查看更多>>摘要：SYL927 and SYL930, two aminopropanediol analogues, are novel Sphingosine-1-phosphate receptor 1 (S1P1) modulators with higher selectivity and pharmacological activity compared with FTY720. Although the immunosuppressive activity of SYLs has been well demonstrated, information regarding the metabolic fates of the two chemicals is limited except for the CYP-catalyzed hydroxylation of SYL930. In this study, the biotransformation schemes of the two promising chemicals were investigated and compared using liver microsomes, S9 fractions and recombinant enzymes, and relevant molecular mechanism was primarily demonstrated by ligand-enzyme docking analysis (CDOCKER). As a result, the hydroxylation at alkyl chain on oxazole ring by the action of CYPs was found for both SYLs in vivo. The SULT-catalyzed sulfonation of the hydroxide was observed for SYL927 while the ADH/ALDH-catalyzed oxidation was only discovered for SYL930. The docking analysis suggested that specific non-covalent forces and/or bonding conformations of the hydroxides with biomacromolecules might be involved in the disparate metabolism of SYLs. Exploring the metabolic characteristics will help clarify the substance base for efficacy and safety of the two drugs. The uncovered structure-metabolism relationship in this study may provide an implication for the design and optimization for other S1P modulators.
查看更多>>摘要：Lactulose is a common laxative and has been widely applied to clinical treatment for constipation. This study aimed to explore the improving effect of lactulose on constipation through the mediation of gut microbiota and intestinal metabolites. BALB/c mice with constipation induced by loperamide were orally treated with lactulose for four weeks. After the treatment, the constipation-related factors were determined. The effect of lactulose on the composition of gut microbiota was assessed by 16S rDNA gene sequencing. Gas chromatography or liquid chromatography-mass spectrometer (GC/LC-MS) analysis was used for the quantification of intestinal metabolites. The treatment of constipated mice with lactulose accelerated intestinal motility, suppressed inflammatory responses, protected gut barrier, and improved metabolisms of water and salt in the intestinal tract. These therapeutic effects were attributed to the reversed gut microbiota dysfunction, which conferred the benefit to the production of intestinal metabolites including bile acids, short-chain fatty acids, and tryptophan catabolites. Further, the depletion of intestinal flora from loperamide- or (loperamide + lactulose)-treated mice confirmed the significance of gut microbiota in the mediation of constipation. In summary, this study leads us to propose that lactulose may improve constipation through a prebiotic effect on gut microbiota and intestinal metabolites.
Bochmann, Esther S.Steidel, AndreasRosenblatt, Karin M.Gessner, David...
10页
查看更多>>摘要：In general, the erosion rate of copovidone-based amorphous solid dispersions (ASDs) in contact with water diminishes with increasing drug load, causing poor drug release from the final drug product. A new easy-to-use tool with low materialand time-consumption, the microscopic erosion time test (METT), was established to allow prediction of the API-specific drug load threshold between an eroding and a non-eroding ASD. This API-specific drug load value is further described as the drug load dispersibility limit (DDL) and is the highest drug load at which an eroding ASD was still observed. A minor increase of 2.5% in drug load above the DDL already led to a non-eroding ASD and it was subsequently connected to the drug load-associated drop in API in vitro dissolution of ASD tablets and an impeded tablet disintegration. In total, 19 APIs in copovidone-based ASDs were characterized via the METT while a subset of these was investigated in more detail, namely indomethacin, celecoxib, dipyridamole, fenofibrate, naproxen and ritonavir. Furthermore, indomethacinand celecoxib-containing ASDs with various drug loads were prepared and characterized to link the METT outcome with ASD tablet in vitro dissolution and disintegration performance.
查看更多>>摘要：Diacylglycerol acyltransferase 1 (DGAT1) plays a pivotal role in lipid metabolism by catalyzing the committed step in triglyceride (TG) synthesis and has been considered as a potential therapeutic target of multiple metabolic diseases, including dyslipidemia, obesity and type 2 diabetes. Here we report a novel DGAT1 inhibitor, Yhhu2407, which showed a stronger DGAT1 inhibitory activity (IC50 = 18.24 +/- 4.72 nM) than LCQ908 (IC50 = 78.24 +/- 8.16 nM) in an enzymatic assay and led to a significant reduction in plasma TG after an acute lipid challenge in mice. Pharmacokinetic studies illustrated that Yhhu2407 displayed a low systemic, liverand intestine-targeted distribution pattern, which is consistent with the preferential tissue expression pattern of DGAT1 and therefore might help to maximize the beneficial pharmacological effects and prevent the occurrence of side effects. Cell-based investigations demonstrated that Yhhu2407 inhibited free fatty acid (FFA)-induced TG accumulation and apolipoprotein B (ApoB)-100 secretion in HepG2 cells. In vivo study also disclosed that Yhhu2407 exerted a beneficial effect on regulating plasma TG and lipoprotein levels in rats, and effectively ameliorated high-fat diet (HFD)-induced dyslipidemia in hamsters. In conclusion, we identified Yhhu2407 as a novel DGAT1 inhibitor with potent efficacy on improving lipid metabolism in rats and HFD-fed hamsters without causing obvious adverse effects.
Siqueira, Marina Micaele RodriguesFreire, Paulo de Tarso CavalcanteCruz, Beatriz Goncalvesde Freitas, Thiago Sampaio...
8页
查看更多>>摘要：Chalcones and their derivatives are substances of great interest for medicinal chemistry due to their antibacterial activities. As the bacterial resistance to clinically available antibiotics has become a worldwide public health problem, it is essential to search for compounds capable of reverting the bacterial resistance. As a possibility, the chalcone class could be an interesting answer to this problem. The chalcones (2E)-1-(4 '-aminophenyl)-3-(phenyl)-prop-2-en-1-one (APCHAL), and (2E)-1-(4 '-aminophenyl)-3-(4-chlorophenyl)-prop-2-en-1-one (ACLOPHENYL) were synthesized by the Claisen-Schmidt condensation and characterized by H-1 and C-13 nuclear magnetic resonance (NMR), Fourier-transform infrared (FT-IR), and mass spectrometry (MS), In addition, microbiological tests were performed to investigate the antibacterial activity, modulatory potential, and efflux pump inhibition against Staphylococcus aureus (S. aureus) multi-resistant strains. Regarding the S. aureus Grampositive model, the APCHAL presented synergism with gentamicin and antagonism with penicillin. APCHAL reduced the Minimum inhibitory concentration (MIC) of gentamicin by almost 70%. When comparing the effects of the antibiotic modifying activity of ACLOPHENYL and APCHAL, a loss of synergism is noted with gentamicin due to the addition of a chlorine to the substance structure. For Escherichia coli (E. coli) a total lack of effect, synergistic or antagonistic, was observed between ACLOPHENYL and the antibiotics. In the evaluation of inhibition of the efflux pump, both chalcones presented a synergistic effect with norfloxacin and ciprofloxacin against S. aureus, although the effect is much less pronounced with ACLOPHENYL. The effect of APCHAL is particularly notable against the K2068 (MepA overexpresser) strain, with synergistic effects with both ciprofloxacin and ethidium bromide. The docking results also show that both compounds bind to roughly the same region of the binding site of 1199B (NorA overexpresser), and that this region overlaps with the preferred binding region of norfloxacin. The APCHAL chalcone may contribute to the prevention or treatment of infectious diseases caused by multidrug-resistant S. aureus.
Gaur, RituVerma, Dipesh KumarAlam, Syed ImteyazKamboj, Dev Vrat...
8页
查看更多>>摘要：Tularemia, a zoonosis generally prevalent in the northern half of the globe, is caused by Francisella tularensis. Among various Francisella tularensis species, subspecies tularensis is the most pathogenic to humans causing the infection through an airborne route, abrasions in the skin, and contact with infected animals. At present no approved vaccine exists for this intracellular pathogen. Principal defensive immunity against Francisella is T-cell mediated immunity, hence, picking out significant T-cell antigens is obligatory for Francisella vaccine advancement. In the present study, an immunoproteomics approach was employed to discover T-cell antigens by infecting dendritic cells derived from monocytes with F. tularensis NCTC10857, followed by immunoaffinity isolation of MHC class I molecules and acidic elution of bound peptides. The tandem mass spectrometry technique was used to identify the sequences of the isolated peptides. Ten MHC class I restricting Francisella derived peptides were successfully identified. Top three isolated peptide sequences were modeled and used for in silico docking study to substantiate their interaction and characterize their binding potential. Virtual docking studies further confirmed a high binding affinity for top three peptides with MHC class I molecule. The outcome of this study has led to identification of the probable vaccine candidates for human studies based on T cell-antigens against Francisella.
Wani, Tanveer A.Alsaif, NawafAlanazi, Mohammed M.Bakheit, Ahmed H....
9页
查看更多>>摘要：Human serum albumin (HSA) is the core protein in the systemic circulation and has a fundamental role in transportation and distribution of ligands in -vivo. In this study, a newly synthesized and patented anticancer dihydropyrimidine derivative; 4-(4-ethoxyphenyl)-5-(3,4,5 trimethoxybenzoyl)-3,4-dihydropyrimidin-2(1H)one (DHP) was evaluated for its binding to HSA. Ligand-HSA interaction is significant factor to attribute the toxicity or therapeutic potential to a ligand. Multi-spectroscopic studies combined with molecular modelling and molecular dynamic simulation (MDS) were conducted to understand the HSA-DHP binding mechanism. In-silico evaluation of DHP for its toxicity and metabolism was also conducted. Reduction in the binding constants was observed from 6.71 x 10(4) - 4.5 x 10(3) at increased temperatures which indicates moderate binding and the interaction was found to follow a static quenching mechanism. Further, Site I on HSA for DHP was established by competition with site specific markers and the results were supported by molecular docking. The stability of the HSA-DHP complex was established with MDS studies. Thermodynamics parameters revealed involvement of hydrogen bonding and van der Waals forces for HSA-DHP binding. An in-silico evaluation of DHP for its toxicity and metabolism provided that the synthesized compound was potentially safe and could be a promising candidate for further studies.
查看更多>>摘要：Due to the increase in bacterial resistance to common antibiotics and the lack of newly approved drugs, antimicrobial peptides (AMP) have been shown to be an alternative to combat infections caused by drug-resistant organisms. In particular, synthetic anti-lipopolysaccharide peptides (SALP) with the lead structure Aspidasept (Pep19-2.5) display a high anti-inflammatory activity in vitro and in vivo systems of endotoxemia and bacteremia. This was found not only when SALP were applied systemically (i.e. against sepsis), but also in topical therapies aimed at treating wound infections. A further important application involves combating common pathologies of the gastrointestinal tract, such as chronic infections of the small intestine and the colon (e.g., Crohn's disease). For the necessary oral application, the active pharmaceutical ingredient (API), Aspidasept (R), must be encapsulated to ensure its protection against the low pH and the hydrolytic enzymes of the gastrointestinal tract. Here, the encapsulation of Aspidasept in polysaccharide matrices, essentially alginate and pectin, was systematically investigated with a variety of physico-chemical techniques. Specifically, we characterized key features of the nanoparticles such as their sizes and size distributions, as well as their stability in different environments mimicking digestive fluids. Finally, we studied the release of the drug from the polysaccharide matrices and the ability of nanoparticles to neutralize endotoxemia in vitro. We showed that our lead formulations exert an optimum inhibitory activity on immune cells stimulated by lipopolysaccharide.
Zorec, Barbara SterleZupancic, SpelaLavric, ZoranDreu, Rok...
10页
查看更多>>摘要：In this work the preparation of drug loaded polymeric nanoparticles using electrospraying method and their subsequent characterization is presented. Our purpose was to incorporate the drug with extremely low solubility and low oxidative stability into polyvinylpyrolidone nanoparticles in order to improve its solubility and preserve its chemical stability and hence evaluate the ability of the technology to stabilize such systems in nanoparticulate form. Through the initial screening and optimization of process parameters and polymer solution properties, we detected different morphologies of electrosprayed product particles, where the use of lower molecular weight polymer resulted in a higher process instability as well as in a broader particle size distribution. On the other hand, the solution containing polyvinylpyrolidone with higher molecular weight showed sensitivity to different flow rates and electric field changes, which again resulted in differing the particle size and morphology. The electrosprayed products, prepared by sufficient process stability and having adequately narrow size distribution span, showed lower initial simvastatin contents than theoretically expected, which indicated an oxidative drug degradation already during the electrospraying process. The addition of antioxidants improved simvastatin chemical stability in the particles, during the process itself as well as after accelerated stability study. With an addition of butylated hydroxyanisole antioxidant mixture into initial polymer solution more than 95% of the drug content was preserved after one month at accelerated conditions, whereas in formulations without antioxidants simvastatin content was less than 6%. Antioxidants addition however did not influence only simvastatin stability but also simvastatin solubility. Surprisingly, antioxidants addition did decrease drug solubility in buffers (pH=4 and pH=6.8) for more than a half without any solid state changes of simvastatin. Potential hydrophobic interaction between simvastatin and antioxidants are hindering the drug solubility in the respective buffer, despite drug being in amorphous state.
查看更多>>摘要：Liquid crystal display (LCD) 3D printing technology is one of the three currently available photocuring threedimensional printing technologies. LCD 3D printers usually use wavelengths in the ultraviolent (UV) range. However, recently introduced light-emitting diodes (LED) projectors enable visible light-induced photo polymerization, which would have an advantage in terms of safety in drug production. The aim of this work was to investigate the feasibility of printing ibuprofen extended release tablets under visible light irradiation and to evaluate characteristics of printed tablets. Influences of exposure time and wavelengths (UV versus visible light) on characteristics of tablets were evaluated. Tablets were printed using 405 nm and 450 nm LED light. Visible light enabled significantly faster printing as well as better dimensions accuracy of printed tablets. It was noticed that printing under 450 nm LED resulted in slightly softer tablets compared to tablets printing with 405 nm LED. Extended ibuprofen release was obtained from all formulations. Exposure time did not have influence on drug release in formulations with low water content. However, in a formulation with higher water content, the exposure time had a pronounced effect on drug release (in eight hours of testing, differences were from 27% to 95%). Wavelength affected the release rate of ibuprofen. Tablets prepared using 450 nm LEDs released ibuprofen faster than tablets prepared with 405 nm LEDs. The main mechanism of ibuprofen release was diffusion, regardless of exposure time and wavelength. Characteristics of obtained tablets indicate that further optimization of this process is necessary, but this new printing process approach opens the possibility for novel wavelength consideration in order to obtain the safe printing process of tablets.
NSTL
Elsevier