeding or estimated worm burdens by treatment arm, with only the MDA+snail control arm within Unguja showing trends towards reduced diversity and altered inbreeding over time. The greatest differences overall, both in terms of parasite fecundity and genetic sub-structuring, were observed between the islands, consistent with Pemba's persistently higher mean infection intensities compared to neighbouring Unguja, and within islands in terms of infection hotspots (across three definitions). These findings highlight the important contribution of population genetic analyses to elucidate extensive genetic diversity and biological drivers, including potential gene-environmental factors, that may override short term selective pressures imposed by differential disease control strategies. Trial Registration: ClinicalTrials.gov ISRCTN48837681.
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Antihelmínticos , Esquistosomiasis Urinaria , Animales , Antihelmínticos/uso terapéutico , Genética de Población , Islas , Praziquantel/uso terapéutico , Schistosoma haematobium/genética , Esquistosomiasis Urinaria/tratamiento farmacológico , Esquistosomiasis Urinaria/epidemiología , Esquistosomiasis Urinaria/prevención & control , Caracoles/genética , Caracoles/parasitología , Tanzanía/epidemiologíaRESUMEN
Telomerase, oncogenes and tumor suppressors are closely associated with tumour occurrence, therefore these structures are being recognized as targets for the development of new anticancer drugs. The efficacy of several molecules in telomerase inhibition and regulation of genes expression, by adduct formation with G-quadruplexes (G4), has been studied by biophysical and biochemical methods with promising results. We report here the synthesis and structural characterization of a small positively charged diketopyrrolo[3,4-c]pyrrole derivative, identified as DPP(PyMe)2, that showed very promising results as G4 stabilizing ligand. The data obtained from UV-Vis and fluorescence experiments suggest that DPP(PyMe)2 presents high affinity to G4 structures. Docking studies and molecular dynamics simulations unraveled the binding modes of the ligand with four G4 structures. The obtained results also allowed us to conclude that the DPP(PyMe)2 ligand binds into the top G-tetrad or in a mixed binding mode depending on the GQ structure. A remarkable selectivity of DPP(PyMe)2 for c-MYC and KRAS 32R in the presence of ds26 was observed by circular dichroism (CD) and fluorescence resonance energy transfer (FRET) melting experiments. CD titrations revealed a stabilization higher than 30 °C in the case of c-MYC G4 structure and, for the same sequence, DPP(PyMe)2 showed the ability to block the activity of Taq polymerase in a dose-dependent manner. The subcellular localization obtained with confocal microscopy corroborates the results obtained by the other techniques and the obtained data suggest that DPP(PyMe)2 is an attractive ligand for the development of G4 labelling probes.
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G-Cuádruplex , ADN/química , Ligandos , Pirroles/farmacología , TelómeroRESUMEN
In this study, we report the preparation of new mono-charged benzoporphyrin complexes by reaction of the appropriate neutral benzoporphyrin with (2,2'-bipyridine)dichloroplatinum(II) and of the analogs' derivatives synthesized through alkylation of the neutral scaffold with iodomethane. All derivatives were incorporated into polyvinylpyrrolidone (PVP) micelles. The ability of the resultant formulations to generate reactive oxygen species was evaluated, mainly the singlet oxygen formation. Then, the capability of the PVP formulations to act as photosensitizers against bladder cancer cells was assessed. Some of the studied formulations were the most active photosensitizers causing a decrease in HT-1376 cells' viability. This creates an avenue to further studies related to bladder cancer cells.
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Antineoplásicos/farmacología , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Porfirinas/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Antineoplásicos/síntesis química , Antineoplásicos/química , Cationes/síntesis química , Cationes/química , Cationes/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Porfirinas/síntesis química , Porfirinas/química , Relación Estructura-Actividad , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Pathogenic viruses are frequently present in marine and estuarine waters, due to poor wastewater (WW) treatments, which consequently affect water quality and human health. Chlorination, one of the most common methods used to ensure microbiological safety in tertiarily treated effluents, may lead to the formation of toxic chemical disinfection by-products on reaction with organic matter present in the effluents. Antimicrobial photodynamic therapy (aPDT) can be a promising disinfecting approach for the inactivation of pathogens, without the formation of known toxic by-products. Additionally, some studies have reported the potentiator effect on aPDT of some compounds, such as potassium iodide (KI) and hydrogen peroxide (H2O2). In the present study, the aPDT efficiency of a PS formulation constituted of five cationic porphyrins (Form) in the inactivation of E. coli T4-like bacteriophage, a model of mammalian viruses, in different aqueous matrices with different organic matter content, was evaluated. Photoinactivation studies were performed at different concentrations of Form and in the presence of the adjuvants KI and H2O2. The results showed that the efficiency of bacteriophage photoinactivation is correlated with the Form concentration, the amount of the organic matter in WW, and the adjuvant type. Form can be an effective alternative to controlling viruses in WW, particularly if combined with H2O2, allowing to significantly reduce PS concentration and treatment time. When combined with KI, the Form is less effective in inactivating T4-like bacteriophage in WW.
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The stability of parasite populations is regulated by density-dependent processes occurring at different stages of their life cycle. In dioecious helminth infections, density-dependent fecundity is one such regulatory process that describes the reduction in egg production by female worms in high worm burden within-host environments. In human schistosomiasis, the operation of density-dependent fecundity is equivocal and investigation is hampered by the inaccessibility of adult worms that are located intravascularly. Current understanding is almost exclusively limited to data collected from two human autopsy studies conducted over 40 years ago, with subsequent analyses having reached conflicting conclusions. Whether egg production is regulated in a density-dependent manner is key to predicting the effectiveness of interventions targeting the elimination of schistosomiasis and to the interpretation of parasitological data collected during monitoring and evaluation activities. Here, we revisit density-dependent fecundity in the two most globally important human Schistosoma spp. using a statistical modelling approach that combines molecular inference on the number of parents/adult worms in individual human hosts with parasitological egg count data from mainland Tanzania and Zanzibar. We find a non-proportional relationship between S. haematobium egg counts and inferred numbers of female worms, providing the first clear evidence of density-dependent fecundity in this schistosome species. We do not find robust evidence for density-dependent fecundity in S. mansoni because of high sensitivity to some modelling assumptions and the lower statistical power of the available data. We discuss the strengths and limitations of our model-based analytical approach and its potential for improving our understanding of density dependence in schistosomiasis and other human helminthiases earmarked for elimination.