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1.
Regul Toxicol Pharmacol ; 133: 105225, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35817211

RESUMO

Some pharmaceutical excipients may cause adverse reactions, excipient-related interactions and/or contraindications. Due to the unique characteristics of the paediatric population, adverse effects may occur to substances generally thought safe. The proportion of topical nasal medicines approved for paediatric use and the prevalence and labelling of excipients with known effect (EKE) in these products were compared in Serbia as a non-EU country and Croatia and Slovenia as EU countries. The study was designed as a post-authorization safety study and safety of excipients was considered in accordance with recommendations of the European Medicines Agency (EMA). More than 90% of topical nasal medicines registered in the three countries were approved for paediatric use and more than half of these paediatric medicines contained EKE that may cause adverse effects. Benzalkonium chloride was found in 52.38%, 55.81% and 59.09% of these products in Serbia, Croatia and Slovenia, respectively. Propylene glycol, benzyl alcohol, ethanol, methyl paraben, propyl paraben and boric acid were also present in a few analysed preparations. A significant number of EKE labelling deficiencies were detected in all three countries, hindering healthcare professionals' access to information needed for adequate patient counselling. A revision of the nasal paediatric medicines' PLs and SmPCs is recommended.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Excipientes , Álcool Benzílico , Criança , Excipientes/efeitos adversos , Humanos , Parabenos , Preparações Farmacêuticas , Propilenoglicol/efeitos adversos
2.
Nat Commun ; 13(1): 3746, 2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-35768404

RESUMO

Engineering subcellular organization in microbes shows great promise in addressing bottlenecks in metabolic engineering efforts; however, rules guiding selection of an organization strategy or platform are lacking. Here, we study compartment morphology as a factor in mediating encapsulated pathway performance. Using the 1,2-propanediol utilization microcompartment (Pdu MCP) system from Salmonella enterica serovar Typhimurium LT2, we find that we can shift the morphology of this protein nanoreactor from polyhedral to tubular by removing vertex protein PduN. Analysis of the metabolic function between these Pdu microtubes (MTs) shows that they provide a diffusional barrier capable of shielding the cytosol from a toxic pathway intermediate, similar to native MCPs. However, kinetic modeling suggests that the different surface area to volume ratios of MCP and MT structures alters encapsulated pathway performance. Finally, we report a microscopy-based assay that permits rapid assessment of Pdu MT formation to enable future engineering efforts on these structures.


Assuntos
Proteínas de Bactérias , Salmonella typhimurium , Proteínas de Bactérias/metabolismo , Engenharia Metabólica , Propilenoglicol/metabolismo , Salmonella typhimurium/metabolismo
3.
Food Funct ; 13(13): 7144-7156, 2022 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-35699056

RESUMO

Ketosis, a common metabolic disorder in dairy cattle, occurs during early lactation and leads to higher concentrations of non-esterified fatty acids (NEFAs) and ß-hydroxybutyrate (BHBA), and is generally believed to be caused by excessive negative energy balance (NEB). Propylene glycol (PG), a gluconeogenic precursor, has been proved to promote gluconeogenesis and alleviate NEB. Oral administration of PG is widely considered one of the most effective therapeutic options for treating ketosis. Thus, in this study, we assessed the effects of PG on rumen microbiota via 16S rDNA analysis. The results show that one dose (500 mL) of PG treatment could rapidly reduce the blood BHBA level in ketosis cows by increasing the level and proportion of propionate in the rumen. Meanwhile, PG also had certain effects on the rumen bacterial community. Compared with before treatment, the relative abundances of Prevotella, Succinivibrionaceae_UCG-001 and Prevotellaceae_UCG-001 increased significantly, while those of Christensenellaceae_R-7_group, Butyrivibrio and Saccharofermentans significantly decreased. LEfSe analysis revealed that after PG treatment, only Rikenellaceae_RC9_gut_group was enriched in the rumen fluid at the genus level. In conclusion, the present study indicates that ketosis is accompanied by alterations in the rumen microbiota community. PG treatment changes the composition of rumen microbiota to a healthier state and contributes to rapid recovery from ketosis. These results support the usage of PG for treating such metabolic diseases that challenge high-yield cows due to their minimized cost and maximized safety without any adverse events.


Assuntos
Doenças dos Bovinos , Cetose , Microbiota , Ácido 3-Hidroxibutírico/metabolismo , Ácido 3-Hidroxibutírico/uso terapêutico , Animais , Bovinos , Doenças dos Bovinos/tratamento farmacológico , Dieta , Feminino , Cetose/tratamento farmacológico , Cetose/veterinária , Lactação , Leite/metabolismo , Propilenoglicol , Rúmen/metabolismo , Rúmen/microbiologia
4.
Nat Commun ; 13(1): 2920, 2022 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-35614058

RESUMO

Bacterial metabolosomes are a family of protein organelles in bacteria. Elucidating how thousands of proteins self-assemble to form functional metabolosomes is essential for understanding their significance in cellular metabolism and pathogenesis. Here we investigate the de novo biogenesis of propanediol-utilization (Pdu) metabolosomes and characterize the roles of the key constituents in generation and intracellular positioning of functional metabolosomes. Our results demonstrate that the Pdu metabolosome undertakes both "Shell first" and "Cargo first" assembly pathways, unlike the ß-carboxysome structural analog which only involves the "Cargo first" strategy. Shell and cargo assemblies occur independently at the cell poles. The internal cargo core is formed through the ordered assembly of multiple enzyme complexes, and exhibits liquid-like properties within the metabolosome architecture. Our findings provide mechanistic insight into the molecular principles driving bacterial metabolosome assembly and expand our understanding of liquid-like organelle biogenesis.


Assuntos
Proteínas de Bactérias , Propilenoglicol , Bactérias/genética , Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Organelas/metabolismo , Propilenoglicol/metabolismo
5.
Aerosp Med Hum Perform ; 93(5): 467-469, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35551723

RESUMO

INTRODUCTION: The previous Spacecraft Maximal Allowable Concentrations (SMACs) for propylene glycol were established based on a study of rodents exposed to propylene glycol (PG) aerosol for 6 h/d, 5 d/wk for 90 d. This study has been used as the basis for the few existing limits, but all exposure concentrations were well above the saturated vapor concentration of ∼100 ppm for pure propylene glycol at room temperature. For this reason, the Environmental Protection Agency and the Agency for Toxic Substances and Disease Registry noted that the method used to generate the aerosols for the two published studies of animal exposures are not relevant to exposure conditions for the general public, and most regulatory agencies have not established inhalation limits for propylene glycol, citing lack of data. Since publication of the PG SMACs in 2008, an acute inhalation study was conducted in healthy human subjects which allows us to revise our assessment. This manuscript provides the rationale for increasing the prior limits for PG in spacecraft air from 32 and 17 ppm to 64 and 32 ppm for off-nominal scenarios/releases (1-h and 24-h limits) and from 9, 3, and 1.5 ppm to 32 ppm for all nominal timeframes (7, 30, and 180 d). Due to a lack of longer-term exposure data, NASA has elected to eliminate the 1000-d SMAC limit at this time.Ryder VE, Williams ES. Revisions to limits for propylene glycol in spacecraft air. Aerosp Med Hum Perform. 2022; 93(5):467-469.


Assuntos
Propilenoglicol , Astronave , Animais , Humanos , Concentração Máxima Permitida , Propilenoglicol/toxicidade , Estados Unidos
6.
AAPS PharmSciTech ; 23(5): 136, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35534759

RESUMO

The present work was to construct a roflumilast (ROF) cream for the treatment of psoriasis and clarify the dual roles of propylene glycol monocaprylate (PGM) in both molecular mobility of the cream, and drug-skin miscibility via drug-PGM-ceramide and drug-PGM-collagen intermolecular interaction. The cream formulation was screened through the stability study and in vitro skin administration study, optimized by Plackett-Burman and Box-Behnken design, and finally verified by the in vivo tissue distribution study. PGM demonstrated a significant drug skin retention enhancement effect (Rmax in vivo = 19.5 µg/g). It increased the molecular mobility of the oil phase of the cream by decreasing the molecular interaction of oil molecules proven by the rheology study (Ec = 3.73 × 10-4 mJ·m-3). More importantly, because of the good stratum corneum (SC) compatibility (∆H = - 403.88 J/g), PGM promoted an orderly flow of SC lipids (X-ray scattering, ΔLPP = 1.18 nm) and entered the viable epidermis/dermis (VE/DE) in large quantities (RPGM = 1186 µg/g), acting as a bridge to connect the drug to collagen through two H-bonds (LengthH-bond = 2.846 Å and 3.313 Å), thus increasing the miscibility of drug and VE/DE significantly (∆H = - 310.10 J/g, Emix = 21.66 kcal/mol). In this study, a ROF cream was developed successfully and the effect of PGM on the skin retention was clarified at molecular level.


Assuntos
Aminopiridinas , Pele , Aminopiridinas/farmacologia , Benzamidas , Colágeno/farmacologia , Ciclopropanos , Preparações Farmacêuticas , Propilenoglicol/química , Propilenoglicóis , Creme para a Pele
7.
Cryobiology ; 106: 32-38, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35523314

RESUMO

Cryopreservation of mammalian zygotes can be advantageous since it enables their flexile use in time and space for alternative purposes such as genome editing. Here we report a simple, quick and inexpensive vitrification protocol for in vitro produced bovine zygotes which enables their bulk preservation. Slaughterhouse-derived oocytes were subjected to in vitro maturation and fertilization (IVF). Ten h after IVF, cumulus-enclosed zygotes were equilibrated in 2% (v/v) ethylene glycol + 2% (v/v) propylene glycol for 13-15 min then vitrified in groups of 52-100 in 2 µL microdrops of 17.5% (v/v) ethylene glycol + 17.5% (v/v) propylene glycol supplemented with 0.3 M sucrose and 50 mg/mL polyvinylpyrrolidone. The presence of cumulus cells is important for the success of the process. Therefore, we applied a modified IVF protocol using a short (30 min) co-incubation interval which allowed zygote culture with attached cumulus cells until vitrification and even reduced polyspermy rates without affecting the total fertilization rate. Vitrified zygotes were similar to their non-vitrified counterparts in terms of survival, post-warming development to the blastocyst stage and blastocyst quality measured by cell numbers and cryo-survival. In conclusion, our vitrification protocol integrated with the modified IVF system enabled the quick cryopreservation of bovine zygotes in large groups without reducing their developmental competence to the blastocyst stage.


Assuntos
Vitrificação , Zigoto , Animais , Blastocisto , Bovinos , Criopreservação/métodos , Crioprotetores/farmacologia , Etilenoglicol/farmacologia , Fertilização In Vitro/métodos , Fertilização In Vitro/veterinária , Mamíferos , Oócitos , Propilenoglicol
8.
Chem Res Toxicol ; 35(5): 890-897, 2022 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-35512282

RESUMO

Nicotine is a dependence-producing component in electronic cigarettes. The nicotine release characteristics of electronic cigarettes are closely connected with human exposure and respiratory health. In this paper, a theoretical model was established to study the effects of the compositions of e-liquids and the heating powers of device on the emission and gas/particle partitioning characteristics of nicotine in aerosols at equilibrium. The simulation results of nicotine emissions were compared with the experimental data. The errors between them were within a reasonable range. At a larger heating power level, a higher nicotine yield and a larger vaporization amount of e-liquids could be observed. Under the same heating power condition, a higher vegetable glycerin content in e-liquids could result in a lower nicotine emission. When the heating powers supplied by the device increased, a larger mass fraction of particle-phase nicotine in aerosols at equilibrium would appear. As more propylene glycol was added into e-liquids, a lower mass fraction of gas-phase nicotine would exist in aerosols at equilibrium. The results may provide more information for the industry to set technical standards for electronic cigarettes and for the government department to make regulatory policies.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Aerossóis , Glicerol , Humanos , Nicotina , Propilenoglicol
9.
Appl Microbiol Biotechnol ; 106(8): 2937-2951, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35416488

RESUMO

Glycerol dehydratase (gdrAB-dhaB123) operon from Klebsiella pneumoniae and NADPH-dependent 1,3-propanediol oxidoreductase (yqhD) from Escherichia coli were stably integrated on the chromosomal DNA of E. coli under the control of the native-host ldhA and pflB constitutive promoters, respectively. The developed E. coli NSK015 (∆ldhA::gdrAB-dhaB123 ∆ackA::FRT ∆pflB::yqhD ∆frdABCD::cat-sacB) produced 1,3-propanediol (1,3-PDO) at the level of 36.8 g/L with a yield of 0.99 mol/mol of glycerol consumed when glucose was used as a co-substrate with glycerol. Co-substrate of glycerol and cassava starch was also utilized for 1,3-PDO production with the concentration and yield of 31.9 g/L and 0.84 mol/mol of glycerol respectively. This represents a work for efficient 1,3-PDO production in which the overexpression of heterologous genes on the E. coli host genome devoid of plasmid expression systems. Plasmids, antibiotics, IPTG, and rich nutrients were omitted during 1,3-PDO production. This may allow a further application of E. coli NSK015 for the efficient 1,3-PDO production in an economically industrial scale. KEY POINTS:  â€¢ gdrAB-dhaB123 and yqhD were overexpressed in E. coli devoid of a plasmid system • E. coli NSK015 produced a high yield of 1,3-PDO at 99% theoretical maximum • Cassava starch was alternatively used as substrate for economical 1,3-PDO production.


Assuntos
Escherichia coli , Glicerol , Escherichia coli/genética , Escherichia coli/metabolismo , Fermentação , Deleção de Genes , Glicerol/metabolismo , Propilenoglicol/metabolismo , Propilenoglicóis/metabolismo , Amido/metabolismo
11.
Langmuir ; 38(14): 4243-4249, 2022 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-35352955

RESUMO

We describe an experimental technique for the production of foams comprised of bubbles in a continuous phase of balanced quantities of aqueous and oil phases. Initially, two highly stable foams are fabricated: one typically made from olive oil with bubbles stabilized using partially fluorinated particles and the other made from a mixture of water and propylene glycol with bubbles stabilized using partially hydrophobic particles. After a rough mixture is prepared, the final mixed foam is fabricated via spinning the components together; the spinning leads to the final foam being well-mixed and dry. Here the final mixed foams are presented in thin-film form. We show the locations and roles of the various components.


Assuntos
Propilenoglicol , Água , Aerossóis , Interações Hidrofóbicas e Hidrofílicas , Água/química
12.
Chembiochem ; 23(9): e202100694, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35229962

RESUMO

A classic example of an all-protein natural nano-bioreactor, the bacterial microcompartment is a prokaryotic organelle that confines enzymes in a small volume enveloped by an outer protein shell. These protein compartments metabolize specific organic molecules, allowing bacteria to survive in restricted nutrient environments. In this work, 1,2-propanediol utilization microcompartment (PduMCP) was used as a model to study the effect of molecular confinement on the stability and catalytic activity of native enzymes in the microcompartment. A combination of enzyme assays, spectroscopic techniques, binding assays, and computational analysis were used to evaluate the impact of the major shell protein PduBB' on the stability and activity of PduMCP's signature enzyme, dioldehydratase PduCDE. While free PduCDE shows ∼45 % reduction in its optimum activity (activity at 37 °C) when exposed to a temperature of 45 °C, it retains similar activity up to 50 °C when encapsulated within PduMCP. PduBB', a major component of the outer shell of PduMCP, preserves the catalytic efficiency of PduCDE under thermal stress and prevents temperature-induced unfolding and aggregation of PduCDE in vitro. We observed that while both PduB and PduB' interact with the enzyme with micromolar affinity, only the PduBB' combination influences its activity and stability, highlighting the importance of the unique PduBB' combination in the functioning of PduMCP.


Assuntos
Ensaios Enzimáticos , Propilenoglicol , Catálise , Células Procarióticas , Temperatura
13.
Microb Biotechnol ; 15(7): 2112-2125, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35298861

RESUMO

Klebsiella pneumoniae is a common strain of bacterial fermentation to produce 1, 3-propanediol (1, 3-PDO). In general, the production of 1, 3-PDO by wild-type K. pneumoniae is relatively low. Therefore, a new gene manipulation of K. pneumoniae was developed to improve the production of 1, 3-PDO by overexpressing in the reduction pathway and attenuating the by-products in the oxidation pathway. Firstly, dhaB and/or dhaT were overexpressed in the reduction pathway. Considering the cost of IPTG, the constitutive promoter P32 was selected to express the key gene. By comparing K.P. pET28a-P32-dhaT with the original strain, the production of 1, 3-PDO was increased by 19.7%, from 12.97 to 15.53 g l-1 (in a 250 ml shaker flask). Secondly, three lldD and budC regulatory sites were selected in the by-product pathway, respectively, using the CRISPR-dCas9 system, and the optimal regulatory sites were selected following the 1, 3-PDO production. As a result, the 1, 3-PDO production by K.P. L1-pRH2521 and K.P. B3-pRH2521 reached up to 19.16 and 18.74 g l-1 , which was increased by 47.7% and 44.5% respectively. Overexpressing dhaT and inhibiting expression of lldD and budC were combined to further enhance the ability of K. pneumoniae to produce 1, 3-PDO. The 1, 3-PDO production by K.P. L1-B3-PRH2521-P32-dhaT reached 57.85 g l-1 in a 7.5 l fermentation tank (with Na+ neutralizer), which is higher than that of the original strain. This is the first time that the 1, 3-PDO production was improved in K. pneumoniae by overexpressing the key gene and attenuating by-product synthesis in the CRISPR-dCas9 system. This study reports an efficient approach to regulate the expression of genes in K. pneumoniae to increase the 1, 3-PDO production, and such a strategy may be useful to modify other strains to produce valuable chemicals.


Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Klebsiella pneumoniae , Fermentação , Glicerol/metabolismo , Klebsiella pneumoniae/genética , Propilenoglicol/metabolismo , Propilenoglicóis/metabolismo
14.
Biotechnol Bioeng ; 119(6): 1450-1466, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35234295

RESUMO

Bioconversion of natural microorganisms generally results in a mixture of various compounds. Downstream processing (DSP) which only targets a single product often lacks economic competitiveness due to incomplete use of raw material and high cost of waste treatment for by-products. Here, we show with the efficient microbial conversion of crude glycerol by an artificially evolved strain and how a catalytic conversion strategy can improve the total products yield and process economy of the DSP. Specifically, Clostridium pasteurianum was first adapted to increased concentration of crude glycerol in a novel automatic laboratory evolution system. At m3 scale bioreactor the strain achieved a simultaneous production of 1,3-propanediol (PDO), acetic and butyric acids at 81.21, 18.72, and 11.09 g/L within only 19 h, respectively, representing the most efficient fermentation of crude glycerol to targeted products. A heterogeneous catalytic step was developed and integrated into the DSP process to obtain high-value methyl esters from acetic and butyric acids at high yields. The coproduction of the esters also greatly simplified the recovery of PDO. For example, a cosmetic grade PDO (96% PDO) was easily obtained by a simple single-stage distillation process (with an overall yield more than 77%). This integrated approach provides an industrially attractive route for the simultaneous production of three appealing products from the crude glycerol fermentation broth, which greatly improve the process economy and ecology.


Assuntos
Ésteres , Glicerol , Butiratos , Catálise , Fermentação , Propilenoglicol , Propilenoglicóis
15.
Transplant Cell Ther ; 28(5): 242-247, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35196581

RESUMO

Autologous hematopoietic cell transplantation (AHCT) remains a standard therapeutic option for patients with multiple myeloma (MM). Outcomes have improved for this patient group after first AHCT, with the use of novel agents in induction, as well as post-transplantation maintenance. High-dose melphalan remains the gold standard as the conditioning regimen for MM. Traditional melphalan is a lyophilized formulation that after reconstitution has insufficient chemical stability and water solubility, thus requiring the addition of propylene glycol to act as a cosolvent to improve these characteristics. After the reconstitution of melphalan with propylene glycol-containing solution, impurities can develop within 30 minutes, and if further dilution occurs, the potency of melphalan diminishes. Propylene glycol is associated with a spectrum of toxicities that can be dose limiting. Evomela is a propylene glycol-free melphalan (PGF-Mel) that at a high dose of 200 mg/2 (100 mg/m2/d for 2 days) is approved for conditioning before AHCT in MM patients. Once reconstituted by directly dissolving in saline solution, PGF-Mel solution can be stored in the vial for up to 1 hour at room temperature or for up to 24 hours at refrigerated temperature (2° to 8°C) with no significant degradation. The demonstrated stability, up to 24 hours at room temperature, results in reduced handling requirements and increased convenience and flexibility of administration. Since its approval, Evomela has been the subject of several retrospective and investigator-initiated studies. This review summarizes the prospective and real-world evidence on practical aspects of PGF-Mel and critically appraises the available data and its clinical implications.


Assuntos
Amiloidose , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Amiloidose/induzido quimicamente , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Melfalan/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Propilenoglicol/uso terapêutico , Estudos Prospectivos , Prostaglandinas F/uso terapêutico , Estudos Retrospectivos
16.
J Control Release ; 343: 755-764, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35150813

RESUMO

The skin provides an attractive alternative to the conventional drug administration routes. Still, it comes with challenges as the upper layer of the skin, the stratum corneum (SC), provides an efficient barrier against permeation of most compounds. One way to overcome the skin barrier is to apply chemical permeation enhancers, which can modify the SC structure. In this paper, we investigated the molecular effect of three different types of glycols in SC: dipropylene glycol (diPG), propylene glycol (PG), and butylene glycol (BG). The aim is to understand how these molecules influence the molecular mobility and structure of the SC components, and to relate the molecular effects to the efficiency of these molecules as permeation enhancers. We used complementary experimental techniques, including natural abundance 13C NMR spectroscopy and wide-angle X-ray diffraction to characterize the molecular consequences of these compounds at different doses in SC at 97% RH humidity and 32 °C. In addition, we study the permeation enhancing effects of the same glycols in comparable conditions using Raman spectroscopy. Based on the results from NMR, we conclude that all three glycols cause increased mobility in SC lipids, and that the addition of glycols has an effect on the keratin filaments in similar manner as Natural Moisturizing Factor (NMF). The highest mobility of both lipids and amino acids can be reached with BG, which is followed by PG. It is also shown that one reaches an apparent saturation level for all three chemicals in SC, after which increased addition of the compound does not lead to further increase in the mobility of SC lipids or protein components. The examination with Raman mapping show that BG and PG give a significant permeation enhancement as compared to SC without any added glycol at corresponding conditions. Finally, we observe a non-monotonic response in permeation enhancement with respect to the concentration of glycols, where the highest concentration does not give the highest permeation. This is explained by the dehydration effects at highest glycol concentrations. In summary, we find a good correlation between the molecular effects of glycols on the SC lipid and protein mobility, and macroscopic permeation enhances of the same molecules.


Assuntos
Epiderme , Glicóis , Epiderme/metabolismo , Glicóis/metabolismo , Glicóis/farmacologia , Lipídeos/química , Permeabilidade , Propilenoglicol/química , Pele/metabolismo
17.
Biomed Res Int ; 2022: 3549061, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35047632

RESUMO

Plumbagin, a bioactive naphthoquinone, has demonstrated potent antitumor potential. However, plumbagin is a sparingly water-soluble compound; therefore, clinical translation requires and will be facilitated by the development of a new pharmaceutical formulation. We have generated an oil-in-water nanoemulsion formulation of plumbagin using a low-energy spontaneous emulsification process with propylene glycol caprylate (Capryol 90) as an oil phase and Labrasol/Kolliphor RH40 as surfactant and cosurfactant excipients. Formulation studies using Capryol 90/Labrasol/Kolliphor RH40 components, based on pseudoternary diagram and analysis of particle size distribution and polydispersity determined by dynamic light scattering (DLS), identified an optimized composition of excipients for nanoparticle formulation. The nanoemulsion loaded with plumbagin as an active pharmaceutical ingredient had an average hydrodynamic diameter of 30.9 nm with narrow polydispersity. The nanoemulsion exhibited long-term stability, as well as good retention of particle size in simulated physiological environments. Furthermore, plumbagin-loaded nanoemulsion showed an augmented cytotoxicity against prostate cancer cells PTEN-P2 in comparison to free drug. In conclusion, we generated a formulation of plumbagin with high loading drug capacity, robust stability, and scalable production. Novel Capryol 90-based nanoemulsion formulation of plumbagin demonstrated antiproliferative activity against prostate cancer cells, warranting thus further pharmaceutical development.


Assuntos
Antineoplásicos , Portadores de Fármacos , Nanopartículas , Naftoquinonas , Propilenoglicol , Neoplasias da Próstata , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Emulsões , Masculino , Camundongos , Nanopartículas/química , Nanopartículas/uso terapêutico , Naftoquinonas/química , Naftoquinonas/farmacologia , Propilenoglicol/química , Propilenoglicol/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia
18.
Environ Sci Pollut Res Int ; 29(27): 41140-41150, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35088268

RESUMO

3-Monochloropropane-1,2-diol (3-MCPD) is a food contaminant formed during acid hydrolysis of vegetable proteins. The toxicological evaluation of smaller doses of 3-MCPD is essential for safety evaluation of this compound. The present study investigates the toxicologic potential of 3-MCPD on male genital organs of rats, applies a correlation between the induced infertility and developed lesions in testes, epididymis, and accessory glands and study the possible mechanisms of 3-MCPD-induced male infertility. Forty rats were randomly divided into four main groups of ten animals each: the control untreated group and three treated groups that were orally administered 3-MCPD at different doses (3, 7.5 and 15 mg/kg b.w) daily via stomach intubation for five successive days per week. Five rats from each group were euthanized after 30 days. The remaining rats were euthanized after 90 days to establish subacute and chronic toxicity studies. Oxidative stress markers, Nrf2 gene expression, semen analysis, and histopathological examination were performed at the end of each experimental period. Results indicated that 3-MCPD induces infertility in male rat via disruption of Nrf2 expression in the testicular tissue with subsequent increased oxidative stress indicators in the testis that affect spermatogenesis and induced testicular degeneration, in addition, induction of epididymal lesions that affect sperm motility and concentration and finally possible development of hyperplastic tissue reactions in accessory glands of intoxicated rats predicting the carcinogenic potential of this compound.


Assuntos
Infertilidade Masculina , alfa-Cloridrina , Animais , Epididimo , Fator de Transcrição de Proteínas de Ligação GA , Humanos , Infertilidade Masculina/induzido quimicamente , Masculino , Fator 2 Relacionado a NF-E2 , Propilenoglicol , Ratos , Motilidade Espermática , Testículo , alfa-Cloridrina/toxicidade
19.
J Med Toxicol ; 18(2): 155-158, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35043364

RESUMO

INTRODUCTION: Severe metabolic acidosis with elevated anion and osmol gap is suggestive of toxic alcohol ingestion. The absence of detectable methanol or ethylene glycol in the serum could mean that metabolism is complete or that other hypotheses have to be considered. Ingestion of less common alcohol or alcoholic ketoacidosis should be investigated as illustrated by the present observation. CASE REPORT: A 46-year-old woman was admitted with altered consciousness in the Emergency Department. In the presence of a high anion gap (peak value 39 mEq/L) metabolic acidosis with mildly increased osmol gap (peak value 19 mOsm/kg), there was a high suspicion of toxic alcohol ingestion in an individual with alcohol use disorder (AUD). Serum arterial lactate concentration was particularly high at 27 mmol/L. Urinalysis failed to reveal the presence of ketone bodies or oxalate crystals. The results of the serum determination of ethanol, methanol, ethylene glycol, and isopropanol were obtained within 2 h and were negative. Due to the severity of lactic metabolic acidosis and the persisting suspicion of intoxication by a less common toxic alcohol, antidotal therapy with ethanol was initiated together with hemodialysis. Correction of lactic metabolic acidosis was obtained. Results of urinalysis obtained later revealed the presence not only of propylene glycol and D-lactate but also of significant concentrations of ß-hydroxybutyrate as a marker of alcoholic ketoacidosis. DISCUSSION: The combination of propylene glycol ingestion and alcoholic ketoacidosis may have contributed to the severity of lactic acidosis.


Assuntos
Acidose Láctica , Acidose , Cetose , Acidose/induzido quimicamente , Acidose/diagnóstico , Acidose/terapia , Acidose Láctica/induzido quimicamente , Acidose Láctica/diagnóstico , Acidose Láctica/terapia , Etanol , Etilenoglicol , Feminino , Humanos , Cetose/induzido quimicamente , Cetose/diagnóstico , Ácido Láctico , Metanol , Pessoa de Meia-Idade , Propilenoglicol
20.
Environ Sci Pollut Res Int ; 29(20): 30537-30547, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35000155

RESUMO

Propylene glycol (PG) is widely used in the foods, pharmaceuticals, oil industry, animal feed, cosmetics and other industries. Because of the existence of a chiral carbon center, PG forms R (Rectus)- and S (Sinister)-enantiomers. Currently, the toxicity study of its R-, S-enantiomers is still very scarce. In this study, we have assessed the developmental toxicity and neurotoxicity of the R-, S-, and RS-PG enantiomers in zebrafish larvae. We found that exposure to R-, S-, and RS-PG enantiomers did not significantly affect the basic developmental endpoints of embryos or larvae (i.e., embryonic movement, hatching, mortality, malformation, heartbeat, body length), indicating that R-, S-, and RS-PG exposures did not exhibit the basic developmental toxicity in zebrafish larvae. The toxicity of three enantiomers was lower than that of ethanol, and there was no significant difference between them. However, R-, S-, and RS-PG exposures with high doses could significantly change the eye diameter and locomotor activity of larval zebrafish, indicating that R-, S-, and RS-PG enantiomers of high doses could potentially exhibit the neurotoxicity and ocular developmental toxicity in zebrafish larvae. Therefore, the potential neurotoxicity and ocular developmental toxicity of R-, S-, and RS-PG enantiomers for infants and toddlers should be considered.


Assuntos
Síndromes Neurotóxicas , Poluentes Químicos da Água , Animais , Embrião não Mamífero , Humanos , Larva , Propilenoglicol , Poluentes Químicos da Água/toxicidade , Peixe-Zebra
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