RESUMEN

Aim: To identify potential antischistosomal agents through 3D pharmacophore-based virtual screening of US FDA approved drugs. Materials & methods: A comprehensive virtual screening was conducted on a dataset of 10,000 FDA approved drugs, employing praziquantel as a template. Promising candidates were selected and assessed for their impact on Schistosoma mansoni viability in vitro and in vivo using S. mansoni infected mice. Results & conclusion: Among the selected drugs, betamethasone and doxazosin demonstrated in vitro efficacy, with effective concentration 50% (EC50) values ranging from 35 to 60 µM. In vivo studies revealed significant (>50%) reductions in worm burden for both drugs. These findings suggest that betamethasone and doxazosin hold promise for repurposing in treating schistosomiasis. Additionally, the study showcases a useful approach for identifying new antischistosomal drugs.

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Discovering new treatments for #schistosomiasis is crucial[Formula: see text]. Our study used virtual screening to identify potential antischistosomal drugs from US FDA approved compounds [Formula: see text]. Promising results in vitro and in vivo. [Formula: see text] #drugdiscovery #tropicaldiseases.

RESUMEN

Poly(p-anisidine) (PPA) is a polyaniline derivative presenting a methoxy (-OCH3) group at the para position of the phenyl ring. Considering the important role of conjugated polymers in novel technological applications, a systematic, combined experimental and theoretical investigation was performed to obtain more insight into the crystallization process of PPA. Conventional oxidative polymerization of p-anisidine monomer was based on a central composite rotational design (CCRD). The effects of the concentration of the monomer, ammonium persulfate (APS), and HCl on the percentage of crystallinity were considered. Several experimental techniques such as X-ray Diffraction (XRD), Scanning Electron Microscopy (SEM), multifractal analysis, Nuclear Magnetic Resonance (13C NMR), Fourier-transform Infrared spectroscopy (FTIR), and complex impedance spectroscopy analysis, in addition to Density Functional Theory (DFT), were employed to perform a systematic investigation of PPA. The experimental treatments resulted in different crystal structures with a percentage of crystallinity ranging from (29.2 ± 0.6)% (PPA1HT) to (55.1 ± 0.2)% (PPA16HT-HH). A broad halo in the PPA16HT-HH pattern from 2θ = 10.0-30.0° suggested a reduced crystallinity. Needle and globular-particle morphologies were observed in both samples; the needle morphology might have been related to the crystalline contribution. A multifractal analysis showed that the PPA surface became more complex when the crystallinity was reduced. The proposed molecular structures of PPA were supported by the high-resolution 13C NMR results, allowing us to access the percentage of head-to-tail (HT) and head-to-head (HH) molecular structures. When comparing the calculated and experimental FTIR spectra, the most pronounced changes were observed in ν(C-H), ν(N-H), ν(C-O), and ν(C-N-C) due to the influence of counterions on the polymer backbone as well as the different mechanisms of polymerization. Finally, a significant difference in the electrical conductivity was observed in the range of 1.00 × 10-9 S.cm-1 and 3.90 × 10-14 S.cm-1, respectively, for PPA1HT and PPA16HT-HH.

Asunto(s)

Polímeros , Compuestos de Anilina , Cristalización/métodos , Polímeros/química , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos X

RESUMEN

The Piper species are a recognized botanical source of a broad structural diversity of lignans and its derivatives. For the first time, Piper tectoniifolium Kunth is presented as a promising natural source of the bioactive (-)-grandisin. Phytochemical analyses of extracts from its leaves, branches and inflorescences showed the presence of the target compound in large amounts, with leaf extracts found to contain up to 52.78% in its composition. A new HPLC-DAD-UV method was developed and validated to be selective for the identification of (-)-grandisin being sensitive, linear, precise, exact, robust and with a recovery above 90%. The absolute configuration of the molecule was determined by X-ray diffraction. Despite the identification of several enantiomers in plant extracts, the major isolated substance was characterized to be the (-)-grandisin enantiomer. In vascular reactivity tests, it was shown that the grandisin purified from botanical extracts presented an endothelium-dependent vasorelaxant effect with an IC50 of 9.8 ± 1.22 µM and around 80% relaxation at 30 µM. These results suggest that P. tectoniifolium has the potential to serve as a renewable source of grandisin on a large scale and the potential to serve as template for development of new drugs for vascular diseases with emphasis on disorders related to endothelial disfunction.

Asunto(s)

Furanos/química , Lignanos/química , Piper/química , Extractos Vegetales/química , Furanos/metabolismo , Lignanos/metabolismo , Piper/metabolismo

RESUMEN

This study presents a green synthesis route to silver nanoparticles (AgNPs) stabilized with cashew gum (CG) or carboxymethylated cashew gum (CCG) using microwave-assisted synthesis and evaluates their antibacterial activity. The antimicrobial activity was measured by determining the minimum inhibitory concentration (MIC) with Staphylococcus aureus and Escherichia coli. In both cases of the presence of CG and CCG, it was found that higher pH lead to more efficient conversion of silver nitrate to AgNPs with well dispersed, spherical and stable particles as well as low crystallinity. CCG-capped AgNPs were slightly smaller (137.0 and 96.3 nm) than those coated with non-modified gum (144.7 and 100.9 nm). The samples presented promising antibacterial activity, especially on Gram-negative bacteria, resulting in significant membrane damage on treated bacteria in comparison to the untreated control, observed by atomic force microscopy. Thus, a quick and efficient synthesis route was applied to produce CGAgNPs and CCGAgNPs with antimicrobial potential.

Asunto(s)

Anacardium , Antibacterianos , Nanopartículas del Metal , Gomas de Plantas , Plata , Antibacterianos/administración & dosificación , Antibacterianos/química , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Nanopartículas del Metal/administración & dosificación , Nanopartículas del Metal/química , Pruebas de Sensibilidad Microbiana , Microondas , Gomas de Plantas/administración & dosificación , Gomas de Plantas/química , Plata/administración & dosificación , Plata/química , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrollo

RESUMEN

In synthesis of silver nanoparticles (AgNPs), the composition of the stabilizer used can be closely related to the effectiveness of the synthesis and to the shape of the final nanoparticles. Recently, the use of collagen as an effective nanoparticle stabilization agent was reported. In this work, synthesis of silver nanoparticles using mixed capping agents is reported. The capping agents used were cashew gum-hydrolyzed collagen; kappa carrageenan-hydrolyzed collagen, and agar-hydrolyzed collagen. We evaluated antibacterial action against Gram-positive and Gram-negative bacteria, as well as antifungal activity and cytotoxicity. Homogenized mixtures of collagen and aqueous cashew gum, carrageenan or agar respectively were used to produce the nanoparticles AgNPcolCashew, AgNPcolCarr and AgNPcolAgar. AgNP characterization was performed using Uv-vis, XRD, TEM and DLS and the biological activities were assayed using MIC and MBC analyses for both antibacterial and antifungal application. Results showed that the AgNPcollcar sample showed the strongest bacterial inhibition with MIC values of 62.5 and 31.25 µM/mL Ag against E. coli and P. aeruginosa respectively. Interestingly, AgNPcollAgar also presented the lowest cytotoxicity when compared with other AgNPs and AgNO3.

Asunto(s)

Colágeno/química , Nanopartículas del Metal/química , Polímeros/química , Plata/química , Plata/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Antibacterianos/toxicidad , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Antifúngicos/toxicidad , Candida albicans/efectos de los fármacos , Técnicas de Química Sintética , Escherichia coli/efectos de los fármacos , Hemólisis/efectos de los fármacos , Hidrólisis , Macrófagos Peritoneales/efectos de los fármacos , Ratones , Pruebas de Sensibilidad Microbiana , Nanotecnología , Pseudomonas aeruginosa/efectos de los fármacos , Ovinos , Plata/toxicidad

Asunto(s)

Anacardium/química , Antiinfecciosos/química , Antineoplásicos/química , Cobre/química , Nanopartículas del Metal/química , Gomas de Plantas/química , Animales , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Supervivencia Celular , Sulfato de Cobre/química , Sulfato de Cobre/toxicidad , Eritrocitos/citología , Macrófagos/citología , Nanopartículas del Metal/toxicidad , Ratones , Ratones Endogámicos BALB C , Ovinos , Staphylococcus aureus/efectos de los fármacos , Propiedades de Superficie , Factores de Tiempo

RESUMEN

Schistosomiasis, caused by helminth flatworms of the genus Schistosoma, is an infectious disease mainly associated with poverty that affects millions of people worldwide. Since treatment for this disease relies only on the use of praziquantel, there is an urgent need to identify new antischistosomal drugs. Piplartine is an amide alkaloid found in several Piper species (Piperaceae) that exhibits antischistosomal properties. The aim of this study was to evaluate the structure­function relationship between piplartine and its five synthetic analogues (19A, 1G, 1M, 14B and 6B) against Schistosoma mansoni adult worms, as well as its cytotoxicity to mammalian cells using murine fibroblast (NIH-3T3) and BALB/cN macrophage (J774A.1) cell lines. In addition, density functional theory calculations and in silico analysis were used to predict physicochemical and toxicity parameters. Bioassays revealed that piplartine is active against S. mansoni at low concentrations (5⁻10 µM), but its analogues did not. In contrast, based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, piplartine exhibited toxicity in mammalian cells at 785 µM, while its analogues 19A and 6B did not reduce cell viability at the same concentrations. This study demonstrated that piplartine analogues showed less activity against S. mansoni but presented lower toxicity than piplartine.

Asunto(s)

Antihelmínticos/farmacología , Piperidonas/farmacología , Extractos Vegetales/farmacología , Schistosoma mansoni/efectos de los fármacos , Células 3T3 , Animales , Antihelmínticos/química , Antihelmínticos/toxicidad , Cricetinae , Fibroblastos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Piper/química , Piperidonas/química , Piperidonas/toxicidad , Extractos Vegetales/química , Extractos Vegetales/toxicidad , Relación Estructura-Actividad Cuantitativa , Caracoles

RESUMEN

Schistosomiasis is a disease caused by parasites of the genus Schistosoma, currently affecting more than 200 million people. Among the various species of this parasite that infect humans, S. mansoni is the most common. Pharmacological treatment is limited to the use of a single drug, praziquantel (PZQ), despite reports of parasite resistance and low efficacy. It is therefore necessary to investigate new potential schistosomicidal compounds. In this study, we tested the efficacy of epiisopilosine (EPIIS) in a murine model of schistosomiasis. A single dose of EPIIS (100 or 400 mg/kg) administered orally to mice infected with adult S. mansoni resulted in reduced worm burden and egg production. The treatment with the lower dose of EPIIS (100 mg/kg) significantly reduced total worm burden by 60.61% (P < 0.001), as well as decreasing hepatosplenomegaly and egg excretion. Scanning electron microscopy revealed morphological changes in the worm tegument after treatment. Despite good activity of EPIIS in adult S. mansoni, oral treatment with single dose of EPIIS 100 mg/kg had only moderate effects in mice infected with juvenile S. mansoni. In addition, we performed cytotoxicity and toxicological studies with EPIIS and found no in vitro cytotoxicity (in HaCaT, and NIH-3T3 cells) at a concentration of 512 µg/mL. We also performed in silico analysis of toxicological properties and showed that EPIIS had low predicted toxicity. To confirm this, we investigated systemic acute toxicity in vivo by orally administering a 2000 mg/kg dose to Swiss mice. Treated mice showed no significant changes in hematological, biochemical, or histological parameters compared to non-treated animals. Epiisopilosine showed potential as a schistosomicidal drug: it did not cause acute toxicity and it displayed an acceptable safety profile in the animal model.

Asunto(s)

Alcaloides/farmacología , Schistosoma mansoni/efectos de los fármacos , Esquistosomiasis mansoni/tratamiento farmacológico , Animales , Línea Celular , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Células 3T3 NIH , Recuento de Huevos de Parásitos/métodos , Praziquantel/farmacología , Esquistosomiasis mansoni/parasitología , Esquistosomicidas/farmacología

RESUMEN

AIM: To develop a self-nanoemulsifying drug-delivery system (SNEDDS) able to improve oral absorption of epiisopiloturine (EPI), and test the antischistosomal activity in a mice model. RESULTS: SNEDDS had a nanoscopic size and was able to enhance EPI bioavailability after oral administration, and SNEDDS-EPI (40 mg.kg-1) improved the in vivo antischistosomal activity of EPI, demonstrating that SNEDDS was able to improve the pharmacokinetics of EPI, and to maintain the pharmacodynamic activity against Schistosoma mansoni in vivo. CONCLUSION: Taken together, these results indicate that SNEDDS-EPI is efficient in reducing worm burden in comparison to treatment with the free version of EPI. [Formula: see text].

Asunto(s)

4-Butirolactona/análogos & derivados , Sistemas de Liberación de Medicamentos , Imidazoles/administración & dosificación , Nanopartículas/administración & dosificación , Esquistosomiasis mansoni/tratamiento farmacológico , 4-Butirolactona/administración & dosificación , 4-Butirolactona/química , 4-Butirolactona/farmacocinética , Administración Oral , Animales , Disponibilidad Biológica , Modelos Animales de Enfermedad , Emulsiones/administración & dosificación , Emulsiones/química , Humanos , Imidazoles/química , Imidazoles/farmacocinética , Ratones , Nanopartículas/química , Tamaño de la Partícula , Schistosoma mansoni/efectos de los fármacos , Schistosoma mansoni/patogenicidad , Esquistosomiasis mansoni/parasitología , Solubilidad

RESUMEN

Schistosomiasis, caused by helminth flatworms of the genus Schistosoma, is one of the most important parasitic diseases in the world, affecting over 200 million people in developing countries. Riparins are natural alkamides found in Aniba riparia (Lauraceae) fruits that possess several pharmacological properties. In this study, we reported the synthesis, characterization and structural analysis of six riparin derivatives (A-F), as well as their schistosomicidal activity against S. mansoni worms together with a biological, pharmacokinetic and toxicological in silico evaluation. Firstly, these compounds were synthesized, purified and characterized by elemental analysis, FT-IR spectroscopy, X-ray diffraction and theoretical calculations to evaluate their stability and conformation. Next, the schistosomicidal activity of the riparins was tested against S. mansoni worms. Bioassays revealed that Riparins E and F were the most active compounds, showing half-maximum inhibitory concentration at low micromolar ranges (IC50 values ~10 µM). Also, confocal laser scanning microscopy studies revealed tegumental damage in parasites after exposition with Riparins B, E and F. Additionally, based on MTT assay, all tested riparins showed no cytotoxic potential toward mammalian cells. Finally, in silico analyses were used to predict the absorption, distribution, metabolism, elimination and toxicity (ADMET) of the compounds. Taken together, the results revealed a promising ADMET profile and suggested that riparins could be starting points for lead optimization programs for natural products with antischistosomal properties.

Asunto(s)

Benzamidas , Fenetilaminas , Esquistosomicidas , Animales , Benzamidas/química , Benzamidas/farmacocinética , Benzamidas/farmacología , Benzamidas/toxicidad , Células CACO-2 , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Simulación por Computador , Humanos , Absorción Intestinal , Modelos Biológicos , Estructura Molecular , Fenetilaminas/química , Fenetilaminas/farmacocinética , Fenetilaminas/farmacología , Fenetilaminas/toxicidad , Difracción de Polvo , Schistosoma mansoni/efectos de los fármacos , Esquistosomicidas/química , Esquistosomicidas/farmacocinética , Esquistosomicidas/farmacología , Esquistosomicidas/toxicidad , Absorción Cutánea , Espectroscopía Infrarroja por Transformada de Fourier , Células Vero , Difracción de Rayos X

RESUMEN

The amphibian skin plays an important role protecting the organism from external harmful factors such as microorganisms or UV radiation. Based on biorational strategies, many studies have investigated the cutaneous secretion of anurans as a source of bioactive molecules. By a peptidomic approach, a novel antioxidant peptide (AOP) with in vitro free radical scavenging ability was isolated from Physalaemus nattereri. The AOP, named antioxidin-I, has a molecular weight [M+H]+ = 1543.69Da and a TWYFITPYIPDK primary amino acid sequence. The gene encoding the antioxidin-I precursor was expressed in the skin tissue of three other Tropical frog species: Phyllomedusa tarsius, P. distincta and Pithecopus rohdei. cDNA sequencing revealed highly homologous regions (signal peptide and acidic region). Mature antioxidin-I has a novel primary sequence with low similarity compared with previously described amphibian's AOPs. Antioxidin-I adopts a random structure even at high concentrations of hydrophobic solvent, it has poor antimicrobial activity and poor performance in free radical scavenging assays in vitro, with the exception of the ORAC assay. However, antioxidin-I presented a low cytotoxicity and suppressed menadione-induced redox imbalance when tested with fibroblast in culture. In addition, it had the capacity to substantially attenuate the hypoxia-induced production of reactive oxygen species when tested in hypoxia exposed living microglial cells, suggesting a potential neuroprotective role for this peptide.

Asunto(s)

Proteínas Anfibias/genética , Péptidos Catiónicos Antimicrobianos/genética , Anuros/fisiología , Infecciones Bacterianas/inmunología , Fibroblastos/fisiología , Microglía/metabolismo , Piel/metabolismo , Proteínas Anfibias/inmunología , Proteínas Anfibias/metabolismo , Animales , Péptidos Catiónicos Antimicrobianos/inmunología , Péptidos Catiónicos Antimicrobianos/metabolismo , Antioxidantes/metabolismo , Clonación Molecular , Depuradores de Radicales Libres/metabolismo , Ratones , Estructura Molecular , Células 3T3 NIH , Neuroprotección , Oxidación-Reducción , Conformación Proteica , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

The vasoactive proline-rich oligopeptide termed BPP-BrachyNH2 (H-WPPPKVSP-NH2) induces in vitro inhibitory activity of angiotensin I-converting enzyme (ACE) in rat blood serum. In the present study, the removal of N-terminal tryptophan or C-terminal proline from BPP-BrachyNH2 was investigated in order to predict which structural components are important or required for interaction with ACE. Furthermore, the toxicological profile was assessed by in silico prediction and in vitro MTT assay. Two BPP-BrachyNH2 analogues (des-Trp1-BPP-BrachyNH2 and des-Pro8-BPP-BrachyNH2) were synthesized, and in vitro and in silico ACE inhibitory activity and toxicological profile were assessed. The des-Trp1-BPP-BrachyNH2 and des-Pro8-BPP-BrachyNH2 were respectively 3.2- and 29.5-fold less active than the BPP-BrachyNH2-induced ACE inhibitory activity. Molecular Dynamic and Molecular Mechanics Poisson-Boltzmann Surface Area simulations (MM-PBSA) demonstrated that the ACE/BBP-BrachyNH2 complex showed lower binding and van der Wall energies than the ACE/des-Pro8-BPP-BrachyNH2 complex, therefore having better stability. The removal of the N-terminal tryptophan increased the in silico predicted toxicological effects and cytotoxicity when compared with BPP-BrachyNH2 or des-Pro8-BPP-BrachyNH2. Otherwise, des-Pro8-BPP-BrachyNH2 was 190-fold less cytotoxic than BPP-BrachyNH2. Thus, the removal of C-terminal proline residue was able to markedly decrease both the BPP-BrachyNH2-induced ACE inhibitory and cytotoxic effects assessed by in vitro and in silico approaches. In conclusion, the aminoacid sequence of BPP-BrachyNH2 is essential for its ACE inhibitory activity and associated with an acceptable toxicological profile. The perspective of the interactions of BPP-BrachyNH2 with ACE found in the present study can be used for development of drugs with differential therapeutic profile than current ACE inhibitors.

Asunto(s)

Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Oligopéptidos/farmacología , Peptidil-Dipeptidasa A/metabolismo , Prolina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/síntesis química , Inhibidores de la Enzima Convertidora de Angiotensina/química , Animales , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Hemólisis , Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Molecular , Oligopéptidos/síntesis química , Oligopéptidos/química , Prolina/química , Ratas , Ratas Wistar , Ovinos , Relación Estructura-Actividad

RESUMEN

Three new isoaigialones, A, B, and C (1-3), along with aigialone (4), were isolated from the crude EtOAc extract of a Phaeoacremonium sp., an endophytic fungus obtained from the leaves of Senna spectabilis. The structures of these compounds were elucidated based on the analysis of spectroscopic data. Compounds 2 and 4 were active against the phytopathogenic fungi Cladosporium cladosporioides and C. sphaerospermum. This is the first report of metabolites produced by an Phaeoacremonium sp., associated with S. spectabilis.

Asunto(s)

Acetales/aislamiento & purificación , Acetales/farmacología , Antifúngicos/aislamiento & purificación , Antifúngicos/farmacología , Ascomicetos/química , Cladosporium/química , Cetonas/aislamiento & purificación , Cetonas/farmacología , Lactonas/aislamiento & purificación , Hojas de la Planta/química , Senna/química , Acetales/química , Antifúngicos/química , Cetonas/química , Lactonas/química , Lactonas/metabolismo , Lactonas/farmacología , Estructura Molecular

RESUMEN

BACKGROUND: Bergenin, a compound derived from gallic acid, is a secondary metabolite of the plant Peltophorum dubium (Spreng.) Taub. OBJECTIVE: In this study, we aimed to characterize the ability of bergenin to eliminate the radicals in non-biological systems. METHODS: We evaluated bergenin's ability to protect erythrocytes from oxidative damage in a biological system. We have elucidated bergenin structure using nuclear magnetic resonance, X-ray diffraction, Fourier transform infrared spectroscopy, and differential scanning calorimetry. We then evaluated its antioxidant capacity in vitro against DPPH•, ABTS•+, hydroxyl radicals, and nitric oxide, and determined its ability to transfer electrons owing to its reduction potential and ability to chelate iron. We also evaluated its protective capacity against oxidative damage produced by AAPH in erythrocytes, its hemolytic properties, its ability to inhibit hemolysis, and its ability to maintain intracellular reduced glutathione homeostasis. RESULTS: Bergenin concentrations between 0.1 and 3mM significantly (p < 0.05) and dose dependently decreased formation of ABTS•+, DPPH•, nitrite ions, OH•, reduced formation ferricyanide, ferrozine-Fe2+complex, inhibited AAPH-induced oxidative hemolysis of erythrocytes, raised GSH levels in the presence of AAPH, inhibited AAPH-induced lipid peroxidation in erythrocytes. CONCLUSION: Bergenin may represent a novel alternative antioxidant, with potential applications in various industries, including drugs, cosmetics, and foods.

Asunto(s)

Antioxidantes/aislamiento & purificación , Antioxidantes/farmacología , Benzopiranos/aislamiento & purificación , Benzopiranos/farmacología , Eritrocitos/efectos de los fármacos , Fabaceae/química , Animales , Antioxidantes/química , Benzopiranos/química , Benzotiazoles/química , Compuestos de Bifenilo/química , Transporte de Electrón/efectos de los fármacos , Eritrocitos/metabolismo , Femenino , Glutatión/metabolismo , Hemólisis/efectos de los fármacos , Homeostasis/efectos de los fármacos , Radical Hidroxilo/química , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Hierro/química , Peroxidación de Lípido/efectos de los fármacos , Modelos Moleculares , Conformación Molecular , Nitritos/química , Picratos/química , Ratas , Ratas Wistar , Ácidos Sulfónicos/química

RESUMEN

Collagen is considered the most abundant protein in the animal kingdom, comprising 30% of the total amount of proteins and 6% of the human body by weight. Studies that examine the interaction between silver nanoparticles and proteins have been highlighted in the literature in order to understand the stability of the nanoparticle system, the effects observed in biological systems, and the appearance of new chemical pharmaceutical products. The objective of this study was to analyze the behavior of silver nanoparticles stabilized with collagen (AgNPcol) and to check the skin permeation capacity and action in paw edema induced by carrageenan. AgNPcol synthesis was carried out using solutions of reducing agent sodium borohydride (NaBH4), silver nitrate (AgNO3) and collagen. Characterization was done by using dynamic light scattering (DLS) and X-ray diffraction (XRD) and AFM. Cellular viability testing was performed by using flow cytometry in human melanoma cancer (MV3) and murine fibroblast (L929) cells. The skin permeation study was conducted using a Franz diffusion cell, and the efficiency of AgNPcol against the formation of paw edema in mice was evaluated. The hydrodynamic diameter and zeta potential of AgNPcol were 140.7±7.8nm and 20.1±0.7mV, respectively. AgNPcol failed to induce early apoptosis, late apoptosis, and necrosis in L929 cells; however, it exhibited enhanced toxicity in cancer cells (MV3) compared to normal cells (L929). AgNPcol demonstrated increased toxicological effects in cancer MV3 cells, promoting skin permeation, and preventing paw edema.

Asunto(s)

Materiales Biocompatibles/química , Colágeno/química , Nanopartículas del Metal/química , Plata/química , Animales , Apoptosis/efectos de los fármacos , Materiales Biocompatibles/farmacología , Materiales Biocompatibles/uso terapéutico , Borohidruros/química , Carragenina/toxicidad , Línea Celular , Dispersión Dinámica de Luz , Edema/inducido químicamente , Edema/tratamiento farmacológico , Humanos , Masculino , Nanopartículas del Metal/toxicidad , Ratones , Microscopía de Fuerza Atómica , Permeabilidad/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Nitrato de Plata/química , Piel/efectos de los fármacos , Piel/metabolismo , Difracción de Rayos X

RESUMEN

Schistosomiasis is a world health problem, and praziquantel is the only drug currently used for the treatment. There is some evidence that extensive monotherapy of praziquantel may be leading to drug resistance in the parasite. In order to find alternative treatments, the effects of the combination of epiisopiloturine (EPI), piplartine (PPT) and praziquantel (PZQ) were evaluated. Similarity analysis of these compounds was performed using optimized molecular structures to compare the shape and the charge modeling of combinations between PZQ and EPI or PPT. Supported by this data, in vitro association of PZQ-PPT, PZQ-EPI, and EPI-PPT was carried out, and the activity of these combinations against Schistosoma mansoni was assessed. The results showed synergistic activity with a combination index (CI) of 0.42 for the treatment with PZQ-PPT. Both PZQ-EPI and EPI-PPT combinations also showed synergistic effects, with CI values of 0.86 and 0.61, respectively. Surface alterations in the tegument of adult schistosomes after the treatments were observed using laser confocal microscopy and scanning electron microscopy. Additionally, the association of EPI-PPT decreased the cytotoxicity when compared with both isolated compounds in three different lines of mammalian cells. Thus, synergistic combinations of PZQ-PPT, PZQ-EPI, and EPI-PPT create the possibility of reduced doses to be used against Schistosoma mansoni.

Asunto(s)

4-Butirolactona/análogos & derivados , Imidazoles/farmacología , Piperidonas/farmacología , Praziquantel/farmacología , Schistosoma mansoni/efectos de los fármacos , 4-Butirolactona/química , 4-Butirolactona/farmacología , Animales , Antiprotozoarios/farmacología , Forma de la Célula/efectos de los fármacos , Chlorocebus aethiops , Cricetinae , Perros , Sinergismo Farmacológico , Quimioterapia Combinada , Imidazoles/química , Células de Riñón Canino Madin Darby , Masculino , Ratones , Microscopía Confocal , Piperidonas/química , Praziquantel/química , Schistosoma mansoni/ultraestructura , Células Vero

RESUMEN

Pilocarpus microphyllus Stapf ex Wardlew (Rutaceae), popularly known as jaborandi, is a plant native to the northern and northeastern macroregions of Brazil. Several alkaloids from this species have been isolated. There are few reports of antibacterial and anthelmintic activities for these compounds. In this work, we report the antibacterial and anthelmintic activity of five alkaloids found in P. microphyllus leaves, namely, pilosine, epiisopilosine, isopilosine, epiisopiloturine and macaubine. Of these, only anthelmintic activity of one of the compounds has been previously reported. Nuclear magnetic resonance, HPLC and mass spectrometry were combined and used to identify and confirm the structure of the five compounds. As regards the anthelmintic activity, the alkaloids were studied using in vitro assays to evaluate survival time and damaged teguments for Schistosoma mansoni adult worms. We found epiisopilosine to have anthelmintic activity at very low concentrations (3.125 µg mL-1 ); at this concentration, it prevented mating, oviposition, reducing motor activity and altered the tegument of these worms. In contrast, none of the alkaloids showed antibacterial activity. Additionally, alkaloids displayed no cytotoxic effect on vero cells. The potent anthelmintic activity of epiisopilosine indicates the potential of this natural compound as an antiparasitic agent. Copyright © 2017 John Wiley & Sons, Ltd.

Asunto(s)

Alcaloides/química , Antihelmínticos/química , Antibacterianos/química , Imidazoles/química , Pilocarpus/química , Extractos Vegetales/química , Hojas de la Planta/química , 4-Butirolactona/análogos & derivados , Animales , Imidazoles/farmacología , Células Vero

RESUMEN

Schistosomiasis is a world health problem, and praziquantel is the only drug currently used for the treatment. There is some evidence that extensive monotherapy of praziquantel may be leading to drug resistance in the parasite. In order to find alternative treatments, the effects of the combination of epiisopiloturine (EPI), piplartine (PPT) and praziquantel (PZQ) were evaluated. Similarity analysis of these compounds was performed using optimized molecular structures to compare the shape and the charge modeling of combinations between PZQ and EPI or PPT. Supported by this data, in vitro association of PZQ-PPT, PZQ-EPI, and EPI-PPT was carried out, and the activity of these combinations against Schistosoma mansoni was assessed. The results showed synergistic activity with a combination index (CI) of 0.42 for the treatment with PZQ-PPT. Both PZQ-EPI and EPI-PPT combinations also showed synergistic effects, with CI values of 0.86 and 0.61, respectively. Surface alterations in the tegument of adult schistosomes after the treatments were observed using laser confocal microscopy and scanning electron microscopy. Additionally, the association of EPI-PPT decreased the cytotoxicity when compared with both isolated compounds in three different lines of mammalian cells. Thus, synergistic combinations of PZQ-PPT, PZQ-EPI, and EPI-PPT create the possibility of reduced doses to be used against Schistosoma mansoni.

RESUMEN

Schistosomiasis, a chronic neglected tropical disease caused by Schistosoma worms, is reported in nearly 80 countries. Although the disease affects approximately 260 million people, the treatment relies exclusively on praziquantel, a drug discovered in the mid-1970s that lacks efficacy against the larval stages of the parasite. In addition, the dependence on a single treatment has raised concerns about drug resistance, and reduced susceptibility has already been found in laboratory and field isolates. Therefore, novel therapies for schistosomiasis are needed, and several approaches have been used to that end. One of these strategies, molecular modeling, has been increasingly integrated with experimental techniques, resulting in the discovery of novel antischistosomal agents.

Asunto(s)

Descubrimiento de Drogas , Modelos Moleculares , Esquistosomicidas/química , Animales , Resistencia a Medicamentos , Schistosoma/efectos de los fármacos , Esquistosomicidas/farmacología

RESUMEN

In this chapter we present in vivo experiments with a new minimally invasive method of monitoring intracranial pressure (ICP). Strain gauge deformation sensors are externally glued onto the exposed skull. The signal from these sensors is amplified, filtered, and sent to a computer with appropriate software for analysis and data storage. Saline infusions into the spinal channel of rats were performed to produce ICP changes, and minimally invasive ICP and direct Codman intraparenchymal ICP were simultaneously acquired in six animals. The similarity between the invasive and minimally invasive methods in response to ICP increase was assessed using Pearson's correlation coefficient. It demonstrated good agreement between the two measures < r > = 0.8 ± 0.2, with a range of 0.31-0.99.

Asunto(s)

Hipertensión Intracraneal/fisiopatología , Presión Intracraneal/fisiología , Cráneo/fisiopatología , Animales , Diseño de Equipo , Hipertensión Intracraneal/diagnóstico , Masculino , Monitoreo Fisiológico , Ratas , Ratas Wistar , Cráneo/fisiología