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1.
AAPS PharmSciTech ; 23(7): 260, 2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36123553

RESUMO

In this study, the addition of monoolein to phosphatidylcholine (PC), tricaprylin, and propylene glycol (PG) mixtures was studied to produce fluid precursor formulations (FIPs) that could transform into hexagonal phase (resistant to aqueous dilution) in vitro and in vivo. The overall goal was to obtain FIPs that could incorporate chemopreventive drugs for subcutaneous administration in the mammary tissue to inhibit the development and/or recurrence of breast cancer. Increasing PG content reduced FIP viscosity up to ~ 2.5-fold, while increases in PC (over monoolein) increased the formation of emulsified systems. The hexagonal phase was observed at 20% of water and higher, with the minimum amount of water necessary for this formation increasing with PG content. The selected FIP formed a depot in vivo after ~ 24 h of administration; its structure was compatible with the hexagonal phase and it remained in the mammary tissue for at least 30 days, prolonging the permanence of a fluorescent probe. In vitro, the release of the synthetic retinoid fenretinide was slow, with ~ 9% of the drug released in 72 h. Consistent with this slow release, fenretinide IC50 in breast cancer cells was ~ 100-fold higher in the selected FIP compared to its solution. The FIP reduced cell migration and presented higher cytotoxicity towards tumor compared to non-tumor cells. Given the limited number of options for pharmacological prevention of breast cancer development and recurrences, this formulation could potentially find applicability to reduce the frequency of administration and improve local concentrations of chemopreventive drugs.


Assuntos
Neoplasias da Mama , Fenretinida , Neoplasias da Mama/tratamento farmacológico , Liberação Controlada de Fármacos , Feminino , Corantes Fluorescentes , Humanos , Fosfatidilcolinas , Propilenoglicol/química , Água/química
2.
Int J Pharm ; 625: 122128, 2022 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-35995318

RESUMO

Solid phase interactions are often the reason for incompatibilities in solid dosage forms. A special situation occurs, if the incompatible compounds are able to migrate within the solid matrix. This study describes for the first time the migration of a plasticizer from the coating into the core and its interaction with the active ingredient located there. This behavior was observed in rifaximin gastro-resistant granules and resulted in the formation of solvates with altered dissolution behavior. For a detailed study, rifaximin was incubated with five plasticizers of different solubility and miscibility as well as different molecular geometry (linear vs branched), (dibutyl sebacate, tributyl citrate, triacetin, polyethylene glycol 400, and propylene glycol). The resulting solid states were analyzed by means of PXRD, supported by thermogravimetric analysis, infrared spectroscopy, and quantitative H NMR. No direct correlation could be demonstrated between the resulting type of solvate/hydrate and the affinity of rifaximin with the respective plasticizers. Interestingly all plasticizers that are able to form type I solvates/hydrates have linear structures. This common feature, which distinguishes them from the more bulky TAC and TBC, seems to be a key characteristic. Rifaximin-PG-solvate formation was not only detected after direct incubation trials, but also observed in enteric coated granules.


Assuntos
Plastificantes , Triacetina , Plastificantes/química , Propilenoglicol , Rifaximina , Solubilidade
3.
Microb Pathog ; 171: 105725, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36007847

RESUMO

Among the important recent observations involving anaerobic respiration was that an electron acceptor produced as a result of an inflammatory response to Salmonella Typhimurium generates a growth advantage over the competing microbiota in the lumen. In this regard, anaerobically, salmonellae can oxidize thiosulphate (S2O32-) converting it into tetrathionate (S4O62-), the process by which it is encoded by ttr gene cluster (ttrSRttrBCA). Another important pathway under aerobic or anaerobic conditions is the 1,2-propanediol-utilization mediated by the pdu gene cluster that promotes Salmonella expansion during colitis. Therefore, we sought to compare in this study, whether Salmonella Heidelberg strains lacking the ttrA, ttrApduA, and ttrACBSR genes experience a disadvantage during cecal colonization in broiler chicks. In contrast to expectations, we found that the gene loss in S. Heidelberg potentially confers an increase in fitness in the chicken infection model. These data argue that S. Heidelberg may trigger an alternative pathway involving the use of an alternative electron acceptor, conferring a growth advantage for S. Heidelberg in chicks.


Assuntos
Galinhas , Salmonelose Animal , Animais , Galinhas/metabolismo , Propilenoglicol/metabolismo , Salmonella , Salmonella typhimurium , Tiossulfatos
4.
Respir Res ; 23(1): 216, 2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-35999544

RESUMO

BACKGROUND: Electronic cigarettes (e-cigarettes) are used worldwide as a substitute for conventional cigarettes. Although they are primarily intended to support smoking cessation, e-cigarettes have been identified as a gateway to smoking habits for young people. Multiple recent reports have described the health effects of inhaling e-cigarettes. E-cigarette liquid (e-liquid) is mainly composed of propylene glycol (PG) and glycerol (Gly), and the aerosol generated by these devices primarily contains these two components. Thus, this study aimed to evaluate the effects of PG and Gly on human small airway epithelial cells (SAECs). METHODS: SAECs were exposed to PG or Gly, and cell proliferation, cell viability, lactate dehydrogenase (LDH) release, DNA damage, cell cycle, and apoptosis were evaluated. Additionally, SAECs derived from chronic obstructive pulmonary disease (COPD) patients (COPD-SAECs) were investigated. RESULTS: Exposure of SAECs to PG significantly inhibited proliferation (1%, PG, p = 0.021; 2-4% PG, p < 0.0001) and decreased cell viability (1-4% PG, p < 0.0001) in a concentration-dependent manner. Gly elicited similar effects but to a reduced degree as compared to the same concentration of PG. PG also increased LDH release in a concentration-dependent manner (3% PG, p = 0.0055; 4% PG, p < 0.0001), whereas Gly did not show a significant effect on LDH release. SAECs exposed to 4% PG contained more cells that were positive for phosphorylated histone H2AX (p < 0.0001), a marker of DNA damage, and an increased proportion of cells in the G1 phase (p < 0.0001) and increased p21 expression (p = 0.0005). Moreover, caspase 3/7-activated cells and cleaved poly (ADP-ribose) polymerase 1 expression were increased in SAECs exposed to 4% PG (p = 0.0054). Furthermore, comparing COPD-SAECs to SAECs without COPD in PG exposure, cell proliferation, cell viability, DNA damage and apoptosis were significantly greater in COPD-SAECs. CONCLUSION: PG damaged SAECs more than Gly. In addition, COPD-SAECs were more susceptible to PG than SAECs without COPD. Usage of e-cigarettes may be harmful to the respiratory system, especially in patients with COPD.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Doença Pulmonar Obstrutiva Crônica , Adolescente , Células Epiteliais/metabolismo , Glicerol , Humanos , Propilenoglicol/toxicidade , Doença Pulmonar Obstrutiva Crônica/metabolismo , Aerossóis e Gotículas Respiratórios
5.
J Pharm Sci ; 111(10): 2758-2764, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35908653

RESUMO

Mesalazine is a low-permeable and low-soluble drug, which makes it a class IV drug in the Biopharmaceutics Classification System. Hence, its solubilization can be helpful for various stages of formulation development. The purpose of this study was to investigate the solubilization manner and thermodynamics of mesalazine in ternary solvent combinations of {ethanol (1) + propylene glycol (2) + water (3)} using the shake-flask technique at (298.2-313.2) K. In the following, the mathematical representation of the acquired solubility data using some popular models was evaluated. The accuracies of the applied models were described by percentages of mean relative deviation (MRD%). Based on obtained results (MRD% < 10.0), it can be concluded that the trained models can adequately predict the solubility of mesalazine in the investigated ternary solvent combinations. The findings also revealed that the solution composition and temperatures greatly influence the solubility of mesalazine. In addition, the thermodynamic characteristics of the mesalazine dissolution process indicate that the mesalazine dissolution process is endothermic and entropy-driven. The generating data in the current work also expands the available solubility database for mesalazine in the solvent mixtures.


Assuntos
Etanol , Água , Mesalamina , Propilenoglicol , Solubilidade , Solventes , Temperatura , Termodinâmica
6.
Chem Res Toxicol ; 35(8): 1410-1417, 2022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-35830545

RESUMO

Flavorants, nicotine, and organic acids are common additives found in the e-liquid carrier solvent, propylene glycol (PG) and/or glycerol (GL), at various concentrations. Some of the most concentrated and prevalent flavorants in e-liquids include trans-cinnamaldehyde, vanillin, and benzaldehyde. Aldehyde flavorants have been shown to react with PG and GL to form flavorant-PG and -GL acetals that have unique toxicity properties in e-liquids before aerosolization. However, there is still much that remains unknown about the effects of different e-cigarette solvents, water, nicotine, and organic acids on the rate of acetalization in e-liquids. We used 1H NMR spectroscopy to determine the first-order initial rate constant, half-life, and % acetal formed at equilibrium for flavorant-acetal formation in simulated e-liquids. Herein, we report that acetalization generally occurs at a faster rate and produces greater yields in e-liquids with higher ratios of GL (relative to PG). trans-Cinnamaldehyde acetals formed the fastest in 100% PG-simulated e-liquids, followed by benzaldehyde and vanillin based on their half-lives and rate constants. The acetal yield was greatest for benzaldehyde in PG e-liquids, followed by trans-cinnamaldehyde and vanillin. Acetalization in PG e-liquids containing aldehyde flavorants was inhibited by water and nicotine but catalyzed by benzoic acid. Flavorant-PG acetal formation was generally delayed in the presence of nicotine, even if benzoic acid was present at 2-, 4-, or 10-fold the nicotine concentration, as compared to the PG e-liquids with 2.5 mg/mL flavorant. Thus, commercial e-liquids with aldehyde flavorants containing a higher GL ratio (relative to PG), little water, no nicotine, nicotine with excess organic acids, or organic acids without nicotine would undergo acetalization the fastest and with the highest yield. Many commercial e-liquids must therefore contain significant amounts of flavorant acetals.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Acetais , Aldeídos , Benzaldeídos , Benzoatos , Aromatizantes/análise , Glicerol/química , Espectroscopia de Ressonância Magnética , Nicotina , Propilenoglicol/química , Solventes/química , Água
7.
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
8.
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
9.
Nat Commun ; 13(1): 3746, 2022 Jun 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
10.
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
11.
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
12.
J Appl Toxicol ; 42(10): 1701-1722, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35543240

RESUMO

Most flavors used in e-liquids are generally recognized as safe for oral consumption, but their potential effects when inhaled are not well characterized. In vivo inhalation studies of flavor ingredients in e-liquids are scarce. A structure-based grouping approach was used to select 38 flavor group representatives (FGR) on the basis of known and in silico-predicted toxicological data. These FGRs were combined to create prototype e-liquid formulations and tested against cigarette smoke (CS) in a 5-week inhalation study. Female A/J mice were whole-body exposed for 6 h/day, 5 days/week, for 5 weeks to air, mainstream CS, or aerosols from (1) test formulations containing propylene glycol (PG), vegetable glycerol (VG), nicotine (N; 2% w/w), and flavor (F) mixtures at low (4.6% w/w), medium (9.3% w/w), or high (18.6% w/w) concentration or (2) base formulation (PG/VG/N). Male A/J mice were exposed to air, PG/VG/N, or PG/VG/N/F-high under the same exposure regimen. There were no significant mortality or in-life clinical findings in the treatment groups, with only transient weight loss during the early exposure adaptation period. While exposure to flavor aerosols did not cause notable lung inflammation, it caused only minimal adaptive changes in the larynx and nasal epithelia. In contrast, exposure to CS resulted in lung inflammation and moderate-to-severe changes in the epithelia of the nose, larynx, and trachea. In summary, the study evaluates an approach for assessing the inhalation toxicity potential of flavor mixtures, thereby informing the selection of flavor exposure concentrations (up to 18.6%) for a future chronic inhalation study.


Assuntos
Fumar Cigarros , Administração por Inalação , Aerossóis/toxicidade , Animais , Feminino , Glicerol/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos , Propilenoglicol/toxicidade , Tabaco
13.
J Bacteriol ; 204(9): e0057621, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-35575582

RESUMO

Bacterial microcompartments (MCPs) are protein-based organelles that house the enzymatic machinery for metabolism of niche carbon sources, allowing enteric pathogens to outcompete native microbiota during host colonization. While much progress has been made toward understanding MCP biogenesis, questions still remain regarding the mechanism by which core MCP enzymes are enveloped within the MCP protein shell. Here, we explore the hypothesis that the shell protein PduB is responsible for linking the shell of the 1,2-propanediol utilization (Pdu) MCP from Salmonella enterica serovar Typhimurium LT2 to its enzymatic core. Using fluorescent reporters, we demonstrate that all members of the Pdu enzymatic core are encapsulated in Pdu MCPs. We also demonstrate that PduB is critical for linking the entire Pdu enzyme core to the MCP shell. Using MCP purifications, transmission electron microscopy, and fluorescence microscopy, we find that shell assembly can be decoupled from the enzymatic core, as apparently empty MCPs are formed in Salmonella strains lacking PduB. Mutagenesis studies reveal that PduB is incorporated into the Pdu MCP shell via a conserved, lysine-mediated hydrogen bonding mechanism. Finally, growth assays and system-level pathway modeling reveal that unencapsulated pathway performance is strongly impacted by enzyme concentration, highlighting the importance of minimizing polar effects when conducting these functional assays. Together, these results provide insight into the mechanism of enzyme encapsulation within Pdu MCPs and demonstrate that the process of enzyme encapsulation and shell assembly are separate processes in this system, a finding that will aid future efforts to understand MCP biogenesis. IMPORTANCE MCPs are unique, genetically encoded organelles used by many bacteria to survive in resource-limited environments. There is significant interest in understanding the biogenesis and function of these organelles, both as potential antibiotic targets in enteric pathogens and also as useful tools for overcoming metabolic engineering bottlenecks. However, the mechanism by which these organelles are formed natively is still not completely understood. Here, we provide evidence of a potential mechanism in S. enterica by which a single protein, PduB, links the MCP shell and metabolic core. This finding is critical for those seeking to disrupt MCPs during pathogenic infections or for those seeking to harness MCPs as nanobioreactors in industrial settings.


Assuntos
Salmonella enterica , Antibacterianos/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Carbono/metabolismo , Regulação Bacteriana da Expressão Gênica , Lisina/metabolismo , Organelas/metabolismo , Propilenoglicol/metabolismo , Propilenoglicóis , Salmonella enterica/genética , Salmonella enterica/metabolismo , Salmonella typhimurium/metabolismo
14.
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
15.
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
16.
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
17.
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
18.
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
20.
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
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