Cyclodextrin-enhanced solubilization and removal of residual-phase chlorinated solvents from porous media

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boving, T.B.; Wang, X.; Brusseau, M.L.

1999-03-01

The development of improved methods for remediation of contaminated aquifers has emerged as a significant environmental priority. One technology that appears to have considerable promise involves the use of solubilization agents such as surfactants and cosolvents for enhancing the removal of residual phase immiscible liquids. The authors examined the use of cyclodextrin, a glucose-based molecule, for solubilizing and removing residual-phase immiscible liquid from porous media. Batch experiments were conducted to measure the degree of trichloroethene (TCE) and tetrachloroethene (PCE) solubilization induced by hydroxypropyl-{beta}-cyclodextrin (HPCD) and methyl-{beta}-cyclodextrin (MCD). These studies revealed that the solubilities of TCE and PCE were enhanced bymore » up to 9.5 and 36.0 times, respectively. Column experiments were conducted to compare water and cyclodextrin-enhanced flushing of Borden sand containing residual saturations of TCE and PCE. The results indicate that solubilization and mass removal were enhanced substantially with the use of cyclodextrins. The effluent concentrations during the steady-state phase of the HPCD and MCD flushing experiments were close to the apparent solubilities measured with the batch experiments, indicating equilibrium concentrations were maintained during the initial phase of cyclodextrin flushing. Mobilization was observed for only the TCE-MCD and PCE-5%MCD experiments.« less

Caveolin-1 is a negative regulator of caveolae-mediated endocytosis to the endoplasmic reticulum.

PubMed

Le, Phuong U; Guay, Ginette; Altschuler, Yoram; Nabi, Ivan R

2002-02-01

Caveolae are flask-shaped invaginations at the plasma membrane that constitute a subclass of detergent-resistant membrane domains enriched in cholesterol and sphingolipids and that express caveolin, a caveolar coat protein. Autocrine motility factor receptor (AMF-R) is stably localized to caveolae, and the cholesterol extracting reagent, methyl-beta-cyclodextrin, inhibits its internalization to the endoplasmic reticulum implicating caveolae in this distinct receptor-mediated endocytic pathway. Curiously, the rate of methyl-beta-cyclodextrin-sensitive endocytosis of AMF-R to the endoplasmic reticulum is increased in ras- and abl-transformed NIH-3T3 cells that express significantly reduced levels of caveolin and few caveolae. Overexpression of the dynamin K44A dominant negative mutant via an adenovirus expression system induces caveolar invaginations sensitive to methyl-beta-cyclodextrin extraction in the transformed cells without increasing caveolin expression. Dynamin K44A expression further inhibits AMF-R-mediated endocytosis to the endoplasmic reticulum in untransformed and transformed NIH-3T3 cells. Adenoviral expression of caveolin-1 also induces caveolae in the transformed NIH-3T3 cells and reduces AMF-R-mediated endocytosis to the endoplasmic reticulum to levels observed in untransformed NIH-3T3 cells. Cholesterol-rich detergent-resistant membrane domains or glycolipid rafts therefore invaginate independently of caveolin-1 expression to form endocytosis-competent caveolar vesicles via rapid dynamin-dependent detachment from the plasma membrane. Caveolin-1 stabilizes the plasma membrane association of caveolae and thereby acts as a negative regulator of the caveolae-mediated endocytosis of AMF-R to the endoplasmic reticulum.

Enhanced rectal absorption and reduced local irritation of the anti-inflammatory drug ethyl 4-biphenylylacetate in rats by complexation with water-soluble beta-cyclodextrin derivatives and formulation as oleaginous suppository.

PubMed

Arima, H; Kondo, T; Irie, T; Uekama, K

1992-11-01

To improve the rectal delivery of ethyl 4-biphenylylacetate (EBA), a prodrug of the anti-inflammatory drug 4-biphenylylacetic acid (BPAA), the use of highly water-soluble 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD) was investigated and compared with the use of the parent beta-cyclodextrin (beta-CyD). Among the three beta-CyDs, HP-beta-CyD was best at improving the rectal bioavailability of EBA in rats after single and multiple administrations of oleaginous suppositories (Witepsol H-5) containing the complexes. To gain insight into the enhancing effect of beta-CyDs, the absorption behaviors of EBA (observed by monitoring BPAA as an active metabolite of EBA) and beta-CyDs themselves were examined in vitro, in situ, and in vivo. The in situ recirculation study revealed that the complexed form of EBA was less absorbable from the rectal lumen in the solution state, but this disadvantageous effect of beta-CyDs was compensated in part by the inhibition of the bioconversion of EBA to BPAA. When beta-CyDs were coadministered with EBA in vivo, however, rather high amounts of HP-beta-CyD (approximately 26% of dose) and DM-beta-CyD (approximately 21% of dose), compared with beta-CyD (approximately 5% of dose), were absorbed from the rat rectum. Thus, the enhancement of rectal absorption of EBA in vivo can be explained by the facts that the hydrophilic beta-CyDs increased the release rate of EBA from the vehicle and stabilized EBA in the rectal lumen and that the drug was partly absorbed in the form of the complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholesterol depletion by methyl-beta-cyclodextrin enhances myoblast fusion and induces the formation of myotubes with disorganized nuclei.

PubMed

Mermelstein, Cláudia S; Portilho, Débora M; Medeiros, Rommel B; Matos, Aline R; Einicker-Lamas, Marcelo; Tortelote, Giovane G; Vieyra, Adalberto; Costa, Manoel L

2005-02-01

The formation of a skeletal muscle fiber begins with the withdrawal of committed mononucleated precursors from the cell cycle. These myoblasts elongate while aligning with each other, guided by recognition between their membranes. This step is followed by cell fusion and the formation of long striated multinucleated myotubes. We used methyl-beta-cyclodextrin (MCD) in primary cultured chick skeletal muscle cells to deplete membrane cholesterol and investigate its role during myogenesis. MCD promoted a significant increase in the expression of troponin T, enhanced myoblast fusion, and induced the formation of large multinucleated myotubes with nuclei being clustered centrally and not aligned at the cell periphery. MCD myotubes were striated, as indicated by sarcomeric alpha-actinin staining, and microtubule and desmin filament distribution was not altered. Pre-fusion MCD-treated myoblasts formed large aggregates, with cadherin and beta-catenin being accumulated in cell adhesion contacts. We also found that the membrane microdomain marker GM1 was not present as clusters in the membrane of MCD-treated myoblasts. Our data demonstrate that cholesterol is involved in the early steps of skeletal muscle differentiation.

Optimization of gas chromatographic method for the enantioseparation of arylpropionic non-steroidal anti-inflammatory drug methyl esters.

PubMed

Petrović, Marinko; Debeljak, Zeljko; Blazević, Nikola

2005-09-15

The gas chromatography (GC) method for enantioseparation of well-known non-steroidal anti-inflammatory drugs ibuprofen, fenoprofen and ketoprofen methyl esters mixture was developed. Best enantioseparation was performed on capillary column with heptakis-(2,3-di-O-methyl-6-O-t-butyldimethyl-silyl)-beta-cyclodextrin stationary phase and hydrogen used as a carrier gas. Initial temperature, program rate and carrier pressure were optimized to obtain best resolution between enantiomers.

Prediction of selectivity for enantiomeric separations of uncharged compounds by capillary electrophoresis involving dual cyclodextrin systems.

PubMed

Abushoffa, Adel M; Fillet, Marianne; Hubert, Phillipe; Crommen, Jacques

2002-03-01

The single-isomer polyanionic cyclodextrin (CD) derivative heptakis-6-sulfato-beta-cyclodextrin (HSbetaCD) has been tested as chiral additive for the enantioseparation of non-steroidal anti-inflammatory drugs, such as fenoprofen, flurbiprofen, ibuprofen and ketoprofen, in capillary electrophoresis, using a pH 2.5 phosphoric acid-triethanolamine buffer in the reversed polarity mode. In most cases, the enantiomers of these acidic compounds, present in uncharged form at that pH, were only poorly resolved with HSbetaCD alone. However, the use of HSbetaCD in combination with the neutral CD derivative, heptakis-(2,3,6-tri-O-methyl)-beta-cyclodextrin (TMbetaCD), which has a particularly high enantioselectivity towards these compounds, has led to complete enantioresolution in reasonably low migration times in most cases. Affinity constants for the enantiomers with the two cyclodextrins were determined, using linear regression in a two-step approach. Affinity constants with the charged HSbetaCD were first calculated in single systems while those with the neutral TMbetaCD were determined in dual systems. Selectivity for the enantiomeric separation of these compounds in dual CD systems could be predicted using recently developed mathematical models.

Anti-inflammatory, analgesic and ulcerogenic properties of S-(+)-ibuproxam, racemic ibuproxam-beta-cyclodextrin and S-(+)-ibuproxam-beta-cyclodextrin.

PubMed

Bole-Vunduk, B; Verhnjak, K; Zmitek, J

1996-11-01

The anti-inflammatory, analgesic and gastric mucosal damage-inducing activities of S-(+)-ibuproxam, and S-(+)-ibuproxam-beta-cyclodextrin, new propionic acid derivatives, and racemic ibuproxam-beta-cyclodextrin were investigated in three animal models and compared with those of racemic ibuproxam, racemic ibuprofen and its optical enantiomer S-(+)-ibuprofen. The anti-inflammatory activities of racemic ibuprofen, S-(+)-ibuprofen and racemic ibuproxam in carrageenan-induced paw oedema in rats were almost equipotent and slightly greater than those of S-(+)-ibuproxam and S-(+)-ibuproxam-beta-cyclodextrin, and significantly greater than that of racemic ibuproxam-beta-cyclodextrin. In abdominal constriction tests in mice, the analgesic effects of racemic ibuproxam, S-(+)-ibuproxam, racemic ibuproxam-beta-cyclodextrin and S-(+)-ibuproxam-beta-cyclodextrin were significantly less pronounced than those of racemic ibuprofen and S-(+)-ibuprofen. Ulcerogenic activity of S-(+)-ibuproxam-beta-cyclodextrin in rats was found to be significantly weaker than that of racemic ibuproxam-beta-cyclodextrin, racemic ibuproxam and S-(+)-ibuproxam and, most notably, weaker than those of racemic ibuprofen and S-(+)ibuprofen. These results indicate that S-(+)-ibuproxam-beta-cyclodextrin could be a novel potent anti-inflammatory and analgesic agent with a therapeutic index more favourable than that of the classical non-steroid anti-inflammatory drugs ibuprofen and ibuproxam.

Simultaneous total antioxidant capacity assay of lipophilic and hydrophilic antioxidants in the same acetone-water solution containing 2% methyl-beta-cyclodextrin using the cupric reducing antioxidant capacity (CUPRAC) method.

PubMed

Ozyürek, Mustafa; Bektaşoğlu, Burcu; Güçlü, Kubilay; Güngör, Nilay; Apak, Reşat

2008-12-07

Antioxidants are health beneficial compounds that can protect cells from the damage caused by unstable molecules known as reactive oxygen species (ROS). This work reports the capacity assay of both lipophilic and hydrophilic antioxidants simultaneously, by making use of their 'host-guest' complexes with methyl-beta-cyclodextrin (M-beta-CD), a cyclic oligosaccharide, in acetonated aqueous medium using the cupric reducing antioxidant capacity (CUPRAC) method. Thus the order of antioxidant potency of various compounds irrespective of their lipophilicity could be established in the same solvent medium. M-beta-CD was introduced as the water solubility enhancer for lipophilic antioxidants. Two percent M-beta-CD (w/v) in an acetone-H(2)O (9:1, v/v) mixture was found to sufficiently solubilize beta-carotene, lycopene, vitamin E, vitamin C, synthetic antioxidants and other phenolic antioxidants. This assay was validated through linearity, additivity, precision, and recovery. The validation results demonstrate that the CUPRAC assay is reliable and robust. In acetonated aqueous solution of M-beta-CD, only CUPRAC and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays were capable of measuring carotenoids together with hydrophilic antioxidants. The CUPRAC antioxidant capacities of a wide range of polyphenolics and flavonoids were experimentally reported in this work as trolox equivalent antioxidant capacity (TEAC) in the CUPRAC assay, and compared to those found by reference methods, ABTS/horseradish peroxidase (HRP)-H(2)O(2) and ferric reducing antioxidant power (FRAP) assays.

Separation of profen enantiomers by capillary electrophoresis using cyclodextrins as chiral selectors.

PubMed

Blanco, M; Coello, J; Iturriaga, H; Maspoch, S; Pérez-Maseda, C

1998-01-09

A method for resolving the enantiomers of various 2-arylpropionic acids (viz. ketoprofen, ibuprofen and fenoprofen) by capillary zone electrophoresis (CZE) using a background electrolyte (BGE) containing a cyclodextrin as chiral selector is proposed. The effects of the type of cyclodextrin used and its concentration on resolution were studied and heptakis-2,3,6-tri- O-methyl-beta-cyclodextrin was found to be the sole effective choice for the quantitative enantiomeric resolution of all the compounds tested. The influence of pH, BGE concentration, capillary temperature and addition of methanol to the BGE on resolution and other separation-related parameters was also studied. The three compounds studied can be enantiomerically resolved with a high efficiency in a short time (less than 20 min) with no capillary treatment. This makes the proposed method suitable for assessing the enantiomeric purity of commercially available pharmaceuticals.

Sorption of agrochemical model compounds by sorbent materials containing beta-cyclodextrin.

PubMed

Wilson, Lee D; Mohamed, Mohamed H; Guo, Rui; Pratt, Dawn Y; Kwon, Jae Hyuck; Mahmud, Sarker T

2010-04-01

Polymeric sorbent materials that incorporate beta-cyclodextrin (CD) have been prepared and their sorption behavior toward two model agrochemical contaminant compounds, p-nitrophenol (PNP) and methyl chloride examined. The sorption of PNP was studied in aqueous solution using ultraviolet-visible (UV-Vis) spectroscopy, whereas the sorption of methyl chloride from the gas phase was studied using a Langmuir adsorption method. The sorption results for PNP in solution were compared between granular activated carbon (GAC), modified GAC, CD copolymers, and CD-based mesoporous silica hybrid materials. Nitrogen porosimetry at 77 K was used to estimate the surface area and pore structure properties of the sorbent materials. The sorbents displayed variable surface areas as follows: copolymers (36.2-157 m(2)/g), CD-silica materials (307-906 m(2)/g), surface modified GAC (657 m(2)/g), and granular activated carbon (approximately 10(3) m(2)/g). The sorption capacities for PNP and methyl chloride with the different sorbents are listed in descending order as follows: GAC > copolymers > surface modified GAC > CD-silica hybrid materials. In general, the differences in the sorption properties of the sorbents were related to the following: (i) surface area of the sorbent, (ii) CD content and accessibility, (iii) and the chemical nature of the sorbent material.

Comparative studies of the influence of cyclodextrins on the stability of the sunscreen agent, 2-ethylhexyl-p-methoxycinnamate.

PubMed

Scalia, Santo; Casolari, Alberto; Iaconinoto, Antonietta; Simeoni, Silvia

2002-11-07

The effects of beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) on the base-catalyzed degradation and light-induced decomposition of the sunscreen agent, trans-2-ethylhexyl-p-methoxycinnamate (trans-EHMC) were investigated. Reversed-phase liquid chromatography was used to study the interaction between natural and modified cyclodextrins, added to the mobile phase, and the sunscreen. Among the available cyclodextrins (beta-CD, HP-beta-CD, hydroxypropyl-alpha-cyclodextrin and hydroxypropyl-gamma-cyclodextrin), only HP-beta-CD and beta-CD produced a significant decrease in the chromatographic retention of trans-EHMC. The complexation of the sunscreen agent with HP-beta-CD and beta-CD was confirmed by thermal analysis and nuclear magnetic resonance spectroscopy. beta-CD depressed the decomposition of trans-EHMC in alkaline solutions more effectively than HP-beta-CD. Moreover, the irradiation-induced degradation of the sunscreen agent in emulsion vehicles was reduced by complexation with beta-CD (the extent of degradation was 26.1% for the complex compared to 35.8% for free trans-EHMC) whereas HP-beta-CD had no significant effect. Therefore, the complex of beta-CD with trans-EHMC enhances the chemical- and photo-stability of the sunscreen agent. Moreover, it limits adverse interactions of the UV filter with other formulation ingredients.

Temperature Dependence of Positron Annihilation in beta-Cyclodextrin and beta-Cyclodextrin Complexes

NASA Astrophysics Data System (ADS)

Hu, Y.; Hsu Hadley, F. H., Jr.; Trinh, T.

1996-11-01

The effects of temperature on positron annihilation in beta-cyclodextrin and beta-cyclodextrin complexed with benzyl salicylate, benzyl acetate, ethyl salicylate, geraniol, linalool and nerol were studied. Samples were prepared by slurry, air-dried and freeze-dried methods. Lifetime spectra were measured as a function of temperature for each sample. Comparison of the annihilation rate and intensity of the longer-lived component showed that positronium formation was affected by guest molecules, preparation methods and temperature variations. Results can be used to explain beta-cyclodextrin complex formation with different guest molecules.

Part I: RNA hydrolysis catalyzed by imidazole compounds. Part II. Hydrophobic acceleration of reactions and mimics of thiamin-dependent enzymes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kool, E.T.

1988-01-01

Catalysts modeled after the active site groups of the enzyme Ribonuclease A were synthesized and tested for catalysis of the hydrolysis of poly(rU), using a quantitative assay. The most effective of all the catalysts is N,N{prime}-bis-imidazolylmethane, which gave a four-fold rate enhancement as compared to N-methyl-imidazole. The structure/activity relationships are discussed in light of the ribonuclease mechanism. Also examined were reactions catalyzed by the coenzyme thiamine. In an investigation of the effects of restricting conformational freedom, a thiazolium salt was attached in two positions to {beta}-cyclodextrin. Since the catalyst gave about the same rate for tritium exchange from benzaldehyde asmore » singly-attached catalysts, we surmise that any rate enhancement due to the restriction of bond rotations has been lost by forcing the structure into less productive conformations. The benzoin condensation catalyzed by cyanide was also investigated. The reaction was shown to be faster in water than in most organic solvents. Kinetic salt effects and the effects of added {beta}- and {gamma}-cyclodextrin were measured in water; salting-out ions and {gamma}-cyclodextrin increase the rate, while salting-in ions and {beta}-cyclodextrin decrease it. Negative salt effects were observed in formamide, ethylene glycol, and DMSO. All these media effects are discussed in relation to the compact, hydrophobic transition state for the reaction.« less

Impact of beta-cyclodextrin and resistant starch on bile acid metabolism and fecal steroid excretion in regard to their hypolipidemic action in hamsters.

PubMed

Trautwein, E A; Forgbert, K; Rieckhoff, D; Erbersdobler, H F

1999-01-29

To examine the impact on bile acid metabolism and fecal steroid excretion as a mechanism involved in the lipid-lowering action of beta-cyclodextrin and resistant starch in comparison to cholestyramine, male golden Syrian hamsters were fed 0% (control), 8% or 12% of beta-cyclodextrin or resistant starch or 1% cholestyramine. Resistant starch, beta-cyclodextrin and cholestyramine significantly lowered plasma total cholesterol and triacylglycerol concentrations compared to control. Distinct changes in the bile acid profile of gallbladder bile were caused by resistant starch, beta-cyclodextrin and cholestyramine. While cholestyramine significantly reduced chenodeoxycholate independently of its taurine-glycine conjugation, beta-cyclodextrin and resistant starch decreased especially the percentage of taurochenodeoxycholate by -75% and -44%, respectively. As a result, the cholate:chenodeoxycholate ratio was significantly increased by 100% with beta-cyclodextrin and by 550% with cholestyramine while resistant starch revealed no effect on this ratio. beta-Cyclodextrin and resistant starch, not cholestyramine, significantly increased the glycine:taurine conjugation ratio demonstrating the predominance of glycine conjugated bile acids. Daily fecal excretion of bile acids was 4-times higher with 8% beta-cyclodextrin and 19-times with 1% cholestyramine compared to control. beta-Cyclodextrin and cholestyramine also induced a 2-fold increase in fecal neutral sterol excretion, demonstrating the sterol binding capacity of these two compounds. Resistant starch had only a modest effect on fecal bile acid excretion (80% increase) and no effect on excretion of neutral sterols, suggesting a weak interaction with intestinal steroid absorption. These data demonstrate the lipid-lowering potential of beta-cyclodextrin and resistant starch. An impaired reabsorption of circulating bile acids and intestinal cholesterol absorption leading to an increase in fecal bile acid and neutral sterol excretion is most likely the primary mechanism responsible for the lipid-lowering action of beta-cyclodextrin. In contrast, other mechanisms involving the alterations in the biliary bile acid profile or repressed hepatic lipogenesis, e.g., VLDL production, appear to be involved in the hypolipidemic effect of resistant starch.

[Ex-situ remediation of PAHs contaminated site by successive methyl-beta-cyclodextrin enhanced soil washing].

PubMed

Sun, Ming-Ming; Teng, Ying; Luo, Yong-Ming; Li, Zhen-Gao; Jia, Zhong-Jun; Zhang, Man-Yun

2013-06-01

Polycyclic aromatic hydrocarbon (PAH) polluted sites caused by abandoned coking plants have attracted great attentions. This study investigated the feasibility of using methyl-beta-cyclodextrin (MCD) solution to enhance ex situ soil washing for extracting PAHs. Treatment with elevated temperature (50 degrees C) in combination with ultrasonication (35 kHz, 30 min) at 100 g x L(-1) was effective. It was found that 96.7% +/- 2.4% of 3-ring PAH, 89.7% +/- 3.2% of 4-ring PAH, 76.3% +/- 2.2% of 5 (+6)-ring PAH and 91.3% +/- 3.1% of total PAHs were removed from soil after five successive washing cycles. The desorption kinetics of PAHs from contaminated soil was determined before and after successive washings. The 400 h Tenax extraction of PAHs from soil was decreasing gradually with increasing washing times. Furthermore, the F(r), F(sl), k(r), k(sl) and k(vl) were significantly lower than those of CK (P < 0.01). Therefore, considering the removal efficiency and potential environmental risk after soil )ashing, successive washing three times was selected as a reasonable parameter. These results have practical implications for site risk assessment and cleanup strategies.

Methyl-{beta}-cyclodextrin enhances the susceptibility of human breast cancer cells to carboplatin and 5-fluorouracil: Involvement of Akt, NF-{kappa}B and Bcl-2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Upadhyay, Ankur Kumar; Singh, Sandeep; Chhipa, Rishi Raj

2006-10-15

The response rates of extensively used chemotherapeutic drugs, carboplatin (Carb) or 5-fluorouracil (5-FU) are relatively disappointing because of considerable side effects associated with their high-dose regimen. In the present study, we determined whether treatment with a cholesterol depleting agent, methyl-{beta}-cyclodextrin (MCD), enhances the weak efficacy of low doses of Carb or 5-FU in human breast cancer cells. Data demonstrate that pretreatment with MCD significantly potentiates the cytotoxic activity of Carb and 5-FU in both MCF-7 and MDA-MB-231. Furthermore, we explored the molecular basis of enhanced cytotoxicity, and our data revealed that low-dose treatment with these drugs in MCD pretreated cellsmore » exhibited significantly decreased Akt phosphorylation, NF-{kappa}B activity and down-regulation in expression of anti-apoptotic protein Bcl-2. In addition, MCD pretreated cells demonstrated an increased intracellular drug accumulation as compared to cells treated with drugs alone. Taken together, our data provide the basis for potential therapeutic application of MCD in combination with other conventional cytotoxic drugs to facilitate reduction of drug dosage that offers a better chemotherapeutic approach with low toxicity.« less

Supramolecular structures on silica surfaces and their adsorptive properties.

PubMed

Belyakov, Vladimir N; Belyakova, Lyudmila A; Varvarin, Anatoly M; Khora, Olexandra V; Vasilyuk, Sergei L; Kazdobin, Konstantin A; Maltseva, Tetyana V; Kotvitskyy, Alexey G; Danil de Namor, Angela F

2005-05-01

The study of adsorptive and chemical immobilization of beta-cyclodextrin on a surface of hydroxylated silicas with various porous structure is described. Using IR spectroscopy, thermal gravimetrical analysis with a programmed heating, and chemical analysis of the silica surface, it is shown that the process of adsorption-desorption of beta-cyclodextrin depends on the porous structure of the silica. The reaction of esterification was used for chemical grafting of beta-cyclodextrin on the surface of hydroxylated silicas. Hydrolytic stability of silicas chemically modified by beta-cyclodextrin apparently is explained by simultaneous formation of chemical and hydrogen bonds between surface silanol groups and hydroxyl groups of beta-cyclodextrin. The uptake of the cations Cu(II), Cd(II), and Pb(II) and the anions Cr(VI) and As(V) by silicas modified with beta-cyclodextrin is investigated as a function of equilibrium ion concentrations. The increase of ion uptake and selectivity of ion extraction in comparison with starting silicas is established. It is due to the formation of surface inclusion complexes of the "host-guest" type in which one molecule of beta-cyclodextrin interacts simultaneously with several ions.

Formation and antimicrobial activity of complexes of beta-cyclodextrin and some antimycotic imidazole derivatives.

PubMed

Van Doorne, H; Bosch, E H; Lerk, C F

1988-04-22

Complex formation between beta-cyclodextrin and six antimycotic imidazole derivatives has been studied. The solubility of all drugs was increased in the presence of beta-cyclodextrin. The smallest increase (approx. 5-fold) was observed for miconazol, and the largest increase (approx. 160-fold) was observed for bifonazol. Apparent 1:1-complex constants were measured and found to decrease in the order: bifonazol greater than ketoconazol greater than tioconazol greater than miconazol greater than itraconazol greater than clotrimazol. The complexes appeared to possess a low, if any, antimicrobial activity. Measurement of inhibition zone sizes, with four test organisms was used to study the release of the antimycotic drugs from topical preparations. The antimycotic drugs were more readily released from topical preparations containing beta-cyclodextrin than from the same vehicles without beta-cyclodextrin. The rationale of beta-cyclodextrin addition to antimycotic topical preparations is discussed.

A soluble and active form of Wnt-3a protein is involved in myogenic differentiation after cholesterol depletion.

PubMed

Portilho, Débora M; Martins, Eliane R; Costa, Manoel L; Mermelstein, Cláudia S

2007-12-22

Cholesterol is one of the major lipids of plasma membranes. Recently, we have shown that cholesterol depletion by methyl-beta-cyclodextrin (M beta CD) induces the activation of the Wnt/beta-catenin pathway and enhances myogenic differentiation. Here, we show that M beta CD-conditioned media accelerates myogenesis in a similar way as M beta CD does, suggesting that the effects induced by M beta CD could be caused by soluble factors present in the culture medium. Soluble Wnt-3 protein is significantly enhanced in M beta CD-conditioned medium. Wnt-3a-enriched media induces myogenesis as much as M beta CD does, whereas Wnt-5a-enriched media inhibits. We suggest that Wnt-3a is involved in the myogenic induction observed after cholesterol depletion.

Enhancement of bioavailability of cinnarizine from its beta-cyclodextrin complex on oral administration with DL-phenylalanine as a competing agent.

PubMed

Tokumura, T; Nanba, M; Tsushima, Y; Tatsuishi, K; Kayano, M; Machida, Y; Nagai, T

1986-04-01

The present investigation is concerned with an improvement of the bioavailability of cinnarizine by administering its beta-cyclodextrin complex together with another compound which competes with the beta-cyclodextrin molecule in complex formation in aqueous solution (competing agent). The bioavailability of cinnarizine on oral administration of the cinnarizine-beta-cyclodextrin inclusion complex was enhanced by the simultaneous administration of DL-phenylalanine as a competing agent, e.g., the AUC was 1.9 and 2.7 times as large as those of the cinnarizine-beta-cyclodextrin complex alone and cinnarizine alone, respectively. The enhancement of AUC and Cmax completely depended on the dose of DL-phenylalanine. It was found from these results that DL-phenylalanine acted as a competing agent in the GI tract and the minimum effective dose required of DL-phenylalanine might be 1 g for 50 mg of cinnarizine in the cinnarizine-beta-cyclodextrin complex. Evaluating the competing effect of DL-phenylalanine in vitro using an absorption simulator, it was found that the decreased penetration rate of cinnarizine through the artificial lipid barrier with addition of beta-cyclodextrin was restored with the addition of DL-phenylalanine.

[Characterization of microstructure of ibuprofen-hydroxypropyl-beta-cyclodextrin and ibuprofen-beta-cyclodextrin by atomic force microscope].

PubMed

Wang, Li-juan; Zhu, Zhao-jing; Che, Ke-ke; Ju, Feng-ge

2008-09-01

The microstructures of ibuprofen-hydroxypropyl-bets-cyclodextrin (IBU-HP-beta-CyD) and ibuprofen-beta-cyclodextrin (IBU-beta-CyD) were observed by atomic force microscope (AFM). The high resolving capability of AFM has the tungsten filament probe with the spring constant of 0.06 N x m(-1). Samples were observed in a small scale scanning area of 10.5 nm x 10.5 nm and 800 x 800 pixels. The original scanning images were gained by tapping mode at room temperature. Their three-dimensional reconstruction of microstructure was performed by G3DR software. The outer diameters of HP-beta-CyD and beta-CyD are 1.53 nm. The benzene diameter of IBU is 0.62 nm, fitting to the inner diameters of HP-beta-CyD and beta-CyD. The benzene and hydrophobic chain of IBU enter into the hole of cyclodextrin at 1:1 ratio. The results were evidenced by IR, X-ray diffraction and the phase solubility.

Simultaneous chiral discrimination of multiple profens by cyclodextrin-modified capillary electrophoresis in normal and reversed polarity modes.

PubMed

La, Sookie; Kim, Jiyung; Kim, Jung-Han; Goto, Junichi; Kim, Kyoung-Rae

2003-08-01

Simultaneous enantioseparations of nine profens for their accurate chiral discrimination were achieved by capillary electrophoresis (CE) in the normal polarity (NP) mode with a single cyclodextrin (CD) system and in the reversed polarity (RP) mode with a dual CD system. The single CD system in the NP mode employed heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin (TMbetaCD) added at 75 mM-100 mM 2-(N-morpholino)ethanesulfonic acid buffer (pH 6.0) as the optimum run buffer. The dual CD system operated in the RP mode used 30 mM TMbetaCD and 1.0% anionic carboxymethyl-beta-cyclodextrin dissolved in pH 3.0, 100 mM phosphoric acid-triethanolamine buffer containing 0.01% hexadimethrine bromide added to reverse the electroosmotic flow. Fairly good enantiomeric resolutions and the opposite enantiomer migration orders were achieved in the two modes. Relative migration times to internal standard under respective optimum conditions were characteristic of each enantiomer with good precision (< 2% relative standard deviation, RSD), thereby enabling to crosscheck the chemical identification of profens and also their accurate chiralities. The method linearity in the two modes was found to be adequate (r > or = 0.9991) for the chiral assay of the profens investigated. Simultaneous enantiomeric purity test of ibuprofen, ketoprofen and flurbiprofen in a mixture was feasible in a single analysis by the present method.

Effect of beta-cyclodextrin in improving the correlation between lycopene concentration and ORAC values.

PubMed

Bangalore, Dharmendra V; McGlynn, William; Scott, Darren D

2005-03-23

Lycopene, a lipophilic antioxidant, plays a crucial role in biological systems. It may play an important role in human biological systems by providing protection against cardiovascular disease and some cancers and by boosting the immune system. The oxygen radical absorbance capacity (ORAC) has been validated as an index of antioxidant activity for many hydrophilic antioxidants but not for lycopene. This study validates the ORAC assay for different concentrations of lycopene in the presence of beta-cyclodextrin, a water-solubility enhancer. Lyc-O-Mato 6% extract was used as a source of lycopene for these experiments. Lycopene was extracted according to a standard spectrophotometric assay procedure in the presence of beta-cyclodextrin at concentrations of 0, 0.4, 0.8, and 1.6%, and the antioxidant activity of lycopene was measured with the ORAC assay. Experiments were conducted in quadruplicate and statistical pooled correlations analyzed. Statistical analysis showed a very high correlation (R2 = 0.99) between ORAC and ascorbic acid concentrations, validating this method. Lycopene concentration correlated poorly with ORAC (R2 = 0.33) in the absence of beta-cyclodextrin. Correlations improved with increasing levels of beta-cyclodextrin (R2 = 0.58 and 0.91 for 0.4 and 0.8% beta-cyclodextrin, respectively). A very high beta-cyclodextrin concentration (1.6%) decreased the correlation between ORAC and lycopene concentration. Inclusion of beta-cyclodextrin in the ORAC assay improves correlation between ORAC and lycopene concentration, thus expanding the scope of the ORAC assay to include an additional fat-soluble antioxidant.

Ion-exclusion chromatography with conductimetric detection of aliphatic carboxylic acids on a weakly acidic cation-exchange resin by elution with benzoic acid-beta-cyclodextrin.

PubMed

Tanaka, Kazuhiko; Mori, Masanobu; Xu, Qun; Helaleh, Murad I H; Ikedo, Mikaru; Taoda, Hiroshi; Hu, Wenzhi; Hasebe, Kiyoshi; Fritz, James S; Haddad, Paul R

2003-05-16

In this study, an aqueous solution consisting of benzoic acid with low background conductivity and beta-cyclodextrin (beta-CD) of hydrophilic nature and the inclusion effect to benzoic acid were used as eluent for the ion-exclusion chromatographic separation of aliphatic carboxylic acids with different pKa values and hydrophobicity on a polymethacrylate-based weakly acidic cation-exchange resin in the H+ form. With increasing concentration of beta-cyclodextrin in the eluent, the retention times of the carboxylic acids decreased due to the increased hydrophilicity of the polymethacrylate-based cation-exchange resin surface from the adsorption of OH groups of beta-cyclodextrin. Moreover, the eluent background conductivity decreased with increasing concentration of beta-cyclodextrin in 1 mM benzoic acid, which could result in higher sensitivity for conductimetric detection. The ion-exclusion chromatographic separation of carboxylic acids with high resolution and sensitivity was accomplished successfully by elution with a 1 mM benzoic acid-10 mM cyclodextrin solution without chemical suppression.

Preparation of olanzapine and methyl-β-cyclodextrin complexes using a single-step, organic solvent-free supercritical fluid process: An approach to enhance the solubility and dissolution properties.

PubMed

Rudrangi, Shashi Ravi Suman; Trivedi, Vivek; Mitchell, John C; Wicks, Stephen Richard; Alexander, Bruce David

2015-10-15

The purpose of this study was to evaluate a single-step, organic solvent-free supercritical fluid process for the preparation of olanzapine-methyl-β-cyclodextrin complexes with an express goal to enhance the dissolution properties of olanzapine. The complexes were prepared by supercritical carbon dioxide processing, co-evaporation, freeze drying and physical mixing. The prepared complexes were then analysed by differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy, solubility and dissolution studies. Computational molecular docking studies were performed to study the formation of molecular inclusion complexation of olanzapine with methyl-β-cyclodextrin. All the binary mixtures of olanzapine with methyl-β-cyclodextrin, except physical mixture, exhibited a faster and greater extent of drug dissolution than the drug alone. Products obtained by the supercritical carbon dioxide processing method exhibited the highest apparent drug dissolution. The characterisation by different analytical techniques suggests complete complexation or amorphisation of olanzapine and methyl-β-cyclodextrin complexes prepared by supercritical carbon dioxide processing method. Therefore, organic solvent-free supercritical carbon dioxide processing method proved to be novel and efficient for the preparation of solid inclusion complexes of olanzapine with methyl-β-cyclodextrin. The preliminary data also suggests that the complexes of olanzapine with methyl-β-cyclodextrin will lead to better therapeutic efficacy due to better solubility and dissolution properties. Copyright © 2015 Elsevier B.V. All rights reserved.

Removal of some organic pollutants in water employing ceramic membranes impregnated with cross-linked silylated dendritic and cyclodextrin polymers.

PubMed

Allabashi, Roza; Arkas, Michael; Hörmann, Gerold; Tsiourvas, Dimitris

2007-01-01

Triethoxysilylated derivatives of poly(propylene imine) dendrimer, polyethylene imine and polyglycerol hyperbranched polymers and beta-cyclodextrin have been synthesized and characterized. These compounds impregnated ceramic membranes made from Al(2)O(3), SiC and TiO(2) and subsequently sol-gel reaction led to their polymerization and chemical bond formation with the ceramic substrates. The resulting organic-inorganic filters were tested for the removal of a variety of organic pollutants from water. They were found to remove of polycyclic aromatic hydrocarbons (up to 99%), of monocyclic aromatic hydrocarbons (up to 93%), trihalogen methanes (up to 81%), pesticides (up to 43%) and methyl-tert-butyl ether (up to 46%).

Molecular printboards: monolayers of beta-cyclodextrins on silicon oxide surfaces.

PubMed

Onclin, Steffen; Mulder, Alart; Huskens, Jurriaan; Ravoo, Bart Jan; Reinhoudt, David N

2004-06-22

Monolayers of beta-cyclodextrin host molecules have been prepared on SiO2 surfaces. An ordered and stable cyano-terminated monolayer was modified in three consecutive surface reactions. First, the cyanide groups were reduced to their corresponding free amines using Red Al as a reducing agent. Second, 1,4-phenylene diisothiocyanate was used to react with the amine monolayer where it acts as a linking molecule, exposing isothiocyanates that can be derivatized further. Finally, per-6-amino beta-cyclodextrin was reacted with these isothiocyanate functions to yield a monolayer exposing beta-cyclodextrin. All monolayers were characterized by contact angle measurements, ellipsometric thickness measurements, Brewster angle Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and time-of-flight secondary ion mass spectrometry, which indicate the formation of a densely packed cyclodextrin surface. It was demonstrated that the beta-cyclodextrin monolayer could bind suitable guest molecules in a reversible manner. A fluorescent molecule (1), equipped with two adamantyl groups for complexation, was adsorbed onto the host monolayer from solution to form a monolayer of guest molecules. Subsequently, the guest molecules were desorbed from the surface by competition with increasing beta-cyclodextrin concentration in solution. The data were fitted using a model. An intrinsic binding constant of 3.3 +/- 1 x 10(5) M(-1) was obtained, which corresponds well to previously obtained results with a divalent guest molecule on beta-cyclodextrin monolayers on gold. In addition, the number of guest molecules bound to the host surface was determined, and a surface coverage of ca. 30% was found.

The influence of cyclomaltooligosaccharides (cyclodextrins) on the enzymatic decomposition of l-phenylalanine catalyzed by phenylalanine ammonia-lyase.

PubMed

Gubica, Tomasz; Pełka, Agnieszka; Pałka, Katarzyna; Temeriusz, Andrzej; Kańska, Marianna

2011-09-27

Cyclomaltohexaose (α-cyclodextrin) and cyclomaltoheptaose (β-cyclodextrin) as well as their four methyl ether derivatives, that is, hexakis(2,3-di-O-methyl)cyclomaltohexaose, hexakis(2,3,6-tri-O-methyl)cyclomaltohexaose, heptakis(2,3-di-O-methyl)cyclomaltoheptaose, and heptakis(2,3,6-tri-O-methyl)cyclomaltoheptaose were investigated as the additives in the course of enzymatic decomposition of l-phenylalanine catalyzed by phenylalanine ammonia-lyase. Only a few of those additives behaved like classical inhibitors of the enzymatic reaction under investigation because the values of the Michaelis constants that were obtained, as well as the maximum velocity values depended mostly atypically on the concentrations of those additives. In most cases cyclodextrins caused mixed inhibition, both competitive and noncompetitive, but they also acted as activators for selected concentrations. This atypical behaviour of cyclodextrins is caused by three different and independent effects. The inhibitory effect of cyclodextrins is connected with the decrease of substrate concentration and unfavourable influence on the flexibility of the enzyme molecules. On the other hand, the activating effect is connected with the decrease of product concentration (the product is an inhibitor of the enzymatic reaction under investigation). All these effects are caused by the ability of the cyclodextrins to form inclusion complexes. Copyright © 2011 Elsevier Ltd. All rights reserved.

Endocytosis of beta-cyclodextrins is responsible for cholesterol reduction in Niemann-Pick type C mutant cells

PubMed Central

Rosenbaum, Anton I.; Zhang, Guangtao; Warren, J. David; Maxfield, Frederick R.

2010-01-01

Niemann-Pick type C disease (NPC) is a lysosomal storage disorder causing accumulation of unesterified cholesterol in lysosomal storage organelles. Recent studies have shown that hydroxypropyl-β-cyclodextrin injections in npc1−/− mice are partially effective in treating this disease. Using cultured fibroblasts, we have investigated the cellular mechanisms responsible for reduction of cholesterol accumulation. We show that decreased levels of cholesterol accumulation are maintained for several days after removal of cyclodextrin from the culture medium. This suggests that endocytosed cyclodextrin can reduce the cholesterol storage by acting from inside endocytic organelles rather than by removing cholesterol from the plasma membrane. To test this further, we incubated both NPC1 and NPC2 mutant cells with cholesterol-loaded cyclodextrin for 1 h, followed by chase in serum-containing medium. Although the cholesterol content of the treated cells increased after the 1-h incubation, the cholesterol levels in the storage organelles were later reduced significantly. We covalently coupled cyclodextrin to fluorescent dextran polymers. These cyclodextrin–dextran conjugates were delivered to cholesterol-enriched lysosomal storage organelles and were effective at reducing the cholesterol accumulation. We demonstrate that methyl-β-cyclodextrin is more potent than hydroxypropyl-β-cyclodextrin in reducing both cholesterol and bis(monoacylglycerol) phosphate accumulation in NPC mutant fibroblasts. Brief treatment of cells with cyclodextrins causes an increase in cholesterol esterification by acyl CoA:cholesterol acyl transferase, indicating increased cholesterol delivery to the endoplasmic reticulum. These findings suggest that cyclodextrin-mediated enhanced cholesterol transport from the endocytic system can reduce cholesterol accumulation in cells with defects in either NPC1 or NPC2. PMID:20212119

Dissecting the Transcriptional Response to Elicitors in Vitis vinifera Cells

PubMed Central

Belchí-Navarro, Sarai; Bru, Roque; Martínez-Zapater, José M.; Lijavetzky, Diego; Pedreño, María A.

2014-01-01

The high effectiveness of cyclic oligosaccharides like cyclodextrins in the production of trans-resveratrol in Vitis vinifera cell cultures is enhanced in the presence of methyl jasmonate. In order to dissect the basis of the interactions among the elicitation responses triggered by these two compounds, a transcriptional analysis of grapevine cell cultures treated with cyclodextrins and methyl jasmonate separately or in combination was carried out. The results showed that the activation of genes encoding enzymes from phenylpropanoid and stilbene biosynthesis induced by cyclodextrins alone was partially enhanced in the presence of methyl jasmonate, which correlated with their effects on trans-resveratrol production. In addition, protein translation and cell cycle regulation were more highly repressed in cells treated with cyclodextrins than in those treated with methyl jasmonate, and this response was enhanced in the combined treatment. Ethylene signalling was activated by all treatments, while jasmonate signalling and salicylic acid conjugation were activated only in the presence of methyl jasmonate and cyclodextrins, respectively. Moreover, the combined treatment resulted in a crosstalk between the signalling cascades activated by cyclodextrins and methyl jasmonate, which, in turn, provoked the activation of additional regulatory pathways involving the up-regulation of MYB15, NAC and WRKY transcription factors, protein kinases and calcium signal transducers. All these results suggest that both elicitors cause an activation of the secondary metabolism in detriment of basic cell processes like the primary metabolism or cell division. Crosstalk between cyclodextrins and methyl jasmonate-induced signalling provokes an intensification of these responses resulting in a greater trans-resveratrol production. PMID:25314001

Physico-chemical and Biological Evaluation of Flavonols: Fisetin, Quercetin and Kaempferol Alone and Incorporated in beta Cyclodextrins.

PubMed

Corina, Danciu; Bojin, Florina; Ambrus, Rita; Muntean, Delia; Soica, Codruta; Paunescu, Virgil; Cristea, Mirabela; Pinzaru, Iulia; Dehelean, Cristina

2017-01-01

Fisetin,quercetin and kaempferol are among the important representatives of flavonols, biological active phytocomounds, with low water solubility. To evaluate the antimicrobial effect, respectively the antiproliferative and pro apoptotic activity on the B164A5 murine melanoma cell line of pure flavonols and their beta cyclodextrins complexes. Incorporation of fisetin, quercetin and kaempferol in beta cyclodextrins was proved by scanning electron microscopy (SEM), differencial scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). Pure compounds and their complexes were tested for antiproliferative (MTT) and pro-apoptotic activity (Annexin V-PI) on the B164A5 murine melanoma cell line and for the antimicrobial properties (Disk Diffusion Method) on the selected strains. The phytocompounds presented in a different manner in vitro chemopreventive activity against B164A5 murine melanoma cell line and weak antimicrobial effect. The three flavonols: fisetin, quercetin and kaempferol were successfully incorporated in beta-cyclodextrin (BCD) and hydroxylpropyl-beta-cyclodextrin (HPBCD). Incorporation in beta cyclodextrins had a mix effect on the biological activity conducing to decrease, increase or consistent effect compared to pure phytocompound, depending on the screened process and on the chosen combination. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Inhibition of Bufo arenarum oocyte maturation induced by cholesterol depletion by methyl-beta-cyclodextrin. Role of low-density caveolae-like membranes.

PubMed

Buschiazzo, Jorgelina; Bonini, Ida C; Alonso, Telma S

2008-06-01

The invaginated structure of caveolae seems to provide an optimal environment for hormone binding leading to oocyte meiotic maturation. We conducted a quantitative analysis of lipids and proteins of detergent-free low-density membranes isolated from Bufo arenarum oocytes and we modulated cellular cholesterol to further understand how these domains perform their regulatory functions in the amphibian system. Light membranes derive from the plasma membrane as suggested by the enrichment in the activity of 5'nucleotidase. Lipid analysis by chromatography techniques revealed that this fraction is enriched in phosphatidylserine and cholesterol and that it evidences an important level of sphingomyelin. The finding of a single 21 kDa caveolin in light membranes indicates the presence of caveolae-like structures in B. arenarum oocytes. In support of this finding, c-Src is significantly associated to this fraction. Cholesterol content of oocytes treated with methyl-beta-cyclodextrin (MbetaCD) decreased when compared to control oocytes. Drug treatment inhibited meiotic maturation in a dose-dependent manner and affected the localization of caveolin and c-Src among membrane fractions. Repletion of cholesterol showed a recovery of the ability of MbetaCD-treated oocytes to mature, particularly at the 25 mM concentration in which reversibility was close to the control level. Results highlight the importance of caveolae-like microdomains for maturation signaling in Bufo oocytes.

Stability of natamycin and its cyclodextrin inclusion complexes in aqueous solution.

PubMed

Koontz, John L; Marcy, Joseph E; Barbeau, William E; Duncan, Susan E

2003-11-19

Aqueous solutions of natamycin and its beta-cyclodextrin (beta-CD), hydroxypropyl beta-cyclodextrin, and gamma-cyclodextrin (gamma-CD) inclusion complexes were completely degraded after 24 h of exposure to 1000 lx fluorescent lighting at 4 degrees C. After 14 days of storage in darkness at 4 degrees C, 92.2% of natamycin remained in active form. The natamycin:beta-CD complex and natamycin:gamma-CD complex were significantly more stable (p < 0.05) than natamycin in its free state in aqueous solutions stored in darkness at 4 degrees C. Clear poly(ethylene terephthalate) packaging with a UV light absorber allowed 85.0% of natamycin to remain after 14 days of storage under 1000 lx fluorescent lighting at 4 degrees C. Natamycin:cyclodextrin complexes can be dissociated for analysis in methanol/water/acetic acid, 60:40:5, v/v/v. Natamycin and its complexes in dissociated form were quantified by reverse phase HPLC with detection by photodiode array at 304 nm.

Separation of the enantiomers of ibuprofen and its major phase I metabolites in urine using capillary electrophoresis.

PubMed

Bjørnsdottir, I; Kepp, D R; Tjørnelund, J; Hansen, S H

1998-03-01

A capillary electrophoresis method for determination of the enantiomers of ibuprofen and its major phase I metabolites: 2'-hydroxyibuprofen and 2'-carboxyibuprofen in urine samples have been developed. Cyclodextrins and linear dextrins have been investigated as chiral selectors. Simultaneous chiral separation of the enantiomers of ibuprofen, 2'-hydroxyibuprofen and 2'-carboxyibuprofen was obtained using a mixture of dextrin 10 and heptakis (2,3,6-tri-O-methyl)-beta-cyclodextrin in a 2-[N-morpholino]ethanesulphonic acid buffer, pH 5.26. The electroosmotic flow was reversed using hexadimethrine bromide as a buffer additive. The method can be used for the determination of the free enantiomers of ibuprofen, 2'-hydroxyibuprofen and 2'-carboxyibuprofen as well as for the indirect determination of their glucuronic acid conjugates in urine samples.

Effect of cyclodextrin complexation on the aqueous solubility and solubility/dose ratio of praziquantel.

PubMed

Maragos, Stratos; Archontaki, Helen; Macheras, Panos; Valsami, Georgia

2009-01-01

Praziquantel (PZQ), the primary drug of choice in the treatment of schistosomiasis, is a highly lipophilic drug that possesses high permeability and low aqueous solubility and is, therefore, classified as a Class II drug according to the Biopharmaceutics Classification System (BCS). In this work, beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) were used in order to determine whether increasing the aqueous solubility of a drug by complexation with CDs, a BCS-Class II compound like PZQ could behave as BCS-Class I (highly soluble/highly permeable) drug. Phase solubility and the kneading and lyophilization techniques were used for inclusion complex preparation; solubility was determined by UV spectroscopy. The ability of the water soluble polymer polyvinylpyrolidone (PVP) to increase the complexation and solubilization efficiency of beta-CD and HP-beta-CD for PZQ was examined. Results showed significant improvement of PZQ solubility in the presence of both cyclodextrins but no additional effect in the presence of PVP. The solubility/dose ratios values of PZQ-cyclodextrin complexes calculated considering the low (150 mg) and the high dose (600 mg) of PZQ, used in practice, indicate that PZQ complexation with CDs may result in drug dosage forms that would behave as a BCS-Class I depending on the administered dose.

Biosynthesis of ketomycin. (II) biomimetic model for beta-lactamase catalysis: host-guest interactions in cyclodextrin-penicillin inclusion complex

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mak, H.W.

The antibiotic ketomycin is formed from shikimic acid via chorismic acid and prephenic acid. Phenylalanine and 2',5'-dihydrophenylalanine derived from shikimic acid are not intermediates in the biosynthesis. Degradation of ketomycin derived from (1,6-/sup 14/C)shikimic acid showed that prephenic acid is converted into ketomycin with stereospecific discrimination between the two enantiotopic edges of the ring, the pro-S-R edge giving rise to the C-2', C-3' side of the cyclohexane ring of ketomycin. The resistance of pathogenic bacteria to the action of ..beta..-lactam antibiotics is mainly ascribed to their ability to produce ..beta..-lactamase to cleave the ..beta..-lactam ring. It is essential to understandmore » the molecular nature of ..beta..-lactamase-penicillin recognition for designing and formulating more effective ..beta..-lactam antibiotics. A biomimetic study of ..beta..-lactamase is therefore initiated. To meet the requirements of hydrophobic and serine protease characteristics of ..beta..-lactamase, ..cap alpha..-cyclodextrin is chosen as a biomimetic model for ..beta..-lactamase. The structural specificity and the chemical dynamics of ..cap alpha..-cyclodextrin-phenoxymethyl penicillin inclusion complex in solid state and in solution have been determined by IR and NMR spectroscopy. The spectral results strongly indicate that the phenyl portion of the phenoxymethyl penicillin forms a stable inclusion complex with the hydrophobic cavity of ..cap alpha..-cyclodextrin in solution as well as in the solid state. Kinetic studies followed by /sup 1/HNMR and HPLC analyses under alkaline condition have shown that the ..cap alpha..-cyclodextrin mimics the catalytic function of serine of ..beta..-lactamase in the stereospecific hydrolysis of the ..beta..-lactam ring of phenoxymethyl penicillin.« less

Novel inclusion complex of ibuprofen tromethamine with cyclodextrins: physico-chemical characterization.

PubMed

Al Omari, Mahmoud M; Daraghmeh, Nidal H; El-Barghouthi, Musa I; Zughul, Mohammad B; Chowdhry, Babur Z; Leharne, Stephen A; Badwan, Adnan A

2009-10-15

Guest-host interactions of ibuprofen tromethamine salt (Ibu.T) with native and modified cyclodextrins (CyDs) have been investigated using several techniques, namely phase solubility diagrams (PSDs), proton nuclear magnetic resonance ((1)H NMR), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffractometry (XRPD), scanning-electron microscopy (SEM) and molecular mechanics (MM). From the analysis of PSD data (A(L)-type) it is concluded that the anionic tromethamine salt of ibuprofen (pK(a)=4.55) forms 1:1 soluble complexes with all CyDs investigated in buffered water at pH 7.0, while the neutral form of Ibu forms an insoluble complex with beta-CyD (B(S)-type) in buffered water at pH 2.0. Ibu.T has a lower tendency to complex with beta-CyD (K(11)=58 M(-1) at pH 7.0) compared with the neutral Ibu (K(11)=4200 M(-1)) in water. Complex formation of Ibu.T with beta-CyD (DeltaG(o)=-20.4 kJ/mol) is enthalpy driven (DeltaH(o)=-22.9 kJ/mol) and is accompanied by a small unfavorable entropy (DeltaS(o)=-8.4 J/mol K) change. (1)H NMR studies and MM computations revealed that, on complexation, the hydrophobic central benzene ring of Ibu.T and part of the isobutyl group reside within the beta-CyD cavity leaving the peripheral groups (carboxylate, tromethamine and methyl groups) located near the hydroxyl group networks at either rim of beta-CyD. PSD, (1)H NMR, DSC, FT-IR, XRPD, SEM and MM studies confirmed the formation of Ibu.T/beta-CyD inclusion complex in solution and the solid state.

Influence of beta-cyclodextrin and chitosan in the formulation of a colon-specific drug delivery system.

PubMed

Rehman, K; Amin, M C I M; Muda, S

2013-12-01

The increase in diseases of the colon underscores the need to develop cost-effective site-directed therapies. We formulated a polysaccharide-based matrix system that could release ibuprofen under conditions simulating those in the colon by employing a wet granulation method. Tablets were prepared in a series of formulations containing a polysaccharide (beta-cyclodextrin and chitosan) matrix system along with ethylcellulose. We characterized physicochemical properties and performed an in vitro drug release assay in the absence and presence of digestive enzymes to assess the ability of the polysaccharides to function as a protective barrier against the upper gastrointestinal environment. Fourier transform infrared spectroscopy studies revealed no chemical interaction between ibuprofen and polysaccharides; however, spectrum analysis suggested the formation of an inclusion complex of beta-cyclodextrin with ibuprofen. The formulations contained 50% ethylcellulose and 50% beta-cyclodextrins (1:1) were proven to be the better formulation that slowly released the drug until 24 h (101.04 ± 0.65% maximum drug release in which 83.08 ± 0.89% drug was released in colonic medium) showed better drug release profiles than the formulations containing chitosan. We conclude that a beta-cyclodextrin drug carrier system may represent an effective approach for treatment of diseases of the colon. © Georg Thieme Verlag KG Stuttgart · New York.

Polycyclic aromatic hydrocarbon analysis with the Mars organic analyzer microchip capillary electrophoresis system.

PubMed

Stockton, Amanda M; Chiesl, Thomas N; Scherer, James R; Mathies, Richard A

2009-01-15

The Mars Organic Analyzer (MOA), a portable microchip capillary electrophoresis (CE) instrument developed for sensitive amino acid analysis on Mars, is used to analyze laboratory standards and real-world samples for polycyclic aromatic hydrocarbons (PAHs). The microfabricated CE separation and analysis method for these hydrophobic analytes is optimized, resulting in a separation buffer consisting of 10 mM sulfobutylether-beta-cyclodextrin, 40 mM methyl-beta-cyclodextrin, 5 mM carbonate buffer at pH 10, 5 degrees C. A PAH standard consisting of seven PAHs found in extraterrestrial matter and two terrestrial PAHs is successfully baseline separated. Limits of detection for the components of the standard ranged from 2000 ppm to 6 ppb. Analysis of an environmental contamination standard from Lake Erie and of a hydrothermal vent chimney sample from the Guaymas Basin agreed with published composition. A Martian analogue sample from the Yungay Hills region of the Atacama Desert was analyzed and found to contain 9,10-diphenylanthracene, anthracene, anthanthrene, fluoranthene, perylene, and benzo[ghi]fluoranthene at ppm levels. This work establishes the viability of the MOA for detecting and analyzing PAHs in in situ planetary exploration.

Parallel beta/alpha-barrels of alpha-amylase, cyclodextrin glycosyltransferase and oligo-1,6-glucosidase versus the barrel of beta-amylase: evolutionary distance is a reflection of unrelated sequences.

PubMed

Janecek, S

1994-10-17

The structures of functionally related beta/alpha-barrel starch hydrolases, alpha-amylase, beta-amylase, cyclodextrin glycosyltransferase and oligo-1,6-glucosidase, are discussed, their mutual sequence similarities being emphasized. Since these enzymes (except for beta-amylase) along with the predicted set of more than ten beta/alpha-barrels from the alpha-amylase enzyme superfamily fulfil the criteria characteristic of the products of divergent evolution, their unrooted distance tree is presented.

Separation of drug stereoisomers by the formation of. beta. -cyclodextrin inclusion complexes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Armstrong, D.W.; Ward, T.J.; Armstrong, R.D.

For many drugs, only racemic mixtures are available for clinical use. Because different stereoisomers of drugs often cause different physiological responses, the use of pure isomers could elicit more exact therapeutic effects. Differential complexation of a variety of drug stereoisomers by immobilized ..beta..-cyclodextrin was investigated. Chiral recognition and racemic resolution were observed with a number of compounds from such clinically useful classes as ..beta..-blockers, calcium-channel blockers, sedative hypnotics, antihistamines, anticonvulsants, diuretics, and synthetic opiates. Separation of the diastereomers of the cardioactive and antimalarial cinchona alkaloids and of two antiestrogens was demonstrated as well. Three dimensional projections of ..beta..-cyclodextrin complexes ofmore » propanol, which is resolved by this technique, and warfarin, which is not, are compared. These studies have improved the understanding and application of the chiral interactions of ..beta..-cyclodextrin, and they have demonstrated a means to measure optical purity and to isolate or produce pure enantiomers of drugs. In addition, this highly specific technique could also be used in the pharmacological evaluation of enantiometric drugs. 27 references, 3 figures, 2 tables.« less

THE BINDING OF COCAINE TO CYCLODEXTRINS. (R826653)

EPA Science Inventory

Abstract

Cocaine binds into -cyclodextrin, but not detectably into

Development of PMMA membranes functionalized with hydroxypropyl-beta-cyclodextrins for controlled drug delivery using a supercritical CO(2)-assisted technology.

PubMed

Temtem, M; Pompeu, D; Jaraquemada, G; Cabrita, E J; Casimiro, T; Aguiar-Ricardo, A

2009-07-06

Cyclodextrin-containing polymers have proved themselves to be useful for controlled release. Herein we describe the preparation of membranes of poly(methylmethacrylate) (PMMA) containing hydroxypropyl-beta-cyclodextrins (HP-beta-CDs) using a supercritical CO(2)-assisted phase inversion method, for potential application as drug delivery devices. Results are reported on the membrane preparation, physical properties, and drug elution profile of a model drug. The polymeric membranes were obtained with HP-beta-CD contents ranging from 0 to 33.4 wt%, by changing the composition of the casting solution, and were further impregnated with ibuprofen using supercritical carbon dioxide (scCO(2)) in batch mode. The influence of the membrane functionalization in the controlled release of ibuprofen was studied by performing in vitro experiments in buffer solution pH at 7.4. The release of the anti-inflammatory drug could be tuned by varying the cyclodextrin content on the membranes.

Complexation of adamantyl compounds by beta-cyclodextrin and monoaminoderivatives.

PubMed

Carrazana, Jorge; Jover, Aida; Meijide, Francisco; Soto, Victor H; Vazquez Tato, José

2005-05-19

Since the beta-cyclodextrin cavity is not a smooth cone but has constrictions in the neighborhoods of the H3 and H5 atoms, the hypothesis that bulky hydrophobic guests can form two isomeric inclusion complexes (one of them, c(p), is formed by the entrance of the guest by the primary side of the cavity, and the other one, c(s), results from the entrance by the secondary side) is checked. Thus, the inclusion processes of two 1-substituted adamantyl derivatives (rimantidine and adamantylmethanol) with beta-cyclodextrin and its two monoamino derivatives at positions 6 (6-NH2beta-CD) and 3 (3-NH2beta-CD) were studied. From rotating-frame Overhauser enhancement spectroscopy experiments, it was deduced that both guests form c(s) complexes with beta-CD and 6-NH2beta-CD but c(p) complexes with 3-NH2beta-CD. In all cases, the hydrophilic group attached to the adamantyl residue protrudes toward the bulk solvent outside the cyclodextrin cavity. The thermodynamic parameters (free energy, equilibrium constant, enthalpy, and entropy) associated with the inclusion phenomena were measured by isothermal titration calorimetry experiments. From these results, the difference in the free energy for the formation of the two complexes, c(s) and c(p), for the same host/guest system has been estimated as being 11.5 +/- 0.8 kJ mol(-1). This large difference explains why under normal experimental conditions only one of the two complexes (c(s)) is detected. It is also concluded that a hyperboloid of revolution can be a better schematic picture to represent the actual geometry of the cyclodextrin cavities than the usual smooth cone or trapezium.

Novel porphyrin conjugates with a potent photodynamic antitumor effect: differential efficacy of mono- and bis-beta-cyclodextrin derivatives in vitro and in vivo.

PubMed

Kralova, Jarmila; Synytsya, Alla; Pouckova, Pavla; Koc, Michal; Dvorak, Michal; Kral, Vladimir

2006-01-01

In the present study we investigated the photosensitizing properties of two novel mono- and bis-cyclodextrin tetrakis (pentafluorophenyl) porphyrin derivatives in several tumor cell lines and in BALB/c mice bearing subcutaneously transplanted syngeneic mouse mammary carcinoma 4T1. Both studied sensitizers were localized mainly in lysosomes and were found to induce cell death by triggering apoptosis in human leukemic cells HL-60. In 4T1 and other cell lines both apoptotic and necrotic modes of cell death occurred depending on drug and light doses. Mono-cyclodextrin porphyrin derivative P(beta-CD)1 exhibited stronger in vitro phototoxic effect than bis-cyclodextrin derivative P(beta-CD)2. However, in vivo P(beta-CD)2 displayed faster tumor uptake with maximal accumulation 6 h after application, leading to complete and prolonged elimination of subcutaneous tumors within 3 days after irradiation (100 J cm(-2)). In contrast, P(beta-CD)1 uptake was slower (48 h) and the reduction of tumor mass was only transient, reaching the maximum at the 12 h interval when a favorable tumor-to-skin ratio appeared. Thus, P(beta-CD)2 represents a new photosensitizing drug displaying fast and selective tumor uptake, strong antitumor activity and fast elimination from the body.

Chiral discrimination in cyclodextrin complexes of amino acid derivatives: beta-cyclodextrin/N-acetyl-L-phenylalanine and N-acetyl-D-phenylalanine complexes.

PubMed

Alexander, Jennifer M; Clark, Joanna L; Brett, Tom J; Stezowski, John J

2002-04-16

In a systematic study of molecular recognition of amino acid derivatives in solid-state beta-cyclodextrin (beta-CD) complexes, we have determined crystal structures for complexes of beta-cyclodextrin/N-acetyl-L-phenylalanine at 298 and 20 K and for N-acetyl-D-phenylalanine at 298 K. The crystal structures for the N-acetyl-L-phenylalanine complex present disordered inclusion complexes for which the distribution of guest molecules at room temperature is not resolvable; however, they can be located with considerable confidence at low temperature. In contrast, the complex with N-acetyl-D-phenylalanine is well ordered at room temperature. The latter complex presents an example of a complex in this series in which a water molecule is included deeply in the hydrophobic torus of the extended dimer host. In an effort to understand the mechanisms of molecular recognition giving rise to the dramatic differences in crystallographic order in these crystal structures, we have examined the intermolecular interactions in detail and have examined insertion of the enantiomer of the D-complex into the chiral beta-CD complex crystal lattice.

Comparative evaluation of ibuprofen/beta-cyclodextrin complexes obtained by supercritical carbon dioxide and other conventional methods.

PubMed

Hussein, Khaled; Türk, Michael; Wahl, Martin A

2007-03-01

The preparation of drug/cyclodextrin complexes is a suitable method to improve the dissolution of poor soluble drugs. The efficacy of the Controlled Particle Deposition (CPD) as a new developed method to prepare these complexes in a single stage process using supercritical carbon dioxide is therefore compared with other conventional methods. Ibuprofen/beta-cyclodextrin complexes were prepared with different techniques and characterized using FTIR-ATR spectroscopy, powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). In addition, the influences of the processing technique on the drug content (HPLC) and the dissolution behavior were studied. Employing the CPD-process resulted in a drug content of 2.8+/-0.22 wt.% in the carrier. The material obtained by CPD showed an improved dissolution rate of ibuprofen at pH 5 compared with the pure drug and its physical mixture with beta-cyclodextrin. In addition CPD material displays the highest dissolution (93.5+/- 2.89% after 75 min) compared to material obtained by co-precipitation (61.3 +/-0.52%) or freeze-drying (90.6 +/-2.54%). This study presents the CPD-technique as a well suitable method to prepare a drug/beta-cyclodextrin complex with improved drug dissolution compared to the pure drug and materials obtained by other methods.

Wnt/beta-catenin pathway activation and myogenic differentiation are induced by cholesterol depletion.

PubMed

Mermelstein, Cláudia S; Portilho, Débora M; Mendes, Fábio A; Costa, Manoel L; Abreu, José Garcia

2007-03-01

Myogenic differentiation is a multistep process that begins with the commitment of mononucleated precursors that withdraw from cell cycle. These myoblasts elongate while aligning to each other, guided by the recognition between their membranes. This step is followed by cell fusion and the formation of long and striated multinucleated myotubes. We have recently shown that cholesterol depletion by methyl-beta-cyclodextrin (MbetaCD) induces myogenic differentiation by enhancing myoblast recognition and fusion. Here, we further studied the signaling pathways responsible for early steps of myogenesis. As it is known that Wnt plays a role in muscle differentiation, we used the chemical MbetaCD to deplete membrane cholesterol and investigate the involvement of the Wnt/beta-catenin pathway during myogenesis. We show that cholesterol depletion promoted a significant increase in expression of beta-catenin, its nuclear translocation and activation of the Wnt pathway. Moreover, we show that the activation of the Wnt pathway after cholesterol depletion can be inhibited by the soluble protein Frzb-1. Our data suggest that membrane cholesterol is involved in Wnt/beta-catenin signaling in the early steps of myogenic differentiation.

A diffuse reflectance comparative study of benzil inclusion within microcrystalline cellulose and beta-cyclodextrin.

PubMed

Vieira Ferreira, Luis F; Ferreira Machado, Isabel; Da Silva, José P; Oliveira, Anabela S

2004-02-01

Diffuse reflectance and laser-induced techniques were used to study photochemical and photophysical processes of benzil adsorbed on two solid powdered supports, microcrystalline cellulose and [small beta]-cyclodextrin. In both substrates, a distribution of ground-state benzil conformers exists, largely dominated by skew conformations where the carbonyl groups are twisted one to the other. Room temperature phosphorescence was observed in air-equilibrated samples in both cases. The decay times vary greatly and the largest lifetime was obtained for benzil/[small beta]-cyclodextrin, showing that this host's cavity accommodates benzil well, enhancing its room temperature phosphorescence. Triplet-triplet absorption of benzil entrapped in cellulose was detected and benzil ketyl radical formation also occurred. With benzil included into [small beta]-cyclodextrin, and following laser excitation, benzoyl radicals were detected on the millisecond timescale. Product analysis and identification of laser-irradiated benzil samples in the two hosts clearly showed that the main degradation photoproducts were benzoic acid and benzaldehyde. The main differences were a larger benzoic acid/benzaldehyde ratio in the case of cellulose and the formation of benzyl alcohol in this support.

Controlled synthesis and inclusion ability of a hyaluronic acid derivative bearing beta-cyclodextrin molecules.

PubMed

Charlot, Aurélia; Heyraud, Alain; Guenot, Pierre; Rinaudo, Marguerite; Auzély-Velty, Rachel

2006-03-01

A new synthetic route to beta-cyclodextrin-linked hyaluronic acid (HA-CD) was developed. This was based on the preparation of a HA derivative selectively modified with adipic dihydrazide (HA-ADH) and a beta-cyclodextrin derivative possessing an aldehyde function on the primary face, followed by their coupling by a reductive amination-type reaction. The CD-polysaccharide was fully characterized in terms of chemical integrity and purity by high-resolution NMR spectroscopy. The complexation ability of the grafted CD was further demonstrated by isothermal titration calorimetry using sodium adamantane acetate (ADAc) and Ibuprofen as model guest molecules. The thermodynamic parameters for the complexation of these negatively charged guest molecules by the beta-CD grafted on negatively charged HA were shown to be largely influenced by the ionic strength of the aqueous medium.

Preparation of alpha-cyclodextrin-terminated polyrotaxane consisting of beta-cyclodextrins and pluronic as a building block of a biodegradable network.

PubMed

Ooya, Tooru; Ito, Akihiro; Yui, Nobuhiko

2005-05-23

A beta-CD-based biodegradable polyrotaxane was prepared by capping both terminals of polypseudorotaxane consisting of hydrazide-terminated PEG-block-PPG-block-PEG (Pluronic P-105) and beta-CD-succinates with mono-aldehyde alpha-CDs. By decreasing pH, the fluorescent intensity of TNS was increased with time, indicating cleavage of the terminal hydrazone bonds followed by beta-CD-succinate release. The terminal alpha-CD moieties of the polyrotaxane are useful for self-assembled formation with some guest molecules. [Diagram: see text

Efficacy of attractive toxic sugar baits (ATSB) against Aedes albopictus with garlic oil encapsulated in beta-Cyclodextrin as the active ingredient

USDA-ARS?s Scientific Manuscript database

We tested the efficacy of attractive toxic sugar bait (ATSB) with garlic oil microencapsulated in beta-cyclodextrin as active ingredient against Aedes albopictus in suburban Haifa, Israel. Two three-acre gardens with high numbers of Ae. albopictus were chosen for perimeter spray treatment with ATSB ...

[In-vitro evaluation of cinnarizine as a competing agent to beta-cyclodextrin inclusion complexes: effect of cinnarizine on the membrane permeation rate of progesterone from its beta-cyclodextrin inclusion complex].

PubMed

Muraoka, Atsushi; Tokumura, Tadakazu; Machida, Yoshiharu

2008-01-01

The use of competing agents is considered a powerful tool for the development of a drug-delivery system with drug/cyclodextrin inclusion complexes. However, there are very few studies examining this issue. To explain this phenomenon, it was thought that a competing agent with a sufficiently high stability constant had not yet been reported. In this study, cinnarizine (CN), which has a high stability constant with beta-cyclodextrin (beta-CD) and unique solubility characteristics, was selected, and its ability as a competing agent was examined in a membrane permeability study. The permeability study showed that the permeation rates of the drugs flurbiprofen, progesterone, and spironolactone decreased with their stability constants with the addition of beta-CD. In one of the drugs, progesterone (Pro), the decrease was restored by the addition of CN. The amount of CN added was a 1:1 molar ratio to the amount of Pro. However, no similar action was induced with the addition of DL-phenylalanine (Phe) in the permeation study at the 1:5 (Pro:Phe) molar ratio. These finding indicate that CN acts as a competing agent, and its action is much stronger than that of Phe.

Direct enantioseparation of catechin and epicatechin in tea drinks by 6-O-alpha-D-glucosyl-beta-cyclodextrin-modified micellar electrokinetic chromatography.

PubMed

Kodama, Shuji; Yamamoto, Atsushi; Matsunaga, Akinobu; Yanai, Hiroko

2004-08-01

Cyclodextrin-modified micellar electrokinetic chromatography was applied to the enantioseparation of catechin and epicatechin using 6-O-alpha-D-glucosyl-beta-cyclodextrin together with sodium dodecyl sulfate and borate-phosphate buffer. Factors affecting chiral resolution and migration time of catechin and epicatechin were studied. The optimum running conditions were found to be 200 mM borate-20 mM phosphate buffer (pH 6.4) containing 25 mM 6-O-alpha-D-glucosyl-beta-cyclodextrin and 240 mM sodium dodecyl sulfate with an effective voltage of +25 kV at 20 degrees C using direct detection at 210 nm. Under these conditions, the resolution (Rs) of racemic catechin and epicatechin were 4.15 and 1.92, respectively. With this system, catechin and epicatechin enantiomers along with other four catechins ((-)-catechin gallate, (-)-epicatechin gallate, (-)-epigallocatechin, (-)-epigallocatechin gallate) and caffeine in tea samples were analyzed successfully. The difference of migration time between catechin and epicatechin is discussed.

Coupling of non-aqueous electrokinetic chromatography using cationic cyclodextrins with electrospray ionization mass spectrometry.

PubMed

Mol, Roelof; de Jong, Gerhardus J; Somsen, Govert W

2008-01-01

Non-aqueous electrokinetic chromatography (NAEKC) using cationic cyclodextrins (CDs) was coupled to electrospray ionization mass spectrometry (ESI-MS). A methanolic background electrolyte (BGE) was used which contained the hydrochloride salts of the single-isomer derivative cyclodextrins 6-monodeoxy-6-mono(2-hydroxy)propylamino-beta-cyclodextrin (IPA-beta-CD) or 6-monodeoxy-6-mono(3-hydroxy)propylamino-beta-cyclodextrin (PA-beta-CD). Applying a reversed capillary electrophoresis (CE) polarity (-30 kV), efficient separation of negatively charged compounds was achieved with plate numbers of up to 190,000. PA-beta-CD appeared to be the most suitable for the separation of various acidic drugs while also providing a high chiral selectivity. Analyte detection was achieved by ESI-MS in the negative-ion mode using a sheath-liquid interface. In order to prevent current drops caused by the cathodic electroosmotic flow, a pressure of 15 mbar was applied on the inlet vial during NAEKC/MS analysis. The effect of the cationic CDs on the MS signal intensities of acidic test drugs was thoroughly studied. When a voltage is applied across the CE capillary, the overall mobility of the cationic CDs is towards the inlet vial so that no CD molecules enter the ion source. The chloride counter ions of the CDs, which migrated towards the capillary outlet, were found to cause ionization suppression, although significant analyte signals could still be detected. Depending on the CD concentration in the BGE, limits of detection for acidic drugs were in the 50-400 ng/mL range in full-scan mode.

Use of cyclodextrins as a cosmetic delivery system for fragrance materials: linalool and benzyl acetate.

PubMed

Numanoğlu, Ulya; Sen, Tangül; Tarimci, Nilüfer; Kartal, Murat; Koo, Otilia M Y; Onyüksel, Hayat

2007-10-19

The aim of this study was to increase the stability and water solubility of fragrance materials, to provide controlled release of these compounds, and to convert these substances from liquid to powder form by preparing their inclusion complexes with cyclodextrins (CDs). For this purpose, linalool and benzyl acetate were chosen as the fragrance materials. The use of beta-cyclodextrin (beta CD) and 2-hydroxypropyl-beta-cyclodextrin (2-HP beta CD) for increasing the solubility of these 2 fragrance materials was studied. Linalool and benzyl acetate gave a B-type diagram with beta CD, whereas they gave an A(L)-type diagram with 2-HP beta CD. Therefore, complexes of fragrance materials with 2-HP beta CD at 1:1 and 1:2 molar ratios (guest:host) were prepared. The formation of inclusion complexes was confirmed using proton nuclear magnetic resonance ((1)H-NMR) spectroscopy and circular dichroism spectroscopy. The results of the solubility studies showed that preparing the inclusion complex with 2-HP beta CD at a 1:1 molar ratio increased the solubility of linalool 5.9-fold and that of benzyl acetate 4.2-fold, whereas the complexes at a 1:2 molar ratio increased the solubility 6.4- and 4.5-fold for linalool and benzyl acetate, respectively. The stability and in vitro release studies were performed on the gel formulations prepared using uncomplexed fragrance materials or inclusion complexes of fragrance materials at a 1:1 molar ratio. It was observed that the volatility of both fragrance materials was decreased by preparing the inclusion complexes with 2-HP beta CD. Also, in vitro release data indicated that controlled release of fragrances could be possible if inclusion complexes were prepared.

Solid-state flurbiprofen and methyl-β-cyclodextrin inclusion complexes prepared using a single-step, organic solvent-free supercritical fluid process.

PubMed

Rudrangi, Shashi Ravi Suman; Kaialy, Waseem; Ghori, Muhammad U; Trivedi, Vivek; Snowden, Martin J; Alexander, Bruce David

2016-07-01

The aim of this study was to enhance the apparent solubility and dissolution properties of flurbiprofen through inclusion complexation with cyclodextrins. Especially, the efficacy of supercritical fluid technology as a preparative technique for the preparation of flurbiprofen-methyl-β-cyclodextrin inclusion complexes was evaluated. The complexes were prepared by supercritical carbon dioxide processing and were evaluated by solubility, differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy, practical yield, drug content estimation and in vitro dissolution studies. Computational molecular docking studies were conducted to study the possibility of molecular arrangement of inclusion complexes between flurbiprofen and methyl-β-cyclodextrin. The studies support the formation of stable molecular inclusion complexes between the drug and cyclodextrin in a 1:1 stoichiometry. In vitro dissolution studies showed that the dissolution properties of flurbiprofen were significantly enhanced by the binary mixtures prepared by supercritical carbon dioxide processing. The amount of flurbiprofen dissolved into solution alone was very low with 1.11±0.09% dissolving at the end of 60min, while the binary mixtures processed by supercritical carbon dioxide at 45°C and 200bar released 99.39±2.34% of the drug at the end of 30min. All the binary mixtures processed by supercritical carbon dioxide at 45°C exhibited a drug release of more than 80% within the first 10min irrespective of the pressure employed. The study demonstrated the single step, organic solvent-free supercritical carbon dioxide process as a promising approach for the preparation of inclusion complexes between flurbiprofen and methyl-β-cyclodextrin in solid-state. Copyright © 2016 Elsevier B.V. All rights reserved.

Chemically grafted polymeric filters for chemical sensors: Hyperbranched poly(acrylic acid) films incorporating {Beta}-cyclodextrin receptors and amine-functionalized filter layers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dermody, D.L.; Peez, R.F.; Bergbreiter, D.E.

1999-02-02

The authors report a new molecular-filter approach for enhancing the selectivity of chemical sensors. Specifically, they describe electrochemical sensors prepared from Au electrodes coated with {beta}-cyclodextrin-functionalized, hyperbranched poly(acrylic acid)(PAA) films capped with a chemically grafted, ultrathin polyamine layer. The hyperbranched PAA film is a highly functionalized framework for covalently binding the {beta}-cyclodextrin molecular receptors. The thin, grafted polyamine overlayer acts as a pH-sensitive molecular filter that selectively passes suitably charged analytes. Poly(amidoamine) dendrimers or poly-D-lysine is used as 10--15-nm-thick filter layers. The results show that at low pH, when the polyamines are fully protonated, positively charged redox probe molecules, suchmore » as benzyl viologen (BV), do not permeate the filter layer. However, at high pH, when the filter layer is uncharged, BV penetrates the filter layer and is reduced at the electrode. The opposite pH dependence is observed for negatively charged redox molecules such as anthraquinone-2-sulfonate (AQS). Both BV and AQS specifically interact with the {beta}-cyclodextrin receptors underlying the polyamine filter layers.« less

Preparation and characterization of PLGA-β-CD polymeric nanoparticles containing methotrexate and evaluation of their effects on T47D cell line.

PubMed

Gorjikhah, Fatemeh; Azizi Jalalian, Farid; Salehi, Roya; Panahi, Yunes; Hasanzadeh, Arash; Alizadeh, Effat; Akbarzadeh, Abolfazl; Davaran, Soodabeh

2017-05-01

Among all cancers that affect women, breast cancer has most mortality rate. It is essential to attain more safe and efficient anticancer drugs. Recent advances in medical nanotechnology and biotechnology have caused in novel improvements in breast and other cancer drug delivery. Methotrexate is an anticancer drug that prevents the dihydrofolate reductase enzyme, which inhibits in the formation of DNA, RNA and proteins which have poor water-solubility. For enhancing the solubility and stability of drugs in delivery systems, we used methotrexate-loaded PLGA- beta-cyclodextrin nanoparticles. The PLGA- beta-cyclodextrin nanoparticles were synthesized by a double emulsion method and characterized with FT-IR and SEM. T47D breast cancer cell lines were treated with equal concentrations of methotrexate-loaded PLGA- beta-cyclodextrin nanoparticles and free methotrexate. MTT assay confirmed that methotrexate-loaded PLGA- beta-cyclodextrin nanoparticles enhanced cytotoxicity and drug delivery in T47D breast cancer cells. These results indicate that encapsulated drugs could be effective in controlled drug release for a sustained period would serve the purpose for long-term treatment of many diseases such as breast cancer.

Analysis of diterpenoic compounds in natural resins applied as binders in museum objects by capillary electrophoresis.

PubMed

Findeisen, Anna; Kolivoska, Viliam; Kaml, Isabella; Baatz, Wolfgang; Kenndler, Ernst

2007-07-20

The exudates of conifers consist mainly of diterpenoic acids of the abietane and pimarane type (abietic, neoabietic, dehydroabietic, palustric, pimaric, isopimaric, levopimaric and sandaracopimaric acid) and larixol acetate. These natural resins were used as adhesives, coatings, varnishes or plasticizers in artistic and historic works since ancient times. For the purpose of conservation and restoration and for art historic examination of such museum objects the identification of the binding media used is undoubtedly of paramount importance. In the present paper, the characterization of these resins based on the pattern of their diterpenoid constituents is carried out by capillary electrophoresis. For separation a background electrolyte which has been initially introduced for the analysis of chlorinated and natural resin acids in waste water was modified and the experimental conditions were adjusted in terms of resolution and analysis time. Separation was carried out in borate buffer at pH 9.25 (ionic strength 20 mmol L(-1)) with methyl-beta-cyclodextrin and sulfobutylether-beta-cyclodextrin as additives to increase selectivity and enhance the solubility of the analytes. With this electrophoretic system the resin acids of interest and larixol acetate--all as anionic cyclodextrin complexes--were separated within 5 min and detected at 200, 250 and 270 nm with a diode array detector. The electrophoretic patterns served for the characterisation of the relevant diterpenoic resins, balsams and copals. Sample pre-treatment was limited to sonication in methanol at 55 degrees C for 30 min. This enables the identification of the resins in mixtures with other binders like plant gums, animal glues or drying oils, even when these media are present in excess. Colophony was identified as resinous constituent of a modelling mass for gilded frames originating from the 19th century.

Molecular structures of the inclusion complexes beta-cyclodextrin-1,2-bis(4-aminophenyl)ethane and beta-cyclodextrin-4,4'-diaminobiphenyl; packing of dimeric beta-cyclodextrin inclusion complexes.

PubMed

Giastas, Petros; Yannakopoulou, Konstantina; Mavridis, Irene M

2003-04-01

The present investigation is part of an ongoing study on the influence of the long end-functonalized guest molecules DBA and BNZ in the crystal packing of beta-cyclodextrin (betaCD) dimeric complexes. The title compounds are 2:2 host:guest complexes showing limited host-guest hydrogen bonding at the primary faces of the betaCD dimers. Within the betaCD cavity the guests exhibit mutual pi...pi interactions and between betaCD dimers perpendicular NH...pi interactions. The DBA guest molecule exhibits one extended and two bent conformations in the complex. The BNZ guest molecule is not planar inside betaCD, in contrast to the structure of BNZ itself, which indicates that the cavity isolates the molecules and forbids the pi...pi stacking of the aromatic rings. NMR spectroscopy studies show that in aqueous solution both DBA and BNZ form strong complexes that have 1:1 stoichiometry and structures similar to the solid state ones. The relative packing of the dimers is the same in both complexes. The axes of two adjacent dimers form an angle close to 20 degrees and have a lateral displacement approximately 2.45 A, both of which characterize the screw-channel mode of packing. Although the betaCD/BNZ complex indeed crystallizes in a space group characterizing the latter mode, the betaCD/DBA complex crystallizes in a space group with novel dimensions not resembling any of the packing modes reported so far. The new lattice is attributed to the three conformations exhibited by the guest in the crystals. However, this lattice can be transformed into another, which is isostructural to that of the betaCD/BNZ inclusion complex, if the conformation of the guest is not taken into account.

Cyclodextrin controlled release of poorly water-soluble drugs from hydrogels.

PubMed

Woldum, Henriette Sie; Larsen, Kim Lambertsen; Madsen, Flemming

2008-01-01

The effect of 2-hydroxypropyl-beta-cyclodextrin and gamma-cyclodextrin on the release of ibuprofen, ketoprofen and prednisolone was studied. Stability constants calculated for inclusion complexes show size dependence for complexes with both cyclodextrins. Hydrogels were prepared by ultraviolet irradiation and release of each model drug was studied. For drugs formulated using cyclodextrins an increase in the achievable concentration and in the release from hydrogels was obtained due to increased solubility, although the solubility of all gamma-cyclodextrin complexes was limited. The load also was increased by adjusting pH for the acidic drugs and this exceeds the increase obtained with gamma-cyclodextrin addition.

Complex formation of sericoside with hydrophilic cyclodextrins: improvement of solubility and skin penetration in topical emulsion based formulations.

PubMed

Rode, T; Frauen, M; Müller, B W; Düsing, H J; Schönrock, U; Mundt, C; Wenck, H

2003-03-01

The main objective of this study was to devise novel methods for improving the solubility of the anti-inflammatory triterpenoid sericoside, the main component of Terminalia sericea extract, thus enabling its incorporation into topical formulations. Sericoside was stabilized by complex formation with hydrophilic derivatives of beta- and gamma-cyclodextrins in a molar ratio of 1.0:1.1. The complex of extract and cyclodextrin was equilibrated in water at 25 degrees C for approximately 24 h. The dehydrated complexes of T. sericea extract and cyclodextrin were characterized by differential scanning calorimetry, thermogravimetry analysis and X-ray diffraction. Complex formation with beta-cyclodextrin as well as gamma-cyclodextrin derivatives was detectable using these three analytical tools; however, only complexes with gamma-cyclodextrin derivatives showed stability upon storage after incorporation into topical o/w or w/o formulations. Furthermore, a T. sericea extract/gamma-cyclodextrin complex incorporated in an o/w formulation resulted in a 2.6-fold higher percutaneous penetration of sericoside in in vitro excised pig skin as compared to pure T. sericea extract. For the first time, the virtually insoluble anti-inflammatory active sericoside was incorporated into a topical emulsion based formulation in a stable manner, resulting in efficient skin penetration. Copyright 2003 Elsevier Science B.V.

[Conversion of 17 alpha-methyltestosterone to methandrostenolone by the bacterium Pimelobacter simplex VKPM Ac-1632 with the presence of cyclodextrins].

PubMed

Druzhinina, A V; Andriushina, V A; Stytsenko, T S; Voĭshvillo, N E

2008-01-01

Conditions of conversion of 17 alpha-methyltestosterone to methandrostenolone with the presence of modified beta-cyclodextrins (methylcyclodextrin, hydroxypropylcyclodextrin, and hydroxyethylcyclodextrin) in the steroid:cyclodextrin ratio 1:1 were studied. The experimental solutions of modified beta-cyclodextrins were prepared in deionized water with 5-7% methanol. Under the conditions found to be optimal, 1,2-dehydrogenation of 17 alpha-methyltestosterone was carried out with 2-4 g/l Pimelobacter simplex VKPM Ac-1632 biomass. At the substrate concentration 5-20 g/l, the reaction occurred for 1-15 h without any by-products. The maximum rate of methandrostenolone accumulation was observed with hydroxypropylcyclodextrin. The methylcyclodextrin solution can be reused for complete 17 alpha-methyltestosterone conversion at the concentration 5 g/l.

(13)C and (15)N solid-state NMR studies on albendazole and cyclodextrin albendazole complexes.

PubMed

Ferreira, M João G; García, A; Leonardi, D; Salomon, Claudio J; Lamas, M Celina; Nunes, Teresa G

2015-06-05

(13)C and (15)N solid-state nuclear magnetic resonance (NMR) spectra were recorded from albendazole (ABZ) and from ABZ:β-cyclodextrin, ABZ:methyl-β-cyclodextrin, ABZ:hydroxypropyl-β-cyclodextrin and ABZ:citrate-β-cyclodextrin, which were prepared by the spray-drying technique. ABZ signals were typical of a crystalline solid for the pure drug and of an amorphous compound obtained from ABZ:cyclodextrin samples. Relevant spectral differences were correlated with chemical interaction between ABZ and cyclodextrins. The number and type of complexes revealed a strong dependence on the cyclodextrin group substituent. Solid-state NMR data were consistent with the presence of stable inclusion complexes. Copyright © 2015 Elsevier Ltd. All rights reserved.

Influencing of resorption and side-effects of salicylic acid by complexing with beta-cyclodextrin.

PubMed

Szejtli, J; Gerlóczy, A; Sebestyén, G; Fónagy, A

1981-04-01

After oral administration of 14C-labelled salicylic acid and its beta-cyclodextrin complex to rats, the blood radioactivity-level increases in the first 2 h than decreases. The blood level obtained with the inclusion complex is somewhat but not significantly lower than with free acid. Since the resorption of cyclodextrin is a considerably slower process, it is very likely that the resorption of salicylic acid take place in the form of free acid after dissociation of the complex. The urinary excretion cumulative curves show that the free salicylic acid is completely excreted, while about 10% of the salicylic acid administered in the form of complex is lost. The cyclodextrin complex formation increases the pK value of all hydroxy-benzoic acids. Direct observations reveals that complex formation decreases the stomach-irritating effect of salicylic acid. The ratio of radioactivity was nearly the same in the organs of animals treated by both free salicylic and cyclodextrin complex.

Polycyclic aromatic hydrocarbon removal from contaminated soils using fatty acid methyl esters.

PubMed

Gong, Zongqiang; Wang, Xiaoguang; Tu, Ying; Wu, Jinbao; Sun, Yifei; Li, Peng

2010-03-01

In this study, solubilization of PAHs from a manufactured gas plant (MGP) soil and two artificially spiked soils using fatty acid methyl esters (FAME) was investigated. PAH removals from both the MGP and the spiked soils by FAME, methanol, soybean oil, hydroxypropyl-beta-cyclodextrin, Triton X-100, and Tween 80 were compared. The effect of FAME:MGP soil ratios on PAH removals was also investigated. Results showed that the FAME mixture synthesized by our lab was more efficient than the cyclodextrin and the two surfactants used for PAH removal from the spiked soils with individual PAH concentrations of 200 and 400 mg kg(-1). However, the difference among three PAH removals by the FAME, soybean oil and methanol was not quite pronounced. The FAME synthesized and market biodiesel exhibited better performance for PAH removals (46% and 35% of total PAH) from the weathered contaminated MGP soil when compared with the other agents (0-31%). Individual PAH removals from the weathered MGP soil were much lower than those from the spiked soils. The percentages of total PAH removals from the MGP soil were 59%, 46%, and 51% for the FAME:MGP soil ratios of 1:2, 1:1, and 2:1, respectively. These results showed that the FAME could be a more attractive alternative to conventional surfactants in ex situ washing of PAH-contaminated soils. 2010 Elsevier Ltd. All rights reserved.

Preparation of novel beta-cyclodextrin functionalized monolith and its application in chiral separation.

PubMed

Lv, Yongqin; Mei, Danping; Pan, Xinxin; Tan, Tianwei

2010-09-15

A novel beta-cyclodextrin (beta-CD) functionalized organic polymer monolith was prepared by covalently bonding ethylenediamine-beta-CD (EDA-beta-CD) to poly(glycidyl methacrylate-co-ethylene glycol dimethacrylate) (poly(GMA-co-EGDMA)) monolith via ring opening reaction of epoxy groups. SEM characterization was performed to confirm the homogeneity of the monolithic polymer. The resulting monolith was then characterized by DSC and XPS elemental analysis to study the thermal stability of the monolith, and to prove the successful immobilization of beta-CD on the polymer substrate. The beta-CD ligand density of 0.68 mmol g(-1) was obtained for the modified monolith, indicating the high reactivity and efficiency of the EDA-beta-CD modifier. The ethylenediamine-beta-CD functionalized monoliths were used for the chiral separation of ibuprofen racemic mixture and showed promising results. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Modulating drug loading and release profile of beta-cyclodextrin polymers by means of cross-linked degree.

PubMed

Wang, Qi-fang; Li, San-ming; Zhang, Yu-yang; Zhang, Hong

2011-02-01

The purpose of the present study is to use beta-cyclodextrin polymers (beta-CDP) with different cross-linked degree (CLD) to form inclusion complexes with ibuprofen and examine the effects of structural and compositional factors of beta-CDP on its drug loading and release behaviors. A series of beta-CDP with different CLD were synthesized and characterized by Fourier Transform Infrared Spectroscopy (FT-IR) and 13C NMR spectrum. The beta-CDP was systemically characterized for the relation between the CLD of beta-CDP and the drug loading and release as well. The results of FT-IR and 13C NMR showed that similar peak-shaped vibration of beta-CDP and beta-CD implies that the polymer keeps the original characteristic structure of beta-CD. The CLD of the beta-CDP played a critical role in the drug loading and release, increasing the CLD resulted in reduction of drug loading, but increase in drug release.

Crystal structures and molecular dynamics studies of the inclusion compounds of β-citronellol in β-cyclodextrin, heptakis(2,6-di-O-methyl)-β-cyclodextrin and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin

NASA Astrophysics Data System (ADS)

Fourtaka, Katerina; Christoforides, Elias; Mentzafos, Dimitris; Bethanis, Kostas

2018-06-01

The crystal structures of the inclusion complexes of the β-citronellol (cl) inβ-Cyclodextrin (β-CD), heptakis(2,6-di-O-methyl)-β-Cyclodextrin (DM-β-CD) and heptakis(2,3,6-tri-O-methyl)-β-Cyclodextrin (TM-β-CD) have being investigated by X-ray crystallography. The cl/β-CD inclusion complex crystallizes in the P1space group forming dimers which are arranged along the c-axis according to the Intermediate Channel packing mode. Inside the dimeric host cavity two enantiomeric guest molecules are accommodated. The inclusion complexes of cl/DM-β-CD and cl/TM-β-CD crystallize in the P212121 space group having both 1:1 guest:host stoichiometry, the guest found always with the (-)-cl enantiomeric configuration. The guest is fully encapsulated inside the DM-β-CD host cavity whereas is partially encapsulated in the TM-β-CD which is severely puckered as in all TM-β-CD complexes and its primary side is efficiently blocked by the methoxy groups. The complex units in the case of cl/DM-β-CD pack along the crystallographic a-axis in a head-to-tail manner forming columns of herringbone mode whereas in the case of cl/TM-β-CD are arranged also head-to-tail, parallel to the b-axis, in a screw-channel mode. MD simulations based on the determined crystal structures showed that in a simulated aqueous environment the guest maintains the inclusion mode observed crystallographically in every case. MM/GBSA-calculations used for comparison of the inclusion complexes binding affinity with each other, indicated that the inclusion of β-citronellol in TM-β-CD is less favorable than in β-CD and DM-β-CD.

A water-soluble, mucoadhesive quaternary ammonium chitosan-methyl-β-cyclodextrin conjugate forming inclusion complexes with dexamethasone.

PubMed

Piras, Anna Maria; Zambito, Ylenia; Burgalassi, Susi; Monti, Daniela; Tampucci, Silvia; Terreni, Eleonora; Fabiano, Angela; Balzano, Federica; Uccello-Barretta, Gloria; Chetoni, Patrizia

2018-03-30

The ocular bioavailability of lipophilic drugs, such as dexamethasone, depends on both drug water solubility and mucoadhesion/permeation. Cyclodextrins and chitosan are frequently employed to either improve drug solubility or prolong drug contact onto mucosae, respectively. Although the covalent conjugation of cyclodextrin and chitosan brings to mucoadhesive drug complexes, their water solubility is restricted to acidic pHs. This paper describes a straightforward grafting of methyl-β-cyclodextrin (MCD) on quaternary ammonium chitosan (QA-Ch60), mediated by hexamethylene diisocyanate. The resulting product is a water-soluble chitosan derivative, having a 10-atom long spacer between the quaternized chitosan and the cyclodextrin. The derivative is capable of complexing the model drug dexamethasone and stable complexes were also observed for the lyophilized products. Furthermore, the conjugate preserves the mucoadhesive properties typical of quaternized chitosan and its safety as solubilizing excipient for ophthalmic applications was preliminary assessed by in vitro cytotoxicity evaluations. Taken as a whole, the observed features appear promising for future processing of the developed product into 3D solid forms, such as controlled drug delivery systems, films or drug eluting medical devices.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Liang; Nachtergaele, Sigrid; Seddon, Annela M.

This paper utilizes cyclodextrin-based host-guest chemistry in a microfluidic device to modulate the crystallization of membrane proteins and the process of concentration of membrane protein samples. Methyl-{beta}-cyclodextrin (MBCD) can efficiently capture a wide variety of detergents commonly used for the stabilization of membrane proteins by sequestering detergent monomers. Reaction Center (RC) from Blastochloris viridis was used here as a model system. In the process of concentrating membrane protein samples, MBCD was shown to break up free detergent micelles and prevent them from being concentrated. The addition of an optimal amount of MBCD to the RC sample captured loosely bound detergentmore » from the protein-detergent complex and improved sample homogeneity, as characterized by dynamic light scattering. Using plug-based microfluidics, RC crystals were grown in the presence of MBCD, giving a different morphology and space group than crystals grown without MBCD. The crystal structure of RC crystallized in the presence of MBCD was consistent with the changes in packing and crystal contacts hypothesized for removal of loosely bound detergent. The incorporation of MBCD into a plug-based microfluidic crystallization method allows efficient use of limited membrane protein sample by reducing the amount of protein required and combining sparse matrix screening and optimization in one experiment. The use of MBCD for detergent capture can be expanded to develop cyclodextrin-derived molecules for fine-tuned detergent capture and thus modulate membrane protein crystallization in an even more controllable way.« less

Dual fluorescence of N-phenylanthranilic acid: Effect of solvents, pH and beta-cyclodextrin.

PubMed

Rajendiran, N; Balasubramanian, T

2007-11-01

Spectral characteristics of N-phenylanthranilic acid (NPAA) have been studied in different solvents, pH and beta-cyclodextrin (beta-CD) and compared with anthranilic acid (2-aminobenzoic acid, 2ABA). In all solvents a dual fluorescence is observed in NPAA, whereas 2ABA gives single emission. Combining the results observed in the absorption, fluorescence emission and fluorescence excitation spectra, it is found that strong intramolecular hydrogen bonding (IHB) interactions present in NPAA molecule. The inclusion complex of NPAA with beta-CD is analysed by UV-vis, fluorimetry, FT-IR, (1)H NMR, scanning electron microscope and AM 1 method. The above spectral studies show that NPAA forms a 1:1 inclusion complex with beta-CD and COOH group present in the beta-CD cavity. A mechanism is proposed to explain the inclusion process.

Enzymatic synthesis of dimaltosyl-{beta}-cyclodextrin via a transglycosylation reaction using TreX, a Sulfolobus solfataricus P2 debranching enzyme

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kang, Hee-Kwon; Cha, Hyunju; Yang, Tae-Joo

2008-02-01

Di-O-{alpha}-maltosyl-{beta}-cyclodextrin ((G2){sub 2}-{beta}-CD) was synthesized from 6-O-{alpha}-maltosyl-{beta}-cyclodextrin (G2-{beta}-CD) via a transglycosylation reaction catalyzed by TreX, a debranching enzyme from Sulfolobus solfataricus P2. TreX showed no activity toward glucosyl-{beta}-CD, but a transfer product (1) was detected when the enzyme was incubated with maltosyl-{beta}-CD, indicating specificity for a branched glucosyl chain bigger than DP2. Analysis of the structure of the transfer product (1) using MALDI-TOF/MS and isoamylase or glucoamylase treatment revealed it to be dimaltosyl-{beta}-CD, suggesting that TreX transferred the maltosyl residue of a G2-{beta}-CD to another molecule of G2-{beta}-CD by forming an {alpha}-1,6-glucosidic linkage. When [{sup 14}C]-maltose and maltosyl-{beta}-CD were reactedmore » with the enzyme, the radiogram showed no labeled dimaltosyl-{beta}-CD; no condensation product between the two substrates was detected, indicating that the synthesis of dimaltosyl-{beta}-CD occurred exclusively via transglycosylation of an {alpha}-1,6-glucosidic linkage. Based on the HPLC elution profile, the transfer product (1) was identified to be isomers of 6{sup 1},6{sup 3}- and 6{sup 1},6{sup 4}-dimaltosyl-{beta}-CD. Inhibition studies with {beta}-CD on the transglycosylation activity revealed that {beta}-CD was a mixed-type inhibitor, with a K{sub i} value of 55.6 {mu}mol/mL. Thus, dimaltosyl-{beta}-CD can be more efficiently synthesized by a transglycosylation reaction with TreX in the absence of {beta}-CD. Our findings suggest that the high yield of (G2){sub 2}-{beta}-CD from G2-{beta}-CD was based on both the transglycosylation action mode and elimination of the inhibitory effect of {beta}-CD.« less

Use of natural and modified cyclodextrins as inhibiting agents of peach juice enzymatic browning.

PubMed

López-Nicolas, José M; Pérez-López, Antonio J; Carbonell-Barrachina, Angel; García-Carmona, Francisco

2007-06-27

Although cyclodextrins (CDs) have been successfully used as antibrowning agents in different fruit juices, no research has studied the effect of these compounds on enzymatic browning in peach juice. In this paper, the color of fresh peach juice was evaluated in the presence of two types of natural (alpha-CD and beta-CD) and a modified (maltosyl-beta-CD) CD, and the effectiveness of these compounds as browning inhibitors was determined using the color space CIELAB system. Moreover, to clarify the mechanism by which CDs inhibit peach juice enzymatic browning, the process was kinetically modeled in the absence and presence of CDs using a colorimetric method; the apparent complexation constants between the mixtures of diphenols present in peach juice and some types of CD were calculated. The results show that the highest affinity constant was presented by alpha-CD (Kc = 18.31 mM-1) followed by maltosyl-beta-CD (Kc = 11.17 mM-1), whereas beta-CD was incapable of inhibiting peach juice enzymatic browning. Cyclodextrin; browning; peach; juice; color; polyphenol oxidase.

Enantioselective analysis of chiral anteiso fatty acids in the polar and neutral lipids of food.

PubMed

Hauff, Simone; Hottinger, Georg; Vetter, Walter

2010-04-01

Anteiso fatty acids (aFA) are substituted with a methyl group on the antepenultimate carbon of the straight acyl chain. This feature leads to a stereogenic center. The 12-methyltetradecanoic acid (a15:0) and the 14-methylhexadecanoic acid (a17:0) are the most common aFA found in food, although they occur only in very small quantities. In this study we used gas chromatography in combination with a chiral stationary phase to determine the enantiomeric distribution of both a15:0 and a17:0 in the neutral and polar lipids of aquatic food samples and cheese. The best suited column was selected out of four custom-made combinations of heptakis(6-O-tert-butyldimethylsilyl-2,3-di-O-methyl)-beta-cyclodextrin (beta-TBDM) with different amount and polarity of an achiral polysiloxane. After separation of polar and neutral lipids of the food samples by solid phase extraction, fatty acid methyl esters were prepared and the fatty acid methyl esters were fractionated by reversed phase high performance liquid chromatography. Measurements of fractions high in aFA by enantioselective GC/MS in the selected ion monitoring mode verified the dominance of the (S)-enantiomers of a15:0 and a17:0 in both lipid fractions. However (R)-enantiomers were detectable in all samples. The relative proportion of the (R)-enantiomers was up to fivefold higher in the polar lipids than in the neutral lipids. The higher proportions in the polar lipids indicate that microorganisms might be involved in the formation of (R)-aFA.

Complexation of morin with three kinds of cyclodextrin. A thermodynamic and reactivity study

NASA Astrophysics Data System (ADS)

Jullian, Carolina; Orosteguis, Teresita; Pérez-Cruz, Fernanda; Sánchez, Paulina; Mendizabal, Fernando; Olea-Azar, Claudio

2008-11-01

Properties of inclusion complexes between morin (M) and β-cyclodextrin (βCD), 2-hydroxypropyl-β-cyclodextrin (HPβCD) and Heptakis (2,6- O-di methyl) β-cyclodextrin (DMβCD) such as aqueous solubility and the association constants of this complex have been determined. The water solubility of morin was increased by inclusion with cyclodextrins. The phase-solubility diagrams drawn from UV spectral measurements are of the A L-type. Also ORAC FL studies were done. An increase in the antioxidant reactivity is observed when morin form inclusion complex with the three cyclodextrin studied. Finally, thermodynamics studies of cyclodextrin complexes indicated that for DMβCD the inclusion is primarily enthalpy-driven process meanwhile βCD and HPβCD are entropy-driven processes. This is corroborated by the different inclusion geometries obtained by 2D-NMR.

Methyl-beta-cyclodextrin increases permeability of Caco-2 cell monolayers by displacing specific claudins from cholesterol rich domains associated with tight junctions.

PubMed

Lambert, Daniel; O'Neill, Catherine A; Padfield, Philip J

2007-01-01

In a previous study we demonstrated that depletion of Caco-2 cell cholesterol results in the loss of tight junction (TJ) integrity through the movement of claudins 3 and 4 and occludin, but not claudin 1, out of the TJs [1]. The aims of this study were to determine whether the major tight junction (TJ) proteins in Caco-2 cells are associated with cholesterol rich, membrane raft-like domains and if the loss of TJ integrity produced by the extraction of cholesterol reflects the dissolution of these domains resulting in the loss of TJ organisation. We have demonstrated that in Caco-2 cells claudins 1, 3, 4 and 7, JAM-A and occludin, are associated with cholesterol rich membrane domains that are insoluble in Lubrol WX. Co-immunoprecipitation studies demonstrated that there is no apparent restriction on the combination of claudins present in the rafts and that interaction between the proteins is dependent on cholesterol. JAM-A was not co-immunoprecipitated with the other TJ proteins indicating that it is resident within in a distinct population of rafts and therefore is likely not directly associated with the claudins/occludin present in the TJ complexes. Depletion of Caco-2 cell cholesterol with methyl-beta-cyclodextrin resulted in the displacement of claudins 3, 4 and 7, JAM-A and occludin, but not claudin 1, out of the cholesterol rich domains. Our data indicate that depletion of cholesterol does not result in the loss of the TJ-associated membrane rafts. However, the sterol is required to maintain the association of key proteins with the TJ associated membrane rafts and therefore the TJs. Furthermore, the data suggest that cholesterol may actually directly stabilise the multi-protein complexes that form the TJ strands. Copyright (c) 2007 S. Karger AG, Basel.

INTERACTIONS OF METHYL ORANGE WITH CYCLODEXTRIN/SODIUM-MONTMORILLONITE SYSTEMS PROBED BY UV-VISIBLE SPECTROSCOPY

EPA Science Inventory

Clay mineral colloids play important roles in the adsorption of polar organic contaminants in the environment. Similarly, cyclodextrins (CD) can entrap poorly water-soluble organic compounds. A combination of CDs and clay minerals affords great opportunities to investigate simult...

The effect of pH and triethanolamine on sulfisoxazole complexation with hydroxypropyl-beta-cyclodextrin.

PubMed

Gladys, Granero; Claudia, Garnero; Marcela, Longhi

2003-11-01

A novel complexation of sulfisoxazole with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was studied. Two systems were used: binary complexes prepared with HP-beta-CD and multicomponent system (HP-beta-CD and the basic compound triethanolamine (TEA)). Inclusion complex formation in aqueous solutions and in solid state were investigated by the solubility method, thermal analysis (differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)), Fourier-transform infrared spectroscopy (FT-IR) and dissolution studies. The solid complexes of sulfisoxazole were prepared by freeze-drying the homogeneous concentrated aqueous solutions in molar ratios of sulfisoxazole:HP-beta-CD 1:1 and 1:2, and sulfisoxazole:TEA:HP-beta-CD 1:1:2. FT-IR and thermal analysis showed differences among sulfisoxazole:HP-beta-CD and sulfisoxazole:TEA:HP-beta-CD and their corresponding physical mixtures and individual components. The HP-beta-CD solubilization of sulfisoxazole could be improved by ionization of the drug molecule through pH adjustments. However, larger improvements of the HP-beta-CD solubilization are obtained when multicomponent systems are used, allowing to reduce the amount of CD necessary to prepare the target formulation.

New strategies for the use of Linum usitatissimum cell factories for the production of bioactive compounds.

PubMed

Almagro, Lorena; García-Pérez, Pascual; Belchí-Navarro, Sarai; Sánchez-Pujante, Pedro Joaquín; Pedreño, M A

2016-02-01

In this work, suspension-cultured cells of Linum usitatissimum L. were used to evaluate the effect of two types of cyclodextrins, β-glucan and (Z)-3-hexenol separately or in combination on phytosterol and tocopherol production. Suspension-cultured cells of L. usitatissimum were able to produce high levels of phytosterols in the presence of 50 mM methylated-β-cyclodextrins (1325.96 ± 107.06 μg g dry weight(-1)) separately or in combination with β-glucan (1278.57 ± 190.10 μg g dry weight(-1)) or (Z)-3-hexenol (1507.88 ± 173.02 μg g dry weight(-1)), being cyclodextrins able to increase both the secretion and accumulation of phytosterols in the spent medium, whereas β-glucan and (Z)-3-hexenol themselves only increased its intracellular accumulation. Moreover, the phytosterol values found in the presence of hydroxypropylated-β-cyclodextrins were lower than those found in the presence of methylated-β-cyclodextrins in all cases studied. However, the results showed that the presence of methylated-β-cyclodextrins did not increase the tocopherols production and only an increase in tocopherol levels was observed when cells were elicited with 50 mM hydroxypropylated-β-cyclodextrins in combination with β-glucan (174 μg g dry weight(-1)) or (Z)-3-hexenol (257 μg g dry weight(-1)). Since the levels of tocopherol produced in the combined treatment were higher than the sum of the individual treatments, a synergistic effect between both elicitors was assumed. To sum up, flax cell cultures elicited with cyclodextrins alone or in combination with β-glucan or (Z)-3-hexenol were able produce phytosterols and tocopherols, and therefore, these elicited suspension-cultured cells of L. usitatissimum can provide an alternative system, which is at the same time more sustainable, economical and ecological for their production. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Novel beta-cyclodextrin derivative functionalized polymethacrylate-based monolithic columns for enantioselective separation of ibuprofen and naproxen enantiomers in capillary electrochromatography.

PubMed

Tian, Yun; Zhong, Cheng; Fu, Enqin; Zeng, Zhaorui

2009-02-06

A novel enantioselective polymethacrylate-based monolithic column for capillary electrochromatography was prepared by ring-opening reaction of epoxy groups from poly(glycidyl methacrylate-co-ethylene dimethacrylate) monolith with a novel beta-cyclodextrin derivative bearing 4-dimethylamino-1,8-naphthalimide functionalities. Conditions for the ring-opening reaction with respect to different reaction parameters were thoroughly optimized to obtain high electroosmotic flow, separation efficiency and enantioselectivity for the analytes. The nonaqueous mobile phase composition regarding acetonitrile-methanol ratio and the concentration of electrolyte were examined to manipulate the hydrophobic inclusion and anion-exchange interaction between the analytes and chiral stationary phase. It was observed that in addition to beta-cyclodextrin cavity, the electrostatic interaction exhibited pronounced influence on the enantioseparation of acidic analytes. Acidic enantiomers (ibuprofen and naproxen) could be separated with separation factor (alpha) values up to 1.08 and a maximum separation efficiency of 86000 plates/m could be achieved.

Synthesis and Evaluation of Cyclodextrin-based Polymers for Patulin Extraction from Aqueous Solutions

USDA-ARS?s Scientific Manuscript database

Patulin is a mycotoxin produced by fungi that contaminate fruits, juices, and other agricultural commodities. Sorption properties of polyurethane-beta-cyclodextrin polymers were evaluated for the ability to remove patulin from solutions, including apple juice. Freundlich isotherm analysis determin...

Predicting the behavior of novel sugar carriers for dry powder inhaler formulations via the use of a cohesive-adhesive force balance approach.

PubMed

Hooton, Jennifer C; Jones, Matthew D; Price, Robert

2006-06-01

The aim of this work was to utilize the recently developed cohesive-adhesive balance (CAB) technique for analyzing quantitative AFM measurements to compare the relative forces of interaction of micronized salbutamol sulfate particles and a selection of specifically grown sugar substrates (beta cyclodextrin, lactose, raffinose, trehalose and xylitol). The interfacial behavior was subsequently related to the in-vitro delivery performance of these sugars as carrier particles in dry powder inhalation (DPI) formulations. The CAB analysis indicated that the rank order of adhesion between salbutamol sulfate and the sugars was beta cyclodextrin < lactose < trehalose < raffinose < xylitol. The beta cyclodextrin was the only substrate with which salbutamol sulfate demonstrated a greater cohesive behavior. All other sugars exhibited an adhesive dominance. In-vitro deposition performance of the salbutamol sulfate based carrier DPI formulations showed that the rank order of the fine particle fraction (FPF) was beta cyclodextrin > lactose > raffinose > trehalose > xylitol. A linear correlation (R(2) = 0.9572) was observed between the FPF and cohesive-adhesive ratios of the AFM force measurements. The observed link between CAB analysis of the interactive forces and in-vitro performance of carrier based formulations suggested a fundamental understanding of the relative balance of the various forces of interaction within a dry powder formulation may provide a critical insight into the behavior of these formulations. (c) 2006 Wiley-Liss, Inc. and the American Pharmacists Association

Determination of binding constants of cyclodextrin inclusion complexes with amino acids and dipeptides by potentiometric titration.

PubMed

Kahle, Claudia; Holzgrabe, Ulrike

2004-10-01

Cyclodextrins are well known for their ability to separate enantiomers of drugs, natural products, and other chiral substances using HPLC, GC, or CE. The resolution of the enantiomers is due to the formation of diastereomeric complexes between the cyclodextrin and the pairs of enantiomers. The aim of this study was to determine the binding constants of the complexes between alpha- and beta-cyclodextrin and the enantiomers of a series of aliphatic and aromatic amino acids, and dipeptides, using a potentiometric titration method. The results of this method are compared to other methods, and correlated to findings in cyclodextrin-modified capillary electrophoresis and possible complex structures. Potentiometric titration was found to be an appropriate tool to determine the binding constants of cyclodextrin inclusion complexes.

Spectrofluorimetric study of the beta-cyclodextrin-ibuprofen complex and determination of ibuprofen in pharmaceutical preparations and serum.

PubMed

Hergert, L A; Escandar, G M

2003-06-13

The inclusion complexation of ibuprofen in beta-cyclodextrin (beta-CD) has been examined by means of spectrofluorimetry at both acid and alkaline pH. The results suggest that stable 1:1 complexes are formed in both media. The analysis of the pK(a) values for ibuprofen in both the absence and presence of beta-CD (4.12 and 4.66, respectively) suggests that in the inclusion complex the carboxylic group is located outside the cyclodextrin (CD) but interacting with it. Further structural characterization of the complex was carried out by means of am1 semiempiral calculations. Based on the obtained results, a spectrofluorimetric method for the determination of ibuprofen in the presence of beta-CD at 10 degrees C was developed in the range of 4.7-58 mug ml(-1). Better limits of detection (1.6 mug ml(-1)) and quantification (4.7 mug ml(-1)) were obtained in this latter case with respect to those obtained in the absence of beta-CD. The method was satisfactorily applied to the quantification of ibuprofen in pharmaceutical preparations. A novel spectrofluorimetric determination of ibuprofen in the presence of beta-CD was also developed for serum samples at concentration levels between 5 and 70 mug ml(-1). It uses second-order fluorescence excitation-emission matrices coupled to an algorithm based on self-weighted alternating trilinear decomposition (SWATLD), and avoids resorting to separative instrumental analyses.

Membrane penetration enhancement of ibuprofen using supersaturation.

PubMed

Iervolino, M; Raghavan, S L; Hadgraft, J

2000-04-05

Permeation enhancement of ibuprofen from supersaturated solutions formed using the cosolvent technique was investigated using silicone as a model membrane. Hydroxpropyl methyl cellulose and hydroxpropyl-beta-cyclodextrin were used to stabilise the supersaturated states. Physical stability studies showed best results for low drug concentrations in a 40:60 propylene glycol/water cosolvent system. Variations in flux across model silicone membranes from saturated solutions were observed as the PG content was increased. The flux of IBU increased with the degree of saturation for solutions prepared in a 40:60 PG/water cosolvent mixture. HPMC and CD were found to be effective in enhancing the stability of supersaturated solutions of IBU. The mechanisms of action are different for the two additives and are discussed.

Application of cyclodextrins in antibody microparticles: potentials for antibody protection in spray drying.

PubMed

Ramezani, Vahid; Vatanara, Alireza; Seyedabadi, Mohammad; Nabi Meibodi, Mohsen; Fanaei, Hamed

2017-07-01

Dry powder formulations are extensively used to improve the stability of antibodies. Spray drying is one of important methods for protein drying. This study investigated the effects of trehalose, hydroxypropyl beta cyclodextrin (HPBCD) and beta cyclodextrin (BCD) on the stability and particle properties of spray-dried IgG. D-optimal design was employed for both experimental design and analysis and optimization of the variables. The size and aerodynamic behavior of particles were determined using laser light scattering and glass twin impinger, respectively. In addition, stability, ratio of beta sheets and morphology of antibody were analyzed using size exclusion chromatography, IR spectroscopy and electron microscopy, respectively. Particle properties and antibody stability were significantly improved in the presence of HPBCD. In addition, particle aerodynamic behavior, in terms of fine-particle fraction (FPF), enhanced up to 52.23%. Furthermore, antibody was better preserved not only during spray drying, but also during long-term storage. In contrast, application of BCD resulted in the formation of larger particles. Although trehalose caused inappropriate aerodynamic property, it efficiently decreased antibody aggregation. HPBCD is an efficient excipient for the development of inhalable protein formulations. In this regard, optimal particle property and antibody stability was obtained with proper combination of cyclodextrins and simple sugars, such as trehalose.

Porphyrin Cyclodextrin Conjugates Modulate Amyloid Beta Peptide Aggregation and Cytotoxicity.

PubMed

Oliveri, Valentina; Zimbone, Stefania; Giuffrida, Maria Laura; Bellia, Francesco; Tomasello, Marianna Flora; Vecchio, Graziella

2018-04-25

Although fibrillar amyloid beta peptide (Aβ) aggregates are one of the major hallmarks of Alzheimer's disease, increasing evidence suggests that soluble Aβ oligomers are the primary toxic species. Targeting the oligomeric species could represent an effective strategy to interfere with Aβ toxicity. In this work, the biological properties of 5[4-(6-O-β-cyclodextrin)-phenyl],10,15,20-tri(4-hydroxyphenyl)-porphyrin and its zinc complex were tested, as new molecules that interact with Aβ and effectively prevent its cytotoxicity. We found that these systems can cross the cell membrane to deliver Aβ intracellularly and promote its clearance. Our results provide evidence for the use of cyclodextrin-porphyrin derivatives as a promising strategy to target amyloid aggregation. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis and characterization of water-soluble hydroxybutenyl cyclomaltooligosaccharides (cyclodextrins).

PubMed

Buchanan, Charles M; Alderson, Susan R; Cleven, Curtis D; Dixon, Daniel W; Ivanyi, Robert; Lambert, Juanelle L; Lowman, Douglas W; Offerman, Rick J; Szejtli, Jozsef; Szente, Lajos

2002-03-15

We have examined the synthesis of hydroxybutenyl cyclomaltooligosaccharides (cyclodextrins) and the ability of these cyclodextrin ethers to form guest-host complexes with guest molecules. The hydroxybutenyl cyclodextrin ethers were prepared by a base-catalyzed reaction of 3,4-epoxy-1-butene with the parent cyclodextrins in an aqueous medium. Reaction byproducts were removed by nanofiltration before the hydroxybutenyl cyclodextrins were isolated by co-evaporation of water-EtOH. Hydroxybutenyl cyclodextrins containing no unsubstituted parent cyclodextrin typically have a degree of substitution of 2-4 and a molar substitution of 4-7. These hydroxybutenyl cyclodextrins are randomly substituted, amorphous solids. The hydroxybutenyl cyclodextrin ethers were found to be highly water soluble. Complexes of HBen-beta-CD with glibenclamide and ibuprofen were prepared and isolated. In both cases, the guest content of the complexes was large, and a significant increase in the solubility of the free drug was observed. Dissolution of the complexes in pH 1.4 water was very rapid, and significant increases in the solubility of the free drugs were observed. Significantly, after reaching equilibrium concentration, a decrease in the drug concentration over time was not observed.

Supramolecular Inclusion in Cyclodextrins: A Pictorial Spectroscopic Demonstration

ERIC Educational Resources Information Center

Haldar, Basudeb; Mallick, Arabinda; Chattopadhyay, Nitin

2008-01-01

A spectroscopic experiment is presented that reveals that the hydrophobically end-modified water-soluble polymeric fluorophore, pyrene end-capped poly(ethylene oxide) (PYPY), interacts differently with [alpha], [beta], and [gamma]-cyclodextrins (CD) to form supramolecular inclusion complexes. The emission spectrum of PYPY in aqueous solution shows…

Sorption of Ochratoxin A from aqueous solutions using beta-cyclodextrin-polyurethane polymer

USDA-ARS?s Scientific Manuscript database

The ability of a cyclodextrin-polyurethane polymer to remove ochratoxin A from aqueous solutions, including wine, was examined by batch rebinding assays and equilibrium sorption isotherms. The results were fit to two parameter models. Freundlich analysis of the sorption isotherm indicates the polyme...

Bioengineering of a cellulosic fabric for insecticide delivery via grafted cyclodextrin.

PubMed

Romi, Roberto; Lo Nostro, Pierandrea; Bocci, Eugenio; Ridi, Francesca; Baglioni, Piero

2005-01-01

beta-Cyclodextrin (beta-CD) can be easily grafted onto cellulosic textiles through covalent bonds. In such a way beta-CD empty cavities provide an efficient tool for entrapping different kinds of hydrophobic molecules on the surface of the fabric and releasing them slowly in time. The capability of cyclodextrins to include hydrophobic molecules such as fragrances, antimicrobial agents, and other chemicals can be then exploited to produce new grafted textiles with peculiar and useful performances. In this work we report the inclusion of two different products, the pyrethroid insecticide permethrin (PERM) and the insect repellent N,N-diethyl-m-toluamide (DEET), into beta-CD molecules grafted on cotton fabric. UV-vis spectrophotometry and thermal analysis confirmed the presence of the guest molecules on the fabric surface. Bioassays were carried out on two mosquito species of medical importance, Aedes aegypti and Anopheles stephensi; knock down effect and mortality were measured using standard World Health Organization (WHO) cone tests. Repellency and irritancy (blood feeding inhibition) were also measured using cage tests and a baited tunnel device. PERM-treated fabrics kept the insecticidal/irritant efficacy even for a long time after the treatment, whereas DEET activity lasted more shortly.

Spectral characteristics of ortho, meta and para dihydroxy benzenes in different solvents, pH and beta-cyclodextrin.

PubMed

Stalin, T; Devi, R Anitha; Rajendiran, N

2005-09-01

Spectral characteristics of ortho, meta and para dihydroxy benzenes (DHB's) have been studied in different solvents, pH and beta-cyclodextrin. Solvent study shows that: (i) the interaction of OH group with the aromatic ring is less than that of amino group both in the ground and excited states, (ii) in absorption, the charge transfer interaction of OH group in para position is larger than ortho and meta positions. pH studies reveals that DHB's are more acidic than phenol. The higher pK(a) value of oDHB (monoanion-dianion) indicates that the formed monoanion is more stabilized by intramolecular hydrogen bonding. DHB's forms a 1:1 inclusion complex with beta-CD. In beta-CD medium, absorption spectra of DHB's mono and dianions shows unusual blue shifts, whereas in the excited state, the spectral characteristics of DHB's follow the same trend in both aqueous and beta-CD medium.

Quantitative structure-property relationship modeling of beta-cyclodextrin complexation free energies.

PubMed

Katritzky, Alan R; Fara, Dan C; Yang, Hongfang; Karelson, Mati; Suzuki, Takahiro; Solov'ev, Vitaly P; Varnek, Alexandre

2004-01-01

CODESSA-PRO was used to model binding energies for 1:1 complexation systems between 218 organic guest molecules and beta-cyclodextrin, using a seven-parameter equation with R2 = 0.796 and Rcv2 = 0.779. Fragment-based TRAIL calculations gave a better fit with R2 = 0.943 and Rcv2 = 0.848 for 195 data points in the database. The advantages and disadvantages of each approach are discussed, and it is concluded that a combination of the two approaches has much promise from a practical viewpoint.

A Molecular docking study to predict enantioseparation of some chiral carboxylic acid derivatives by methyl-β-cyclodextrin

NASA Astrophysics Data System (ADS)

Nurhidayah, E. S.; Ivansyah, A. L.; Martoprawiro, M. A.; Zulfikar, M. A.

2018-05-01

A molecular docking study, using molecular mechanics calculations with Arguslab, was used to help predict the enantioseparation of some guest molecules of chiral carboxylic acid derivatives by heptakis-2,6-di-O-methyl-β-cyclodextrin (DIMEB) and heptakis-2,3,6-tri-O-methyl-β-cyclodextrin (TRIMEB) as host molecules. The small differences in the binding free energy values (ΔΔG) obtained from Arguslab did not indicate any significant enantioseparation. From the molecular docking simulation results, it is predicted that in the case of DIMEB as host molecule, R-enantiomer of Etodolac, Fenoprofen, Indoprofen, Ketorolac, and Naproxen will be eluted first than S-enantiomer; However, S-enantiomer of Carprofen, Flurbiprofen, Ketoprofen, Pirprofen, Proglumide, Sulindac, Surprofen, and Zaltoprofen will be eluted first than R-enantiomer by DIMEB as host molecule. When TRIMEB is used as a host molecule, R-enantiomer of Carprofen, Flurbiprofen, Indoprofen, Ketoprofen, Naproxen, Pirprofen, and Surprofen will be eluted first than S-enantiomer; However, S-enantiomer of Etodolac, Fenoprofen, Ketorolac, Proglumide, Sulindac and Zaltoprofen will be eluted first than R-enantiomer by TRIMEB as host molecule.

Synthesis of uniform cyclodextrin thioethers to transport hydrophobic drugs

PubMed Central

Becker, Lisa F; Schwarz, Dennis H

2014-01-01

Summary Methyl and ethyl thioether groups were introduced at all primary positions of α-, β-, and γ-cyclodextrin by nucleophilic displacement reactions starting from the corresponding per-(6-deoxy-6-bromo)cyclodextrins. Further modification of all 2-OH positions by etherification with iodo terminated triethylene glycol monomethyl ether (and tetraethylene glycol monomethyl ether, respectively) furnished water-soluble hosts. Especially the β-cyclodextrin derivatives exhibit very high binding potentials towards the anaesthetic drugs sevoflurane and halothane. Since the resulting inclusion compounds are highly soluble in water at temperatures ≤37 °C they are good candidates for new aqueous dosage forms which would avoid inhalation anaesthesia. PMID:25550759

Synthesis of anatase TiO2 nanoparticles with beta-cyclodextrin as a supramolecular shell.

PubMed

Li, Landong; Sun, Xiaohong; Yang, Yali; Guan, Naijia; Zhang, Fuxiang

2006-11-20

We report a novel, green hydrothermal-synthesis route to well-dispersed anatase TiO2 nanoparticles with particle sizes of 9-16 nm in the presence of beta-CD (beta-cyclodextrin). During the synthesis process, the CD-containing synthesis mixture assembled in both longitudinal and latitudinal directions. Driven by the interaction between molecules, the beta-CDs assembled in the longitudinal direction to form long-chain compounds, whereas in the latitudinal direction, they tended to form regular aggregates through coordination with the Ti species from the hydrolysis of tetrabutyl titanate. In view of the effect of the coordination and the steric hindrance of beta-CDs as a supramolecular shell, homogeneous nuclei and slow growth of TiO2 crystals during the synthesis process was observed, which was responsible for the formation of uniform TiO2 nanoparticles. The low beta-CD dosage and the high product yield (>90%) demonstrated well the potential of this synthesis route in the large-scale industrial production of anatase nanoparticles.

Influence of the preparation method on the physicochemical properties of indomethacin and methyl-β-cyclodextrin complexes.

PubMed

Rudrangi, Shashi Ravi Suman; Bhomia, Ruchir; Trivedi, Vivek; Vine, George J; Mitchell, John C; Alexander, Bruce David; Wicks, Stephen Richard

2015-02-20

The main objective of this study was to investigate different manufacturing processes claimed to promote inclusion complexation between indomethacin and cyclodextrins in order to enhance the apparent solubility and dissolution properties of indomethacin. Especially, the effectiveness of supercritical carbon dioxide processing for preparing solid drug-cyclodextrin inclusion complexes was investigated and compared to other preparation methods. The complexes were prepared by physical mixing, co-evaporation, freeze drying from aqueous solution, spray drying and supercritical carbon dioxide processing methods. The prepared complexes were then evaluated by scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction, solubility and dissolution studies. The method of preparation of the inclusion complexes was shown to influence the physicochemical properties of the formed complexes. Indomethacin exists in a highly crystalline solid form. Physical mixing of indomethacin and methyl-β-cyclodextrin appeared not to reduce the degree of crystallinity of the drug. The co-evaporated and freeze dried complexes had a lower degree of crystallinity than the physical mix; however the lowest degree of crystallinity was achieved in complexes prepared by spray drying and supercritical carbon dioxide processing methods. All systems based on methyl-β-cyclodextrin exhibited better dissolution properties than the drug alone. The greatest improvement in drug dissolution properties was obtained from complexes prepared using supercritical carbon dioxide processing, thereafter by spray drying, freeze drying, co-evaporation and finally by physical mixing. Supercritical carbon dioxide processing is well known as an energy efficient alternative to other pharmaceutical processes and may have application for the preparation of solid-state drug-cyclodextrin inclusion complexes. It is an effective and economic method that allows the formation of solid complexes with a high yield, without the use of organic solvents and problems associated with their residues. Copyright © 2015 Elsevier B.V. All rights reserved.

Functionalization of Cyclodextrins with N-Hydroxyphthalimide Moiety: A New Class of Supramolecular Pro-Oxidant Organocatalysts.

PubMed

Melone, Lucio; Petroselli, Manuel; Pastori, Nadia; Punta, Carlo

2015-08-31

N-hydroxyphthalimide (NHPI) is an organocatalyst for free-radical processes able to promote the aerobic oxidation of a wide range of organic substrates. In particular, NHPI can catalyze the hydroperoxidation of polyunsaturated fatty acids (PUFA). This property could be of interest for biological applications. This work reports the synthesis of two β-cyclodextrin derivatives (CD5 and CD6) having a different degree of methylation and bearing a NHPI moiety. These compounds, having different solubility in water, have been successfully tested for the hydroperoxidation of methyl linoleate, chosen as the PUFA model molecule.

[Effect of absorption enhancers on nasal ginsenoside Rg1 delivery and its nasal ciliotoxicity].

PubMed

Chen, Xin-mei; Zhu, Jia-bi; Sun, Wei-dong; Zhang, Li-jian

2006-02-01

The enhancing activity and safety of several absorption enhancers were evaluated as potential nasal absorption enhancers to increase intranasal absorption of ginsenoside Rg1. Nasal circulatory perfusion test in vivo had been employed to investigate the effect of absorption enhancers for nasal mucosa absorption of ginsenoside Rgl in rats. The safety of the absorption enhancers were evaluated by testing cilia movement of the in situ toad palate model, the hemolysis of erythrocyte membrane of the rabbit, leaching of protein and LDH from the mice nasal mucosa and the effect on cilia structural and specific cellular changes of nasal mucosa. Absorption enhancers were necessary to facilitate ginsenoside Rg1 absorption by nasal mucosa. Among the absorption enhancers 1% sodium deoxycholate had great effect to facilite ginsenoside Rgl absorption by nasal mucosa; 1% dipotassium glycyrrhizinate and 1% azone had moderate effect to facilitate ginsenoside Rg1 absorption by nasal mucosa; 1% Tween-80, 2% beta-cyclodextrin, 0.5% borneol (dissolved in paraffin liquid), 0.5% chitosan, 5% hydroxypropyl-beta-cyclodextrin and 0.1% EDTA had low effect to facilitate ginsenoside Rgl absorption by nasal mucosa. 1% sodium deoxycholate, 1% azone and 1% dipotassium glycyrrhizinate had serious nasal toxicity; 1% Tween-80, 2% beta-cyclodextrin, 5% hydroxypropyl-beta-cyclodextrin had moderate nasal toxicity; 0.5% borneol (dissolved in paraffin liquid), 0.5% chitosan and 0.1% EDTA have little nasal toxicity. 0.5% borneol and 0.5% chitosan were the promising candidates having a good balance between enhancing activity and safety for nasal ginsenoside Rg1 delivery.

Novel polymeric monolith materials with a β-cyclodextrin-graphene composite for the highly selective extraction of methyl jasmonate.

PubMed

Yu, Xinhong; Ling, Xu; Zou, Li; Chen, Zilin

2017-04-01

A novel polymeric monolith column with a  β-cyclodextrin-graphene composite was prepared for extraction of methyl jasmonate. A simple, sensitive, and effective polymeric monolith microextraction with high-performance liquid chromatography method has been presented for the determination. To carry out the best microextraction efficiency, several parameters such as sample flow rate, sample volume, and sample pH value were systematically optimized. In addition, the method validation showed a wide linear range of 5-2000 ng/mL, with a good linearity and low limits of detection for methyl jasmonate. The proposed method was successfully applied for the determination of methyl jasmonate in wintersweet flowers with recoveries of 90.67%. The result was confirmed by high-performance liquid chromatography with mass spectrometry. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Drug-beta-cyclodextrin containing pellets prepared with a high-shear mixer.

PubMed

Gainotti, Alessandro; Bettini, Ruggero; Gazzaniga, Andrea; Colombo, Paolo; Giordano, Ferdinando

2004-01-01

This work was aimed at investigating the preparation of beta-cyclodextrin-microcrystalline cellulose pellets by means of a high-shear mixer, both in the absence or in the presence of ibuprofen as model drug. Drug loading of pellets was accomplished by means of two alternative techniques: 1) solution layering or 2) powder layering. The prepared pellets were characterised in terms of size distribution, shape factor, friability and dissolution rate. The interaction between ibuprofen and beta-cyclodextrin was monitored by Differential Scanning Calorimetry (DSC). Micro Fourier Transform Infrared spectroscopy (MicroFTIR) was applied to determine the distribution of components within each pellet on a micro scale. Pellets with narrow size distribution and containing up to about 90% of BCD were prepared using water as binder. The process yield resulted around 84 and 63% for drug-free and medicate pellets respectively. Drug loaded pellets with favourable technological and biopharmaceutical characteristics can be obtained both by powder or solution layering techniques. The latter proved to be more suitable for producing pellets with high drug contents, reduced friability and high drug dissolution rates.

ORAC-fluorescein assay to determine the oxygen radical absorbance capacity of resveratrol complexed in cyclodextrins.

PubMed

Lucas-Abellán, C; Mercader-Ros, M T; Zafrilla, M P; Fortea, M I; Gabaldón, J A; Núñez-Delicado, E

2008-03-26

The effect of the complexation of resveratrol with hydroxypropyl-beta-cyclodextrins (HP-beta-CDs) on the antioxidant capacity of the polyphenol is studied for the first time by means of the oxygen radical absorbance capacity (ORAC) method, using fluorescein (FL) as the fluorescent probe. The method is validated through its linearity, precision, and accuracy for measuring the ORAC of resveratrol in the absence or presence of cyclodextrins (CDs). The complexation of resveratrol in CDs increased the net area under the FL decay curve (net AUC) of resveratrol up to its saturation level, at which the polyphenol showed almost double the antioxidant activity it shows in the absence of CDs. The complexation constant ( K c) between resveratrol and HP-beta-CDs was calculated by linear regression of the phase solubility diagram ( K c = 18048 M (-1)). The antioxidant activity of resveratrol was dependent on the complexed resveratrol because CDs acts as a controlled dosage reservoir that protects resveratrol against rapid oxidation by free radicals. In this way, its antioxidant activity is prolonged and only reaches its maximum when all the resveratrol is complexed.

Illustration of a simple and versatile scheme for reversing enantiomeric elution order and facilitating enantiomeric impurity determination in capillary electrophoresis.

PubMed

Magnusson, Jeanette; Wan, Hong; Blomberg, Lars G

2002-09-01

Determination of enantiomeric purity is most often done under overload conditions, which leads to deformed peaks. In general, the best resolutions are obtained when the small peak appears before the large peak in the electropherogram. To be able to determine the R(+)-impurity in the S(-)-form as well as the S(-)-impurity in the R(+)-form the elution orders have to be reversed. The present paper describes reversal of enantiomeric elution order for the basic analyte propranolol and the acidic analyte ibuprofen. For propranolol, a charged heptakis-(6-sulfo)-beta-cyclodextrin (CD) is used in the background electrolyte. For ibuprofen, a mix of the charged heptakis-(6-sulfo)-beta-CD and the uncharged heptakis-(2,3,6-tri-O-methyl)-beta-CD is used in the background electrolyte. The use of a coated capillary and reversal of the polarity shift the elution order, buffer composition is unchanged in both cases. The enantiomers of propranolol and ibuprofen are well separated on both the coated and uncoated capillaries. Detection limits of enantiomer impurities are investigated using spiked samples of both propranolol and ibuprofen.

A supramolecular complex between proteinases and beta-cyclodextrin that preserves enzymatic activity: physicochemical characterization.

PubMed

Denadai, Angelo M L; Santoro, Marcelo M; Lopes, Miriam T P; Chenna, Angélica; de Sousa, Frederico B; Avelar, Gabriela M; Gomes, Marco R Túlio; Guzman, Fanny; Salas, Carlos E; Sinisterra, Rubén D

2006-01-01

Cyclodextrins are suitable drug delivery systems because of their ability to subtly modify the physical, chemical, and biological properties of guest molecules through labile interactions by formation of inclusion and/or association complexes. Plant cysteine proteinases from Caricaceae and Bromeliaceae are the subject of therapeutic interest, because of their anti-inflammatory, antitumoral, immunogenic, and wound-healing properties. In this study, we analyzed the association between beta-cyclodextrin (betaCD) and fraction P1G10 containing the bioactive proteinases from Carica candamarcensis, and described the physicochemical nature of the solid-state self-assembled complexes by Fourier transform infrared (FTIR) spectroscopy, thermogravimetry (TG), differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), and nuclear magnetic resonance (NMR), as well as in solution by circular dichroism (CD), isothermal titration calorimetry (ITC), and amidase activity. The physicochemical analyses suggest the formation of a complex between P1G10 and betaCD. Higher secondary interactions, namely hydrophobic interactions, hydrogen bonding and van der Waals forces were observed at higher P1G10 : betaCD mass ratios. These results provide evidence of the occurrence of strong solid-state supramolecular non-covalent interactions between P1G10 and betaCD. Microcalorimetric analysis demonstrates that complexation results in a favorable enthalpic contribution, as has already been described during formation of similar betaCD inclusion compounds. The amidase activity of the complex shows that the enzyme activity is not readily available at 24 hours after dissolution of the complex in aqueous buffer; the proteinase becomes biologically active by the second day and remains stable until day 16, when a gradual decrease occurs, with basal activity attained by day 29. The reported results underscore the potential for betaCDs as candidates for complexing cysteine proteinases, resulting in supramolecular arrays with sustained proteolytic activity.

Water-soluble cyclodextrin polymers for enhanced relative recovery of hydrophobic analytes during microdialysis sampling.

PubMed

Ao, Xiaoping; Stenken, Julie A

2003-09-01

Microdialysis relative recovery (RR) enhancement using different water-soluble, epichlorohydrin-based cyclodextrin polymers (CD-EPS) was studied in vitro for different analytes, amitryptiline, carbamazepine, hydroquinone, ibuprofen, and 4-nitrophenol. When compared to the native CDs (alpha, beta, and gamma) on a per mole basis, the CD-EPS enhanced microdialysis RR was either statistically greater or the same. beta-CD-EPS was more highly retained than native beta-CD by a 20 000 Da molecular weight cutoff (MWCO) polycarbonate membrane, but showed no statistical difference for loss across a 100 000 Da MWCO polyethersulfone membrane (PES). When the same weight percent of beta-CD or beta-CD-EPS was included in the microdialysis perfusion fluid, the beta-CD-EPS produced a higher microdialysis RR than native beta-CD for all analytes across the PES membrane. However, enhancements for the PC membrane were statistically insignificant when beta-CD and beta-CD-EPS were compared on a per mole basis. These results suggest that CD-EPS may be used as effective enhancement agents during microdialysis sampling and for some membranes provide the additional advantage of being retained more than native CDs.

Comparison of sublingual tablets with nitroglycerin complexed with beta-cyclodextrin or titrated with crosspovidone--technological approach.

PubMed

Centkowska, Katarzyna; Sznitowska, Małgorzata

2008-01-01

Fast disintegrating sublingual tablets containing nitroglycerin either complexed with beta-cyclodextrin (NTG-CD) or titrated with crosspovidone (NTG-CP) were prepared using Starch 1500 or StarLac as disintegrants. Regarding disintegration time and stability of the active substance Starch 1500 was more appropriate for NTG-CD while for NTG-CP StarLac was suitable. Stability of NTG was better in NTG-CD tablets than in NTG-CP tablets, however, within 12 months of storage at 25 degrees C the loss of NTG in all formulations was still greater than 10%.

Solubilization of ibuprofen with β-cyclodextrin derivatives: energetic and structural studies.

PubMed

di Cagno, Massimiliano; Stein, Paul C; Skalko-Basnet, Nataša; Brandl, Martin; Bauer-Brandl, Annette

2011-06-01

The aim of this work was to investigate the complexation of ibuprofen as model drug with various β-cyclodextrins (native β-cyclodextrin, hydroxypropyl-β-cyclodextrin with two different molar degrees of substitution, and methyl-β-cyclodextrin). Solutions of the commercially available β-cyclodextrins were prepared in phosphate buffer (73mM). The pH value was adjusted to 7.4 and the solutions were isotonized with NaCl. A solution of ibuprofen was prepared in the same way. A thermal activity monitor was used for isothermal titration calorimetry (ITC). (1)H NMR analysis was employed to investigate the structures of the complexes. ITC analysis showed that each type of β-cyclodextrin had its characteristic values of both enthalpy and mass equilibrium constant for the complexation processes with the drug molecules. (1)H NMR spectroscopy of the complexes showed through significant differences in chemical shifts that the physical interaction between the cyclodextrins and ibuprofen molecules were also different, probably due to different three-dimensional arrangements of ibuprofen in the cyclodextrin cavity, induced by the different substituents bonded to the glucose rings. These differences were connected to the thermodynamic parameters of the complexes. Copyright © 2011 Elsevier B.V. All rights reserved.

Enhanced transport of low-polarity organic compounds through soil by cyclodextrin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brusseau, M.L.; Wang, X.; Hu, Q.

1994-05-01

The removal of low-polarity organic compounds from soils and aquifers by water flushing is often constrained by sorption interactions. There is great interest in developing systems that can enhance the transport of organic compounds through porous media, thus facilitating remediation. We investigated the potential of hydroxypropyl-[beta]-cyclodextrin (HPCD), a microbially produced compound, to reduce the sorption and to enhance the transport of several low-polarity organic compounds. The results show that cyclodextrin does not interact with the two porous media used in the study. As a result, there is no retardation of cyclodextrin during transport. The retardation of compounds such as anthracene,more » pyrene, and trichlorobiphenyl was significantly (orders of magnitude) reduced in the presence of cyclodextrin. The enhancement effect of the cyclodextrin was predictable with a simple equation based on three-phase partitioning. The nonreactive nature of cyclodextrin combined with its large affinity for low-polarity organic compounds makes cyclodextrin a possible candidate for use in in-situ remediation efforts. 22 refs., 6 figs., 3 tabs.« less

Spectrofluorimetric study of host-guest complexation of ibuprofen with beta-cyclodextrin and its analytical application.

PubMed

Manzoori, Jamshid L; Amjadi, Mohammad

2003-03-15

The characteristics of host-guest complexation between beta-cyclodextrin (beta-CD) and two forms of ibuprofen (protonated and deprotonated) were investigated by fluorescence spectrometry. 1:1 stoichiometries for both complexes were established and their association constants at different temperatures were calculated by applying a non-linear regression method to the change in the fluorescence of ibuprofen that brought about by the presence of beta-CD. The thermodynamic parameters (deltaH, deltaS and deltaG) associated with the inclusion process were also determined. Based on the obtained results, a sensitive spectrofluorimetric method for the determination of ibuprofen was developed with a linear range of 0.1-2 microg ml(-1) and a detection limit of 0.03 microg ml(-1). The method was applied satisfactorily to the determination of ibuprofen in pharmaceutical preparations. Copyright 2002 Elsevier Science B.V.

Convenient QSAR model for predicting the complexation of structurally diverse compounds with beta-cyclodextrins.

PubMed

Pérez-Garrido, Alfonso; Morales Helguera, Aliuska; Abellán Guillén, Adela; Cordeiro, M Natália D S; Garrido Escudero, Amalio

2009-01-15

This paper reports a QSAR study for predicting the complexation of a large and heterogeneous variety of substances (233 organic compounds) with beta-cyclodextrins (beta-CDs). Several different theoretical molecular descriptors, calculated solely from the molecular structure of the compounds under investigation, and an efficient variable selection procedure, like the Genetic Algorithm, led to models with satisfactory global accuracy and predictivity. But the best-final QSAR model is based on Topological descriptors meanwhile offering a reasonable interpretation. This QSAR model was able to explain ca. 84% of the variance in the experimental activity, and displayed very good internal cross-validation statistics and predictivity on external data. It shows that the driving forces for CD complexation are mainly hydrophobic and steric (van der Waals) interactions. Thus, the results of our study provide a valuable tool for future screening and priority testing of beta-CDs guest molecules.

Efficient photosensitized splitting of the thymine dimer/oxetane unit on its modifying beta-cyclodextrin by a binding electron donor.

PubMed

Tang, Wen-Jian; Song, Qin-Hua; Wang, Hong-Bo; Yu, Jing-Yu; Guo, Qing-Xiang

2006-07-07

Two modified beta-cyclodextrins (beta-CDs) with a thymine dimer and a thymine oxetane adduct respectively, TD-CD and Ox-CD, have been prepared, and utilized to bind an electron-rich chromophore, indole or N,N-dimethylaniline (DMA), to form a supramolecular complex. We have examined the photosensitized splitting of the dimer/oxetane unit in TD-CD/Ox-CD by indole or DMA via an electron-transfer pathway, and observed high splitting efficiencies of the dimer/oxetane unit. On the basis of measurements of fluorescence spectra and splitting quantum yields, it is suggested that the splitting reaction occurs in a supramolecular complex by an inclusion interaction between the modified beta-CDs and DMA or indole. The back electron transfer, which leads low splitting efficiencies for the covalently-linked chromophore-dimer/oxetane compounds, is suppressed in the non-covalently-bound complex, and the mechanism has been discussed.

Hydroxypropyl-beta-cyclodextrin enhanced determination for the Vitamin B12 by fluorescence quenching method.

PubMed

Sun, Jing; Zhu, Xiashi; Wu, Ming

2007-05-01

A novel fluorescence quenching method for the determination of Vitamin B12(VB12) had been developed. It was based on that the fluorescence intensity of erythrosine sodium(ES) could be enhanced by Hydroxypropyl-beta-cyclodextrin(HP-beta-CD) due to the formation of inclusion complex (HP-beta-CD-ES), while the fluorescence intensity of HP-beta-CD-ES was diminished after adding VB12 into the system, and there was a linear relationship between the fluorescence quenching value of the system (DeltaF) and the concentration of VB12 (c). The mechanism of the determination of VB12 was discussed. The results showed that under the optimal conditions, the linear range of calibration curve for the determination of VB12 was 0.0 approximately 2.1 x 10(-5) mol/L, and the detection limit was 1.8 x 10(-7) mol/ L. It could be satisfactorily applied to the determination of VB12 in injections.

Effect of the chiral discrimination on the vibrational properties of (R)-, (S)- and (R, S)-ibuprofen/methyl-β-cyclodextrin inclusion complexes

NASA Astrophysics Data System (ADS)

Crupi, V.; Guella, G.; Majolino, D.; Mancini, I.; Paciaroni, A.; Rossi, B.; Venuti, V.; Verrocchio, P.; Viliani, G.

2011-05-01

The effects of chiral discrimination of ibuprofen (IBP) on the complexation process with methyl-β-cyclodextrin (Me-β-CD) were investigated in the solid phase by FTIR-ATR spectroscopy and numerical simulation. The inclusion mechanism was deduced from the temperature-dependent analysis of the vibrational spectra, in the C=O stretching region, of complexes formed by Me-β-CD with the two enantiomeric and the racemic forms of IBP. The mechanism turned out to be enthalpy-driven, with IBP enantiomers giving rise to more stable inclusion complexes with respect to the racemate.

New ethanol and propylene glycol free gel formulations containing a minoxidil-methyl-β-cyclodextrin complex as promising tools for alopecia treatment.

PubMed

Lopedota, Angela; Cutrignelli, Annalisa; Denora, Nunzio; Laquintana, Valentino; Lopalco, Antonio; Selva, Stefano; Ragni, Lorella; Tongiani, Serena; Franco, Massimo

2015-05-01

New topical totally aqueous formulations that improve the low water solubility of minoxidil and realize an adequate permeability of drug in the skin are proposed. These formulations are lacking in propylene glycol and alcohol that are the principal irritant ingredients present in minoxidil commercial solutions. In order to enhance poor water solubility of minoxidil randomly methyl-β-cyclodextrin was used, and four hydrogels such as, calcium alginate, sodium alginate, carbopol 934 and hydroxyethylcellulose were utilized to ensure a prolonged time of contact with the scalp. The inclusion complex minoxidil/methyl-β-cyclodextrin with a molar ratio 1:1 was obtained by freeze drying and evaluated by NMR, FT-IR and DSC analysis. An apparent stability constant of formed inclusion complex was calculated by phase solubility diagram and its value was 400 M(-1). The solid inclusion complex was used to prepare gel formulations with similar dose to minoxidil commercial solution. The gels were evaluated for various technological parameters including rheological behavior, in vitro drug release and ex vivo permeation through pig skin. The best performance was observed for the calcium alginate formulation.

Simultaneous determination of ingredients in a cold medicine by cyclodextrin-modified microemulsion electrokinetic chromatography.

PubMed

Okamoto, Hitoshi; Nakajima, Toshiaki; Ito, Yuji; Aketo, Takao; Shimada, Kenji; Yamato, Susumu

2005-03-09

Cyclodextrin-modified microemulsion electrokinetic chromatography (CD-MEEKC) was used to simultaneously determine 14 active ingredients (thiamine nitrate, anhydrous caffeine, acetaminophen, riboflavin, guaifenesin, pseudoephedrine hydrochloride, ascorbic acid, ethenzamide, DL-methylephedrine hydrochloride, dihydrocodeine phosphate, ibuprofen, noscapine, carbinoxamine maleate, and bromhexine hydrochloride) in a cold medicine. Separation of the ingredients was optimized by changing the SDS concentration and oil type and the addition of 2-propanol and cyclodextrin (CD) to the separation solution. The separation selectivity was improved dramatically by changing CD type. All of the active ingredients and formulation excipients were successfully separated with the use of a separation solution consisting of 0.81% (w/w) pentane, 6.61% (w/w) 1-butanol, 2% (w/w) 2-propanol, 4.47% (w/w) SDS, and 86.11% (w/w) 10 mM sodium tetraborate solution with 3 mM 2,6-di-O-methyl-beta-CD. The established method was then validated and demonstrated to be applicable to the determination of the active ingredients in a model cold medicine. No interference from the formulation excipients was observed. Good linearities were obtained with correlation coefficients above 0.999. Recovery and precision ranged from 99.1 to 100.7% and from 0.5 to 2.8% R.S.D., respectively. The detection limit for ingredients ranged from 0.6 to 4.2 microg ml(-1). Good agreement was obtained between the established method and the traditional HPLC method. These results suggest that CD-MEEKC can be used for the determination of multiple ingredients in cold medicine.

Temperature sensitive poly[N-isopropylacrylamide-co-(acryloyl beta-cyclodextrin)] for improved drug release.

PubMed

Zhang, Jian-Tao; Huang, Shi-Wen; Liu, Ji; Zhuo, Ren-Xi

2005-03-15

The model drugs ibuprofen (IBU) and tegafur (T-Fu) were loaded into poly[N-isopropylacrylamide-co-(acryloyl beta-cyclodextrin)] [P(NIPA-co-A-CD)] and PNIPA hydrogels by immersing dried gels in IBU or T-Fu alcohol solutions until they reached equilibrium. Drug release studies were carried out in water at 25 degrees C. In contrast to the release time of conventional PNIPA hydrogel, that of IBU from the beta-CD incorporated hydrogel was significantly prolonged and the drug loading was also greatly increased, which may be the result of the formation of inclusion complexes between CD and ibuprofen. However, another hydrophilic drug, tegafur, did not display these properties because it could not form a complex with the CD groups. [diagram in text].

Complex formation of beta-cyclodextrin in aqueous media with poly(N,N-dimethylacrylamide)containing pendent perfluorooctanesulfonamido groups. Final Report, September 15, 1998 - September 14, 1999

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dr. Thieo Hogen-Esch

1999-11-01

The effect of time on the viscosity of solutions of 0.50--1.0 weight % polyacrylamide copolymers containing 2-(N-ethylperfluorooctanesulfonamido)ethyl acrylate (FOSA) comonomer units was monitored at constant shear rates varying from 0.60 to 3.0 sec{sup {minus}1}. The viscosities decreased to a plateau over a period of about thirty minutes. The copolymer solutions sheared at much higher shear rates of 24 sec{sup {minus}1} showed pronounced shear thinning but regained most of their original viscosities after standing for 20 minutes. Heating the solutions less than one hour caused an increase in the low shear viscosity whereas longer heating times decreased solution viscosities presumably duemore » to hydrolysis of the acrylate groups. Addition of beta-cyclodextrin to solutions of the hydrophobically modified polyacrylamide resulted in sharply decreased copolymer viscosities at cyclodextrin concentrations on the order of about 10{sup {minus}3} M. The above is consistent with competitive hydrophobic association of the perfluorocarbon groups of the copolymer with the cyclodextrin disrupting the mutual association of the perfluorocarbon groups.« less

Piroxicam/2-hydroxypropyl-beta-cyclodextrin inclusion complex prepared by a new fluid-bed coating technique.

PubMed

Zhang, Xingwang; Wu, Danni; Lai, Jie; Lu, Yi; Yin, Zongning; Wu, Wei

2009-02-01

This work was aimed at investigating the feasibility of fluid-bed coating as a new method to prepare cyclodextrin inclusion complex. The inclusion complex of the model drug piroxicam (PIX) and 2-hydroxypropyl-beta-cyclodextrin (HPCD) in aqueous ethanol solution was sprayed and deposited onto the surface of the pellet substrate upon removal of the solvent. The coating process was fluent with high coating efficiency. Scanning electron microscopy revealed a coarse pellet surface, and a loosely packed coating structure. Significantly enhanced dissolution, over 90% at 5 min, was observed at stoichiometric PIX/HPCD molar ratio (1/1) and at a ratio with excessive HPCD (1/2). Differential scanning calorimetry and powder X-ray diffractometry confirmed absence of crystallinity of PIX at PIX/HPCD molar ratio of 1/1 and 1/2. Fourier transform-infrared spectrometry and Raman spectrometry revealed interaction between PIX and HPCD adding evidence on inclusion of PIX moieties into HPCD cavities. Solid-state (13)C NMR spectrometry indicated possible inclusion of PIX through the pyridine ring. It is concluded that fluid-bed coating has potential to be used as a new technique to prepare cyclodextrin inclusion complex.

The influence of the preparation methods on the inclusion of model drugs in a beta-cyclodextrin cavity.

PubMed

Salústio, P J; Feio, G; Figueirinhas, J L; Pinto, J F; Cabral Marques, H M

2009-02-01

The work aims to prove the complexation of two model drugs (ibuprofen, IB and indomethacin, IN) by beta-cyclodextrin (betaCD), and the effect of water in such a process, and makes a comparison of their complexation yields. Two methods were considered: kneading of a binary mixture of the drug, betaCD, and inclusion of either IB or IN in aqueous solutions of betaCD. In the latter method water was removed by air stream, spray-drying and freeze-drying. To prove the formation of complexes in final products, optical microscopy, UV spectroscopy, IR spectroscopy, DSC, X-ray and NMR were considered. Each powder was added to an acidic solution (pH=2) to quantify the concentration of the drug inside betaCD cavity. Other media (pH=5 and 7) were used to prove the existence of drug not complexed in each powder, as the drugs solubility increases with the pH. It was observed that complexation occurred in all powders, and that the fraction of drug inside the betaCD did not depend neither on the method of complexation nor on the processes of drying considered.

Self-healing pH-sensitive poly[(methyl vinyl ether)-alt-(maleic acid)]-based supramolecular hydrogels formed by inclusion complexation between cyclodextrin and adamantane.

PubMed

Ma, Xiaoe; Zhou, Naizhen; Zhang, Tianzhu; Hu, Wanjun; Gu, Ning

2017-04-01

Self-healing materials are of interest for drug delivery, cell and gene therapy, tissue engineering, and other biomedical applications. In this work, on the base of biocompatible polymer poly(methyl vinyl ether-alt-maleic acid) (P(MVE-alt-MA)), host polymer β-cyclodextrin-grafted P(MVE-alt-MA) (P(MVE-alt-MA)-g-β-CD) and guest polymer adamantane-grafted P(MVE-alt-MA) (P(MVE-alt-MA)-g-Ad) were first prepared. Then through taking advantage of the traditional host-guest interaction of β-cyclodextrin and adamantane, a novel self-healing pH-sensitive physical P(MVE-alt-MA)-g-β-CD/P(MVE-alt-MA)-g-Ad supramolecular hydrogels were obtained after simply mixing the aqueous solution of host polymer and guest polymer. This kind of supramolecular hydrogels not only possess pH-sensitivity, but also possess the ability to repair themselves after being damaged. Copyright © 2016 Elsevier B.V. All rights reserved.

Functional analysis of alpha5beta1 integrin and lipid rafts in invasion of epithelial cells by Porphyromonas gingivalis using fluorescent beads coated with bacterial membrane vesicles.

PubMed

Tsuda, Kayoko; Furuta, Nobumichi; Inaba, Hiroaki; Kawai, Shinji; Hanada, Kentaro; Yoshimori, Tamotsu; Amano, Atsuo

2008-01-01

Porphyromonas gingivalis, a periodontal pathogen, was previously suggested to exploit alpha5beta1 integrin and lipid rafts to invade host cells. However, it is unknown if the functional roles of these host components are distinct from one another during bacterial invasion. In the present study, we analyzed the mechanisms underlying P. gingivalis invasion, using fluorescent beads coated with bacterial membrane vesicles (MV beads). Cholesterol depletion reagents including methyl-beta-cyclodextrin (MbetaCD) drastically inhibited the entry of MV beads into epithelial cells, while they were less effective on bead adhesion to the cells. Bead entry was also abolished in CHO cells deficient in sphingolipids, components of lipid rafts, whereas adhesion was negligibly influenced. Following MbetaCD treatment, downstream events leading to actin polymerization were abolished; however, alpha5beta1 integrin was recruited to beads attached to the cell surface. Dominant-negative Rho GTPase Rac1 abolished cellular engulfment of the beads, whereas dominant-negative Cdc42 did not. Following cellular interaction with the beads, Rac1 was found to be translocated to the lipid rafts fraction, which was inhibited by MbetaCD. These results suggest that alpha5beta1 integrin, independent of lipid rafts, promotes P. gingivalis adhesion to epithelial cells, while the subsequent uptake process requires lipid raft components for actin organization, with Rho GTPase Rac1.

Chiral discrimination of sibutramine enantiomers by capillary electrophoresis and proton nuclear magnetic resonance spectroscopy.

PubMed

Lee, Yong-Jae; Choi, Seungho; Lee, Jinhoo; Nguyen, NgocVan Thi; Lee, Kyungran; Kang, Jong Seong; Mar, Woongchon; Kim, Kyeong Ho

2012-03-01

Capillary electrophoresis (CE) and proton nuclear magnetic resonance spectroscopy ((1)H-NMR) have been used to discriminate the enantiomers of sibutramine using cyclodextrin derivatives. Possible correlation between CE and (1)H-NMR was examined. Good correlation between the (1)H-NMR shift non-equivalence data for sibutramine and the degree of enantioseparation in CE was observed. In CE study, a method of enantiomeric separation and quantitation of sibutramine was developed using enantiomeric standards. The method was based on the use of 50 mM of phosphate buffer of pH 3.0 with 10 mM of methyl-beta-cyclodextrin (M-β-CD). 0.05% of LOD, 0.2% of LOQ for S-sibutramine enantiomer was achieved, and the method was validated and applied to the quantitative determination of sibutramine enantiomers in commercial drugs. On a 600 MHz (1)H-NMR analysis, enantiomer signal separation of sibutramine was obtained by fast diastereomeric interaction with a chiral selector M-β-CD. For chiral separation and quantification, N-methyl proton peaks (at 2.18 ppm) were selected because of its being singlet and simple for understanding of diastereomeric interaction. Effects of temperature and concentration of chiral selector on enantiomer signal separation were investigated. The optimum condition was 0.5 mg/mL of sibutramine and 10 mg/mL of M-β-CD at 10°C. Distinguishment of 0.5% of S-sibutramine in R-sibutramine was found to be possible by (1)H-NMR with M-β-CD as chiral selector. Host-guest interaction between sibutramine and M-β-CD was confirmed by (1)H-NMR studies and CE studies. A Structure of the inclusion complex was proposed considering (1)H-NMR and 2D ROESY studies.

Enantiodifferentiation of whisky and cognac lactones using gas chromatography with different cyclodextrin chiral stationary phases.

PubMed

Schmarr, Hans-Georg; Mathes, Maximilian; Wall, Kristina; Metzner, Frank; Fraefel, Marius

2017-09-22

The chiral lactone 5-butyl-4-methyloxolan-2-one or 5-butyl-4-methyldihydro-2(3H)-furanone, often named whisky lactone, is found in oak wood, then contributing to the appreciated flavor of beverages stored in such wooden barrels. Its next higher homologue is named cognac lactone (5-pentyl-4-methyloxolan-2-one or 5-pentyl-4-methyldihydro-2(3H)-furanone), however is much less known, probably due to its minor concentration level. In order to study the direct enantioseparation of both lactones by gas chromatography on chiral stationary phases, individual enantiomers, particularly for cognac lactone were made available. This was achieved by baker's yeast reduction of synthesized ethyl 3-methyl-4-oxononanoate or, after hydrolysis, of the corresponding 4-ketoacid, that gave access to individual enantiomers of cognac lactone. Good enantioseparation was achieved for both whisky and cognac lactone with high values for the chiral resolution with 6-O-tert. butyl dimethylsilyl-2,3-dialkylated or 6-O-tert. butyl dimethylsilyl-2,3-diacylated cyclodextrin derivatives as chiral selectors. The influence of the nature and position of derivatization of the cyclodextrin moiety revealed a strong impact on the chiral recognition mechanism, as the investigated alkylated derivatives heptakis-(2,6-di-O-iso-pentyl-3-O-allyl)-β-cyclodextrin and octakis-(2,3-di-O-pentyl-6-O-methyl)-γ-cyclodextrin did not provide any or only minor chiral selectivity for the two lactones. Copyright © 2017 Elsevier B.V. All rights reserved.

Characterization of complexes between phenethylamine enantiomers and β-cyclodextrin derivatives by capillary electrophoresis-Determination of binding constants and complex mobilities.

PubMed

Wahl, Joachim; Furuishi, Takayuki; Yonemochi, Etsuo; Meinel, Lorenz; Holzgrabe, Ulrike

2017-04-01

To optimize chiral separation conditions and to improve the knowledge of enantioseparation, it is important to know the binding constants K between analytes and cyclodextrins and the electrophoretic mobilities of the temporarily formed analyte-cyclodextrin-complexes. K values for complexes between eight phenethylamine enantiomers, namely ephedrine, pseudoephedrine, methylephedrine and norephedrine, and four different β-cyclodextrin derivatives were determined by affinity capillary electrophoresis. The binding constants were calculated from the electrophoretic mobility values of the phenethylamine enantiomers at increasing concentrations of cyclodextrins in running buffer. Three different linear plotting methods (x-reciprocal, y-reciprocal, double reciprocal) and nonlinear regression were used for the determination of binding constants with β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin, methyl-β-cyclodextrin and 6-O-α-maltosyl-β-cyclodextrin. The cyclodextrin concentration in a 50 mM phosphate buffer pH 3.0 was varied from 0 to 12 mM. To investigate the influence of the binding constant values on the enantioseparation the observed electrophoretic selectivities were compared with the obtained K values and the calculated enantiomer-cyclodextrin-complex mobilities. The different electrophoretic mobilities of the temporarily formed complexes were crucial factors for the migration order and enantioseparation of ephedrine derivatives. To verify the apparent binding constants determined by capillary electrophoresis, a titration process using ephedrine enantiomers and β-cyclodextrin was carried out. Furthermore, the isothermal titration calorimetry measurements gave information about the thermal properties of the complexes. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cyclodextrin-enhanced degradation of toluene and p-toluic acid by Pseudomonas putida.

PubMed Central

Schwartz, A; Bar, R

1995-01-01

Degradation of an immiscible aromatic solvent, toluene, and a water-soluble aromatic compound, p-toluic acid, by a Pseudomonas putida strain in the presence of beta-cyclodextrin (beta-CD) was investigated. The ability of CDs to interact with hydrophobic organics and form inclusion compounds was exploited in this study to remove or alleviate the toxicities of substrates and consequently to enable or enhance degradation. Liquid toluene was found to be highly toxic to P. putida. However, this phase toxicity was removed when crystalline beta-CD-complexed toluene was provided as the substrate. The latter was fully degraded at a concentration of up to 10 g/liter. Degradation of toluene vapors was enhanced in the presence of beta-CD as a result of reduced molecular toxicity and facilitated absorption of the gaseous substrate. Similarly, beta-CD alleviated the inhibitory effect of p-toluic acid on P. putida. This protective effect of CD was remarkably more prominent when the microbial culture was shock loaded with an otherwise toxic dose of p-toluic acid (1.8 g/liter). PMID:7618884

Sol-gel technique for the preparation of beta-cyclodextrin derivative stationary phase in open-tubular capillary electrochromatography.

PubMed

Wang, Y; Zeng, Z; Guan, N; Cheng, J

2001-07-01

A novel open-tubular capillary electrochromatography (OT-CEC) column coated with 2,6-dibutyl-beta-cyclodextrin (DB-beta-CD) was prepared using sol-gel technique. In the sol-gel approach, owing to the three-dimensional network of sol-gel and the strong chemical bond between the stationary phase and the surface of capillary columns, good chromatographic characteristics and unique selectivity in separating isomers were shown. We achieved high efficiencies of 5-14 x 10(4) plates/m for the isomeric nitrophenols using the sol-gel-derived DB-beta-CD columns. The migration time reproducibility of the separation of the isomeric nitrophenols was better than 2.2% over five runs and 4.5% from column to column. These sol-gel-coated DB-beta-CD columns have shown improved separations of isomeric aminophenols, isomeric dihydroxybenzenes and isomeric nitrophenols, in comparison with the sol-gel matrix capillary column. The influences of buffer pH and methanol solvent on separation were investigated. The chiral resolution of enantiomers such as ibuprofen and binaphthol was explored primarily.

Using molecular recognition of beta-cyclodextrin to determine molecular weights of low-molecular-weight explosives by MALDI-TOF mass spectrometry.

PubMed

Zhang, Min; Shi, Zhen; Bai, Yinjuan; Gao, Yong; Hu, Rongzu; Zhao, Fenqi

2006-02-01

This study presents a novel method for determining the molecular weights of low molecular weight (MW) energetic compounds through their complexes of beta-cyclodextrin (beta-CD) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) in a mass range of 500 to 1700 Da, avoiding matrix interference. The MWs of one composite explosive composed of 2,6-DNT, TNT, and RDX, one propellant with unknown components, and 14 single-compound explosives (RDX, HMX, 3,4-DNT, 2,6-DNT, 2,5-DNT, 2,4,6-TNT, TNAZ, DNI, BTTN, NG, TO, NTO, NP, and 662) were measured. The molecular recognition and inclusion behavior of beta-CD to energetic materials (EMs) were investigated. The results show that (1) the established method is sensitive, simple, accurate, and suitable for determining the MWs of low-MW single-compound explosives and energetic components in composite explosives and propellants; and (2) beta-CD has good inclusion and modular recognition abilities to the above EMs.

Evaluation of antitumor effects of folate-conjugated methyl-β-cyclodextrin in melanoma.

PubMed

Motoyama, Keiichi; Onodera, Risako; Tanaka, Nao; Kameyama, Kazuhisa; Higashi, Taishi; Kariya, Ryusho; Okada, Seiji; Arima, Hidetoshi

2015-01-01

Melanoma is a life-threatening disorder and its incidence is increasing gradually. Despite the numerous treatment approaches, conventional systemic chemotherapy has not reduced the mortality rate among melanoma patients, probably due to the induction of toxicity to normal tissues. Recently, we have developed folate-conjugated methyl-β-cyclodextrin (FA-M-β-CyD) and clarified its potential as a new antitumor agent involved in autophagic cell death. However, it remains uncertain whether FA-M-β-CyD exerts anticancer effects against melanomas. Therefore, in this study, we investigated the effects of FA-M-β-CyD on the folate receptor-α (FR-α)-expressing melanoma cell-selective cytotoxic effect. FA-M-β-CyD showed cytotoxic effects in Ihara cells, a human melanoma cell line expressing FR-α. In sharp contrast to methyl-β-cyclodextrin, FA-M-β-CyD entered Ihara cells [FR-α(+)] through FR-α-mediated endocytosis. Additionally, FA-M-β-CyD elicited the formation of autophagosomes in Ihara cells. Notably, FA-M-β-CyD suppressed melanoma growth in BALB/c nude recombinase-activating gene-2 (Rag-2)/Janus kinase 3 (Jak3) double deficient mice bearing Ihara cells. Therefore, these results suggest that FA-M-β-CyD could be utilized as a potent anticancer agent for melanoma chemotherapy by regulating autophagy.

Self-association and cyclodextrin solubilization of drugs.

PubMed

Loftsson, Thorsteinn; Magnúsdóttir, Auethur; Másson, Már; Sigurjónsdóttir, Jóhanna F

2002-11-01

Phase-solubility diagrams are frequently used to calculate stoichiometry of drug/cyclodextrin complexes. Linear diagrams (A(L)-type systems) are thought to indicate that the complexes are first order with respect to cyclodextrin and first or higher order with respect to the drug. Positive deviation from linearity (A(P)-type systems) are thought to indicate formation of complexes that are first order with respect to the drug but second or higher order with respect to cyclodextrin. The phase solubility of several different compounds, i.e., cholesterol, ibuprofen, diflunisal, alprazolam, 17beta-estradiol and diethylstilbestrol, and various charged and uncharged cyclodextrins was investigated. Phase-solubility diagrams of cholesterol in aqueous cyclodextrin solutions were all of A(P) type. However, the phase-solubility diagrams obtained with charged cyclodextrins could not be fitted to complexes of second or higher order with respect to cyclodextrin. The phase-solubility diagrams of ibuprofen and diflunisal were of A(L) type with slope greater than unity indicating formation of 2:1 drug/cyclodextrin complexes. However, Job's plots and space filling docking studies indicated that 1:1 complexes were formed. These and other observations show that stoichiometry of drug/cyclodextrin complexes cannot be derived from simple phase-solubility studies. Furthermore, the results indicate that drug/cyclodextrin complexes can self-associate to form water-soluble aggregates, which then can further solubilize the drug through non-inclusion complexation. Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:2307-2316, 2002

Separation of hydroxynorketamine stereoisomers using capillary electrophoresis with sulfated β-cyclodextrin and highly sulfated γ-cyclodextrin.

PubMed

Sandbaumhüter, Friederike A; Theurillat, Regula; Thormann, Wolfgang

2017-08-01

The racemic N-methyl-d-aspartate receptor antagonist ketamine is used in anesthesia, analgesia and the treatment of depressive disorders. It is known that interactions of hydroxylated norketamine metabolites and 5,6-dehydronorketamine (DHNK) with the α 7 -nicotinic acetylcholine receptor and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor are responsible for the antidepressive effects. Ketamine and its first metabolite norketamine are not active on these receptors. As stereoselectivity plays a role in ketamine metabolism, a cationic capillary electrophoresis based method capable of resolving and analyzing the stereoisomers of four hydroxylated norketamine metabolites, norketamine and DHNK was developed. The assay is based on liquid/liquid extraction of the analytes from the biological matrix, electrokinetic sample injection across a buffer plug and analysis of the stereoisomers in a phosphate background electrolyte (BGE) at pH 3 comprising a mixture of sulfated β-cyclodextrin (5 mg/mL) and highly sulfated γ-cyclodextrin (0.1%). The method was used to analyze samples of an in vitro study in which ketamine was incubated with equine liver microsomes and in plasma samples of dogs and horses that were collected after an i.v. bolus injection of racemic ketamine. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Capillary electrophoretic enantioseparation of basic drugs using a new single-isomer cyclodextrin derivative and theoretical study of the chiral recognition mechanism.

PubMed

Liu, Yongjing; Deng, Miaoduo; Yu, Jia; Jiang, Zhen; Guo, Xingjie

2016-05-01

A novel single-isomer cyclodextrin derivative, heptakis {2,6-di-O-[3-(1,3-dicarboxyl propylamino)-2-hydroxypropyl]}-β-cyclodextrin (glutamic acid-β-cyclodextrin) was synthesized and used as a chiral selector in capillary electrophoresis for the enantioseparation of 12 basic drugs, including terbutaline, clorprenaline, tulobuterol, clenbuterol, procaterol, carvedilol, econazole, miconazole, homatropine methyl bromide, brompheniramine, chlorpheniramine and pheniramine. The primary factors affecting separation efficiency, which include the background electrolyte pH, the concentration of glutamic acid-β-cyclodextrin and phosphate buffer concentration, were investigated. Satisfactory enantioseparations were obtained using an uncoated fused-silica capillary of 50 cm (effective length 40 cm) × 50 μm id with 120 mM phosphate buffer (pH 2.5-4.0) containing 0.5-4.5 mM glutamic acid-β-cyclodextrin as background electrolyte. A voltage of 20 kV was applied and the capillary temperature was kept at 20°C. The results proved that glutamic acid-β-cyclodextrin was an effective chiral selector for studied 12 basic drugs. Moreover, the possible chiral recognition mechanism of brompheniramine, chlorpheniramine and pheniramine on glutamic acid-β-cyclodextrin was investigated using the semi-empirical Parametric Method 3. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Functional characteristics of cyclodextrin glucanotransferase from alkalophilic Bacillus sp. BL-31 highly specific for intermolecular transglycosylation of bioflavonoids.

PubMed

Go, Young-Hoon; Kim, Tae-Kwon; Lee, Kwang-Woo; Lee, Yong-Hyun

2007-09-01

The functional characteristics of a beta-cyclodextrin glucanotransferase (CGTase) excreted from alkalophilic Bacillus sp. BL-31 that is highly specific for the intermolecular transglycosylation of bioflavonoids were investigated. The new beta-CGTase showed high specificities for glycosyl acceptor bioflavonoids, including naringin, rutin, and hesperidin, and especially naringin. The transglycosylation of naringin into glycosyl naringin was then carried out under the conditions of 80 units of CGTase per gram of maltodextrin, 5 g/l of naringin, 25 g/l of maltodextrin, and 1 mM Mn2+ ion at 40 degrees C for 6 h, resulting in a high conversion yield of 92.1%.

Measurement of monomolecular binding constants of neutral phenols into the beta-cyclodextrin by continuous frontal analysis in capillary and microchip electrophoresis via a competitive assay.

PubMed

Le Saux, Thomas; Hisamoto, Hideaki; Terabe, Shigeru

2006-02-03

Measurement of binding constant by chip electrophoresis is a very promising technique for the high throughput screening of non-covalent interactions. Among the different electrophoretic methods available that yield the binding parameters, continuous frontal analysis is the most appropriate for a transposition from capillary electrophoresis (CE) to microchip electrophoresis. Implementation of this methodology in microchip was exemplified by the measurement of inclusion constants of 2-naphtalenesulfonate and neutral phenols (phenol, 4-chlorophenol and 4-nitrophenol) into beta-cyclodextrin by competitive assays. The issue of competitor choice is discussed in relation to its appropriateness for proper monitoring of the interaction.

Supersaturating drug delivery systems: effect of hydrophilic cyclodextrins and other excipients on the formation and stabilization of supersaturated drug solutions.

PubMed

Brewster, M E; Vandecruys, R; Verreck, G; Peeters, J

2008-03-01

Supersaturating drug delivery systems (SDDS) utilize two important design elements in their preparation including converting the drug of interest into a high energy state or other rapidly dissolving form to facilitate the formation of supersaturated drug solutions and providing a means for stabilizing the formed supersaturated solution such that significant drug absorption is possible from the gastrointestinal tract. This has been referred to as a "spring" and "parachute" approach. The current effort is designed to assess materials which may affect properties in SDDS. To this end, a series of excipients was tested in a co-solvent/solvent quench method to assess their ability to attain and maintain supersaturation for a group of 14 drug development candidates. The approach focussed on hydrophilic cyclodextrins including hydroxypropyl-beta-cyclodextrin (HPbetaCD) and sulfobutyl-beta-cyclodextrin (SBEbetaCD). Various rheological polymers and surfactants were also included in the study. Consistent with previous investigations, the pharmaceutical polymers, as a class, had minimal effects on the extent of supersaturation but tended to be good stabilizers while the surfactants tended to provide for the greatest degree of supersaturation but the formed systems were poorly stable. This study found that hydrophilic cyclodextrins, especially SBEbetaCD, gave superior results in terms of attaining and maintaining supersaturation. A knowledge of the behavior and performance of excipients in this context can be useful in designing solid oral dosage forms for difficult-to-formulate drugs and drug candidates.

Combining strategies to optimize a gel formulation containing miconazole: the influence of modified cyclodextrin on textural properties and drug release.

PubMed

Ribeiro, Andreza Maria; Figueiras, Ana; Freire, Cristina; Santos, Delfim; Veiga, Francisco

2010-06-01

Miconazol, an antimycotic drug, is commonly formulated into semisolid formulations designed to be applied in the oral cavity to treat oral candidiasis. However, given its limited aqueous solubility, permeation through the biological membranes is low and therefore its activity is also limited. Cyclodextrins (CDs) have been widely used to increase the solubility and stability of poorly water-soluble drugs. The aim of this study is to formulate a gel containing an inclusion complex between a modified CD, methyl-beta-cyclodextrin (MbetaCD), and miconazole (MCZ). The influence of the CD on the textural properties of the prepared gel and the drug release from formulation were evaluated. The gels were prepared using two polymers, Carbopol 71G and Pluronic F127, which were selected taking into account their bioadhesiveness and thermal-sensitive gelling properties, respectively. Texture profile analyses were performed at two different temperatures to ascertain the influence of the temperature on the gel texture properties. The in vitro MCZ release profiles from the prepared gel and the commercial gel formulations were evaluated and compared using modified Franz diffusion cells. The addition of MbetaCD to the gel resulted in a decrease of the gel adhesiveness and firmness, and the MCZ release profile through f1 and f2 proved to be similar to the commercial product. A gel comprising miconazol in the form of an inclusion complex with MbetaCD showed suitable textural properties to be applied to the buccal mucosa. The MbetaCD enhanced the solubility of the MCZ in the gel formulation resulting in adequate in vitro drug release profiles.

Comparative evaluation of polymeric and amphiphilic cyclodextrin nanoparticles for effective camptothecin delivery.

PubMed

Cirpanli, Yasemin; Bilensoy, Erem; Lale Doğan, A; Caliş, Sema

2009-09-01

Camptothecin (CPT) is a potent anticancer agent. The clinical application of CPT is restricted by poor water solubility and instability under physiological conditions. Solubilization and stabilization of CPT were realized through nanoparticulate systems of amphiphilic cyclodextrins, poly(lactide-co-glycolide) (PLGA) or poly-epsilon-caprolactone (PCL). Nanoparticles were prepared with nanoprecipitation technique, whereas cyclodextrin nanoparticles were prepared from preformed inclusion complexes of CPT with amphiphilic cyclodextrins. Polymeric nanoparticles, on the other hand, were loaded with CPT:HP-beta-CD inclusion complex to solubilize and stabilize the drug. Mean particle sizes were under 275 nm, and polydispersity indices were lower than 0.2 for all formulations. Drug-loading values were significantly higher for amphiphilic cyclodextrin nanoparticles when compared with those for PLGA and PCL nanoparticles. Nanoparticle formulations showed a significant controlled release profile extended up to 12 days for amphiphilic cyclodextrin nanoparticles and 48h for polymeric nanoparticles. Anticancer efficacy of the nanoparticles was evaluated in comparison with CPT solution in dimethyl sulfoxide (DMSO) on MCF-7 breast adenocarcinoma cells. Amphiphilic cyclodextrin nanoparticles showed higher anticancer efficacy than PLGA or PCL nanoparticles loaded with CPT and the CPT solution in DMSO. These results indicated that CPT-loaded amphiphilic cyclodextrin nanoparticles might provide a promising carrier system for the effective delivery of this anticancer drug having bioavailability problems.

Preparation, characterization and in vitro evaluation of a new nucleotide analogue prodrug cyclodextrin inclusion complexes.

PubMed

Diab, Roudayna; Jordheim, Lars P; Degobert, Ghania; Peyrottes, Suzanne; Périgaud, Christian; Dumontet, Charles; Fessi, Hatem

2009-01-01

Bis(tbutyl-S-acyl-2-thioethyl)-cytidine monophosophate is a new cytotoxic mononucleotide prodrug which have been developed to reverse the cellular resistance to nucleoside analogues. Unfortunately, its in vivo utilisation was hampered by its poor water solubility, raising the need of a molecular vector capable to mask its physicochemical characteristics although without affecting its cytotoxic activity. Hydroxypropyl-beta-cyclodextrin was used to prepare the prodrug inclusion complexes, allowing it to be solubilized in water and hence to be used for in vitro and in vivo experiments. A molar ratio of the cyclodextrin: prodrug of 3 was sufficient to obtain complete solubilization of the prodrug. The inclusion complex was characterized by differential scanning calorimetry, which revealed the disappearance of the melting peak of the prodrug suggesting the formation of inclusion complex. Proton Nuclear Magnetic Resonance spectroscopy provided a definitive proof of the inclusion complex formation, which was evidenced by the large chemical shift displacements observed for protons located in the interior of the hydrophobic cyclodextrin cavity. The complex retained its cytotoxic activity as shown by in vitro cell survival assays on murine leukemia cells. These results provided a basis for potential therapeutic applications of co-formulation of this new nucleotide analogue with hydroxypropyl-beta-CD in cancer therapy.

Surface effects and desorption of tetracycline supramolecular complex on bovine dentine.

PubMed

Pataro, A L; Franco, C F; Santos, V R; Cortés, M E; Sinisterra, R D

2003-03-01

The aim of this in vitro study was to evaluate the antimicrobial activity, the substantivity, and surface effects of the inclusion compound tetracycline: beta-cyclodextrin on bovine roots. The antimicrobial activity was assessed by dentine slabs which had been immersed in the inclusion complex in concentrations 8.0%, 4.0%, 2.0%, 1.0%, 0.5% and 0.25% for 5min compared to a control of tetracycline hydrochloride. Each slab was tested in a broth of overnight culture of Actinobacillus actinomycetemcomitans (Y4-FDC). The inclusion complex significantly inhibited the A. actinomycetemcomitans (p<0.01) verified at concentrations from 1.0% to 8.0%. The substantivity of tetracycline was evaluated by the measure of desorption from the slabs previously immersed in solution samples and removed at 24h intervals. The tetracycline encapsulated in beta-cyclodextrin showed a flow rate near to zero order in comparison to free tetracycline. The surface morphology determined by SEM showed a more homogeneous and integrated layer with the complex compared to the effect of free tetracycline. We concluded that the root surfaces treated with tetracycline: beta-cyclodextrin release lower concentrations of active drug over 5 days at inhibitory concentrations against A. actinomycetemcomitans with enhanced disponibility in comparison to tetracycline.

Functionalized β-cyclodextrin based potentiometric sensor for naproxen determination.

PubMed

Lenik, Joanna; Łyszczek, Renata

2016-04-01

Potentiometric sensors based on neutral β-cyclodextrins: (2-hydroxypropyl)-β-cyclodextrin, heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, heptakis(2,3,6-tri-O-benzoyl)-β-cyclodextrin and anionic β-cyclodextrin: (2-hydroxy-3-N,N,N-trimethylamino)propyl-β-cyclodextrin chloride for naproxen are described. Inclusion complexes of naproxen with the above-mentioned cyclodextrins were studied using IR spectroscopy. The electrode surface was made from PVC membranes doped with the appropriate β-cyclodextrin as ionophores and quaternary ammonium chlorides as positive charge additives that were dispersed in plasticizers. The optimum membrane contains heptakis(2,3,6-tri-O-benzoyl)-β-cyclodextrin, o-nitrophenyloctyl ether and tetraoctyl ammonium chloride as a lipophilic salt. The electrode is characterized by a Nernstian response slope of -59.0 ± 0.5 mV decade(-1) over the linear range of 5.0 × 10(-5)-1.0 × 10(-2) mol L(-1) and the detection limit 1.0 × 10(-5) mol L(-1), as well as the response time 10s. It can be used in the pH range 6.2-8.5 for 10 months without any considerable deterioration. Incorporation of β-cyclodextrins improved the electrode selectivity towards naproxen ions from several inorganic and organic interferents and some common drug excipients due to concovalent interactions (host molecule-guest molecule). The notable advantages of the naproxen-selective electrode include its high sensitivity, high selectivity, cost-effectiveness as well as accurate and comfortable application in drug analysis and milk samples. Copyright © 2015. Published by Elsevier B.V.

Development of a capillary electrophoresis method for the determination of the chiral purity of dextromethorphan by a dual selector system using quality by design methodology.

PubMed

Krait, Sulaiman; Heuermann, Matthias; Scriba, Gerhard K E

2018-03-01

Dextromethorphan is a centrally acting antitussive drug, while its enantiomer levomethorphan is an illicit drug with opioid analgesic effects. As capillary electrophoresis has been proven as an ideal technique for enantiomer analysis, the present study was conducted in order to develop a capillary electrophoresis-based limit test for levomethorphan. The analytical target profile was defined as a method that should be able to determine levomethorphan with acceptable precision and accuracy at the 0.1 % level. From initial scouting experiments, a dual selector system consisting of sulfated β-cyclodextrin and methyl-α-cyclodextrin was identified. The critical process parameters were evaluated in a fractional factorial resolution IV design followed by a central composite face-centered design and Monte Carlo simulations for defining the design space of the method. The selected working conditions consisted of a 30/40.2 cm, 50 μm id fused-silica capillary, 30 mM sodium phosphate buffer, pH 6.5, 16 mg/mL sulfated β-cyclodextrin, and 14 mg/mL methyl-α-cyclodextrin at 20°C and 20 kV. The method was validated according to ICH guideline Q2(R1) and applied to the analysis of a capsule formulation. Furthermore, the apparent binding constants between the enantiomers and the cyclodextrins as well as complex mobilities were determined to understand the migration behavior of the analytes. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The Synthesis of N-Acetyllactosamine Functionalized Dendrimers, and the Functionalization of Silica Surfaces Using Tunable Dendrons and beta-Cyclodextrins

NASA Astrophysics Data System (ADS)

Ennist, Jessica Helen

Galectin-3 is beta-galactoside binding protein which is found in many healthy cells. In cancer, the galectin-3/tumor-associated Thomsen-Friedenreich antigen (TF antigen) interaction has been implicated in heterotypic and homotypic cellular adhesion and apoptotic signaling pathways. However, a stronger mechanistic understanding of the role of galectin-3 in these processes is needed. N-acetyllactosamine (LacNAc) is a non-native ligand for galectin-3 which binds with comparable affinity to the TF antigen and therefore an important ligand to study galectin-3 mediated processes. To study galectin-3 mediated homotypic cellular aggregation, four generations of polyamidoamine (PAMAM) dendrimers were functionalized with N-acetyllactosamine using a four-step chemoenzymatic route. The enzymatic step controlled the regiochemistry of the galactose addition to N-acetylglucosamine functionalized dendrimers using a recombinant beta-1,4-Galactosyltransferase-/UDP-4'-Gal Epimerase Fusion Protein (lgtB-galE). Homotypic cellular aggregation, which is promoted by the presence of galectin-3 as it binds to glycosides at the cell surface, was studied using HT-1080 fibrosarcoma, A549 lung, and DU-145 prostate cancer cell lines. In the presence of small LacNAc functionalized PAMAM dendrimers, galectin-3 induced cancer cellular aggregation was inhibited. However, the larger glycodendrimers induced homotypic cellular aggregation. Additionally, novel poly(aryl ether) dendronized silica surfaces designed for reversible adsorbtion of targeted analytes were synthesized, and characterization using X-ray Photoelectron Spectroscopy (XPS) was performed. Using a Cu(I) mediated cycloaddition "click" reaction, beta-cyclodextrin was appended to dendronized surfaces via triazole formation and also to a non-dendronized surface for comparison purposes. First generation G(1) dendrons have more than 6 times greater capacity to adsorb targeted analytes than slides functionalized with monomeric beta-cyclodextrin and are 2 times greater than slides functionalized with larger generation dendrons. This study reported beta-cyclodextrin functionalized surfaces can undergo a triggered release of the adsorbent, but otherwise retained the targeted analyte through multiple aqueous washes. Therefore, a new generation of G(1) dendronized surfaces capable of reversible adsorption were developed by heterogeneously appending sulfonic acid/pyridine end-groups. Auger Electron Spectroscopy (AES) was used to quantify the ratio of groups installed. Furthermore, G(1) dendronized surfaces were functionalized homogenously with sulfonic acid and pyridine for comparison and with chiral amino acids for chiral recognition studies.

Use of reversed phase high pressure liquid chromatography for the physicochemical and thermodynamic characterization of oxyresveratrol/beta-cyclodextrin complexes.

PubMed

Rodríguez-Bonilla, Pilar; López-Nicolás, José Manuel; García-Carmona, Francisco

2010-06-01

Knowledge of the complexation process of oxyresveratrol with beta-cyclodextrin (beta-CD) under different physicochemical conditions is essential if this potent antioxidant compound is to be used successfully in both food and pharmaceutical industries as ingredient of functional foods or nutraceuticals, despite its poor stability and bioavailability. In this paper, the complexation of oxyresveratrol with natural CDs was investigated for first time using RP-HPLC and mobile phases to which alpha-, beta-, and gamma-CD were added. Among natural CDs, the interaction of oxyresveratrol with beta-CD was more efficient than with alpha- and gamma-CD. The decrease in the retention times with increasing concentrations of beta-CD (0-4 mM) showed that the formation constants (KF) of the oxyresveratrol/beta-CD complexes were strongly dependent on both the water-methanol proportion and the temperature of the mobile phase employed. However, oxyresveratrol formed complexes with beta-CD with a 1:1 stoichiometry in all the physicochemical conditions tested. Moreover, to obtain information about the mechanism of the oxyresveratrol affinity for beta-CD, the thermodynamic parameters DeltaG degrees, DeltaH degrees and DeltaS degrees were obtained. Finally, to gain information on the effect of the structure of different compounds belonging to the stilbenoids family on the KF values, the complexation of other molecules, resveratrol, pterostilbene and pinosylvin, was studied and compared with the results obtained for the oxyresveratrol/beta-CD complexes. Copyright 2010 Elsevier B.V. All rights reserved.

Disruption of lipid rafts interferes with the interaction of Toxoplasma gondii with macrophages and epithelial cells.

PubMed

Cruz, Karla Dias; Cruz, Thayana Araújo; Veras de Moraes, Gabriela; Paredes-Santos, Tatiana Christina; Attias, Marcia; de Souza, Wanderley

2014-01-01

The intracellular parasite Toxoplasma gondii can penetrate any warm-blooded animal cell. Conserved molecular assemblies of host cell plasma membranes should be involved in the parasite-host cell recognition. Lipid rafts are well-conserved membrane microdomains that contain high concentrations of cholesterol, sphingolipids, glycosylphosphatidylinositol, GPI-anchored proteins, and dually acylated proteins such as members of the Src family of tyrosine kinases. Disturbing lipid rafts of mouse peritoneal macrophages and epithelial cells of the lineage LLC-MK2 with methyl-beta cyclodextrin (M β CD) and filipin, which interfere with cholesterol or lidocaine, significantly inhibited internalization of T. gondii in both cell types, although adhesion remained unaffected in macrophages and decreased only in LLC-MK2 cells. Scanning and transmission electron microscopy confirmed these observations. Results are discussed in terms of the original role of macrophages as professional phagocytes versus the LLC-MK2 cell lineage originated from kidney epithelial cells.

Simultaneous determination of anthraquinones, their 8-beta-D-glucosides, and sennosides of Rhei Rhizoma by capillary electrophoresis.

PubMed

Koyama, Junko; Morita, Izumi; Fujiyoshi, Hirotaka; Kobayashi, Norihiro

2005-05-01

The simultaneous separation and determination of major anthraquinones (emodin, chrysophanol, rhein and their glucosides, aloe-emodin, sennoside A, and sennoside B) of Rhei Rhizoma were achieved by cyclodextrin modified capillary zone electrophoresis. The running electrolyte used in this method was 0.005 M alpha-cyclodextrin in 0.03 M borate buffer (pH 10.0) containing 20% acetonitrile, with an applied voltage of 20 kV.

Influence of hydroxypropyl beta-cyclodextrin on the corneal permeation of pilocarpine.

PubMed

Aktaş, Yeşim; Unlü, Nurşen; Orhan, Mehmet; Irkeç, Murat; Hincal, A Atilla

2003-02-01

The influence of hydroxypropyl beta-cyclodextrin (HPbetaCD) on the corneal permeation of pilocarpine nitrate was investigated by an in vitro permeability study using isolated rabbit cornea. Pupillary-response pattern to pilocarpine nitrate with and without HPbetaCD was examined in rabbit eye. Corneal permeation of pilocarpine nitrate was found to be four times higher after adding HPbetaCD into the formulation. The reduction of pupil diameter (miosis) by pilocarpine nitrate was significantly increased as a result of HPbetaCD addition into the simple aqueous solution of the active substance. The highest miotic response was obtained with the formulation prepared in a vehicle of Carbopol 940. It is suggested that ocular bioavailability of pilocarpine nitrate could be improved by the addition of HPbetaCD.

Unique organogel formation with macroporous materials constructed by the freeze-drying of aqueous cyclodextrin solutions.

PubMed

Marui, Yasuhiro; Kikuzawa, Akira; Kida, Toshiyuki; Akashi, Mitsuru

2010-07-06

Macroporous cyclodextrin materials (MP-alpha-, beta-, and gamma-CDs) were easily fabricated by the freeze-drying of aqueous solutions of alpha-, beta-, and gamma-CDs. These MP-CDs showed the absorption ability toward various organic solvents and oils to give organogels at ambient temperature. The morphological changes of the MP-CD microstructures were observed through the absorption of organic solvents. In particular, the absorption of polar organic solvents with hydrogen-bond forming ability, including 1,4-dioxane and ethanol, by the MP-CDs caused remarkable morphological changes in the microstructures. The absorption of these polar solvents by MP-alpha- and gamma-CDs resulted in the formation of channel-type assemblies of alpha- and gamma-CDs, respectively.

Molecular Bases of cyclodextrin Adapter Interactions with Engineered Protein Nanopores

DOE Office of Scientific and Technical Information (OSTI.GOV)

Banerjee, A.; Mikhailova, E; Cheley, S

2010-01-01

Engineered protein pores have several potential applications in biotechnology: as sensor elements in stochastic detection and ultrarapid DNA sequencing, as nanoreactors to observe single-molecule chemistry, and in the construction of nano- and micro-devices. One important class of pores contains molecular adapters, which provide internal binding sites for small molecules. Mutants of the {alpha}-hemolysin ({alpha}HL) pore that bind the adapter {beta}-cyclodextrin ({beta}CD) {approx}10{sup 4} times more tightly than the wild type have been obtained. We now use single-channel electrical recording, protein engineering including unnatural amino acid mutagenesis, and high-resolution x-ray crystallography to provide definitive structural information on these engineered protein nanoporesmore » in unparalleled detail.« less

Inhibition of interaction between epigallocatechin-3-gallate and myofibrillar protein by cyclodextrin derivatives improves gel quality under oxidative stress.

PubMed

Zhang, Yumeng; Chen, Lin; Lv, Yuanqi; Wang, Shuangxi; Suo, Zhiyao; Cheng, Xingguang; Xu, Xinglian; Zhou, Guanghong; Li, Zhixi; Feng, Xianchao

2018-06-01

High levels of polyphenols can interact with myofibrillar proteins (MPs), causing damage to a MP emulsion gel. In this study, β-cyclodextrins were used to reduce covalent and non-covalent interaction between epigallocatechin-3-gallate (EGCG) and MPs under oxidative stress. The loss of both thiol and free amine groups and the unfolding of MPs caused by EGCG (80 μM/g protein) were significantly prevented by β-cyclodextrins, and the structural stability and solubility were improved. MP emulsion gel treated with EGCG (80 μM/g protein) had the highest cooking loss (68.64%) and gel strength (0.51 N). Addition of β-cyclodextrins significantly reduced cooking loss (26.24-58.20%) and improved gel strength (0.31-0.41 N) of MP emulsion gel jeopardized by EGCG under oxidative stress. Damage to the emulsifying properties of MPs caused by EGCG was significantly prevented by addition of β-cyclodextrins. β-cyclodextrins reduced interaction between EGCG and MPs in the order Methyl-β-cyclodextrin > (2-Hydroxypropyl)-β-cyclodextrin > β-cyclodextrin. In absence of EGCG, addition of β-cyclodextrins partly protected MPs from oxidative attack and improved its solubility. It is concluded that β-cyclodextrins does not markedly reduce the antioxidant ability of EGCG according to carbonyl analysis, and can effectively increase EGCG loading to potentially provide more durable antioxidant effect for meat products during processing, transportation and storage. Copyright © 2018 Elsevier Ltd. All rights reserved.

Intramolecular Oxidative O-Demethylation of an Oxoferryl Porphyrin Complexed with a Per-O-methylated β-Cyclodextrin Dimer.

PubMed

Kitagishi, Hiroaki; Kurosawa, Shun; Kano, Koji

2016-11-22

The intramolecular oxidation of ROCH 3 to ROCH 2 OH, where the latter compound spontaneously decomposed to ROH and HCHO, was observed during the reaction of the supramolecular complex (met-hemoCD3) with cumene hydroperoxide in aqueous solution. Met-hemoCD3 is composed of meso-tetrakis(4-sulfonatophenyl)porphinatoiron(III) (Fe III TPPS) and a per-O-methylated β-cyclodextrin dimer having an -OCH 2 PyCH 2 O- linker (Py=pyridine-3,5-diyl). The O=Fe IV TPPS complex was formed by the reaction of met-hemoCD3 with cumene hydroperoxide, and isolated by gel-filtration chromatography. Although the isolated O=Fe IV TPPS complex in the cyclodextrin cage was stable in aqueous solution at 25 °C, it was gradually converted to Fe II TPPS (t 1/2 =7.6 h). This conversion was accompanied by oxidative O-demethylation of an OCH 3 group in the cyclodextrin dimer. The results indicated that hydrogen abstraction by O=Fe IV TPPS from ROCH 3 yields HO-Fe III TPPS and ROCH 2 . . This was followed by radical coupling to afford Fe II TPPS and ROCH 2 OH. The hemiacetal (ROCH 2 OH) immediately decomposed to ROH and HCHO. This study revealed the ability of oxoferryl porphyrin to induce two-electron oxidation. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cyclodextrin modified hydrogels of PVP/PEG for sustained drug release.

PubMed

Nielsen, Anne Louise; Madsen, Flemming; Larsen, Kim Lambertsen

2009-02-01

Hydrogels are water swollen networks of polymers and especially hydrogels consisting of poly vinylpyrrolidone/poly ethyleneglycol-dimethacrylate (PVP/PEG-DMA) blends show promising wound care properties. Enhanced functionality of the hydrogels can be achieved by incorporating drugs and other substances that may assist wound healing into the gel matrix. Controlling the release of active compounds from the hydrogels may be possible by carefully modifying the polymer matrix. For this purpose, cyclodextrins (CD) were grafted to the polymer matrix in 4-5 w/w% in an attempt to retard the release of water-soluble drugs. Ibuprofenate (IBU) was chosen as model drug and loaded in IBU/CD ratios of 0.6, 1.2, and 2.5. Vinyl derivatives of alpha-, beta- and gamma-CD were produced, added to the prepolymer blend and cured by UV-light. During this curing process the CD derivatives were covalently incorporated into the hydrogel matrix. The modified hydrogels were loaded with ibuprofenate by swelling. The release of the model drug from CD modified hydrogels show that especially covalently bonded beta-cyclodextrin can change both the release rate and the release profile of ibuprofen.

Composite material of DNA and cyclodextrin-immobilized poly(ethyleneimine): Accumulation of harmful compounds from multi-component solution.

PubMed

Yamada, Masanori; Hori, Minako; Tabuchi, Shinya

2010-08-01

Water-soluble beta-cyclodextrin-immobilized poly(ethyleneimine) (PEICD) was synthesized by the grafting of beta-cyclodextrin to the branched poly(ethyleneimine). In an aqueous solution, this PEICD polymer could encapsulate bisphenol A, known to be a harmful compound. Additionally, the stability constant of bisphenol A to the PEICD polymer was 1.1 x 10(4)M(-1). However, the water-solubility of PEICD has been making it difficult to utilize it as an environmental material. Therefore, we prepared the DNA-PEICD composite material by mixing the double-stranded DNA and PEICD. This DNA-PEICD composite material was extremely stable in water and possessed both properties of the intercalation into the double-stranded DNA and the encapsulation into the CD cavity. As a result, this material can accumulate various harmful compounds, such as dioxin- and polychlorobiphenyl (PCB)-derivatives and bisphenol A, from a multi-component solution. Therefore, the DNA-PEICD composite material may have the potential to be used as an environmental material. Copyright 2010 Elsevier B.V. All rights reserved.

Simultaneous determination of several antalgic drugs based on their interactions with beta-cyclodextrin by capillary zone electrophoresis.

PubMed

Wei, Wei; Yu, Xiaodong; Ju, Huangxin

2004-03-01

The binding constants of beta-cyclodextrin (beta-CD) with antalgic drugs such as naproxen, ketoprofen, ibuprofen, acemetacin, and aspirin are determined by affinity capillary electrophoresis. Based on these interactions, a reliable method for the separation and simultaneous determinations of these compounds in the presence of 5.0 mM beta-CD in phosphate buffer solution is presented by capillary zone electrophoresis with UV detection at 214 nm for naproxen and 200 nm for the others. The linear ranges for naproxen, ketoprofen, ibuprofen, acemetacin, aspirin, and caffeine detections are from 2.0 to 800, 2.5 to 1000, 2.5 to 700, 2.5 to 700, 2.0 to 800, and 1.5 to 800 microg/mL, respectively. Their detection limits are 1.0, 0.5, 0.5, 1.5, 1.5, and 1.0 microg/mL at a signal to noise ratio of 3, respectively. This method has been successfully applied to the detections of these drugs in the pharmaceutical formulations (tablets or capsules) and urine samples.

Solubility of (+/-)-ibuprofen and S (+)-ibuprofen in the presence of cosolvents and cyclodextrins.

PubMed

Nerurkar, Jayanti; Beach, J W; Park, M O; Jun, H W

2005-01-01

Aqueous solubility is an important parameter for the development of liquid formulations and in the determination of bioavailability of oral dosage forms. Ibuprofen (IB), a nonsteroidal anti-inflammatory drug, is a chiral molecule and is currently used clinically as a racemate (racIB). However, the S form of ibuprofen or S(+)-ibuprofen (SIB) is the biologically active isomer and is primarily responsible for the antiinflammatory activity. Phase solubility studies were carried out to compare the saturation solubilities of racIB and SIB in the presence of common pharmaceutical solvents such as glycerol, sorbitol solution, propylene glycol (PG), and polyethylene glycol (PEG 300) over the range of 20% to 80% v/v in aqueous based systems. The solubilities of the two compounds were also compared in the presence of cyclodextrins such as beta cyclodextrin (CD), hydroxypropyl beta cyclodextrin (HPCD), and beta cyclodextrin sulfobutyl ether sodium salt (CDSB) over the range of 5% to 25% w/v. Solubility determinations were carried at 25 degrees C and 37 degrees C. Cosolvents exponentially increased the solubility of both SIB and racIB, especially in the presence of PG and PEG 300. Glycerol was not very effective in increasing the aqueous solubilities of both compounds, whereas sorbitol solution had a minimal effect on their solubility. PG and PEG 300 increased the solubility of SIB by 400-fold and 1500-fold, respectively, whereas the rise in solubility for racIB was 193-fold and 700-fold, respectively, at 25 degrees C for the highest concentration of the cosolvents used (80% v/v). Of the two compounds studied, higher equilibrium solubilities were observed for SIB as compared with racIB. The derivatized cyclodextrins increased the aqueous solubility of racIB and SIB in a concentration-dependent manner giving AL type of phase diagrams. The phase solubility diagrams indicated the formation of soluble inclusion complexes between the drugs and HPCD and CDSB, which was of 1:1 stoichiometry. The addition of underivatized CD reduced the solubility of racIB and SIB via the formation of an insoluble complex. The S form formed more stable complexes with HPCD and CDSB as compared with raclB. The solubilization process is discussed in terms of solvent polarity and differential solid-state structure of raclB and SIB. The thermodynamic parameters for the solubilization process are presented.

Evidence of formation of site-selective inclusion complexation between beta-cyclodextrin and poly(ethylene oxide)-block-poly(propylene oxide)- block-poly(ethylene oxide) copolymers.

PubMed

Tsai, Chi-Chun; Zhang, Wen-Bin; Wang, Chien-Lung; Van Horn, Ryan M; Graham, Matthew J; Huang, Jing; Chen, Yongming; Guo, Mingming; Cheng, Stephen Z D

2010-05-28

A series of inclusion complexes of poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (PEO-b-PPO-b-PEO) with beta-cyclodextrin (beta-CD) was prepared. Their formation, structure, and dynamics were investigated by solution two-dimensional rotating-frame Overhauser effect spectroscopy (2D ROESY) and one-dimensional (1D) and 2D solid-state (13)C NMR. The inclusion complexes between the PEO-b-PPO-b-PEO copolymers and the beta-CDs were formed in aqueous solution and detected by 2D ROESY. The high efficiency of cross polarization and spin diffusion experiments in (13)C solid-state NMR showed that the mobility of the PPO blocks dramatically decreases after beta-CD complexation, indicating that they are selectively incorporated onto the PPO blocks. The hydrophobic cavities of beta-CD restrict the PPO block mobility, which is evidence of the formation of inclusion complexes in the solid state. The 2D wide-line separation NMR experiments suggested that beta-CDs only thread onto the PPO blocks while forming the inclusion complexes. The stoichiometry of inclusion complexes was studied using (1)H NMR, and a 3:1 (PO unit to beta-CD) was found for all inclusion complexes, which indicated that the number of threaded beta-CDs was only dependent on the molecular weight of the PPO blocks. 1D wide angle x-ray diffraction studies demonstrated that the beta-CD in the inclusion complex formed a channel-like structure that is different from the pure beta-CD crystal structure.

Influence of beta-cyclodextrin complexation on glipizide release from hydroxypropyl methylcellulose matrix tablets.

PubMed

Shivakumar, H N; Desai, B G; Pandya, Saumyak; Karki, S S

2007-01-01

Glipizide was complexed with beta-cyclodextrin in an attempt to enhance the drug solubility. The phase solubility diagram was classified as A(L) type, which was characterized by an apparent 1:1 stability constant that had a value of 413.82 M(-1). Fourier transform infrared spectrophotometry, differential scanning calorimetry, powder x-ray diffractometry and proton nuclear magnetic resonance spectral analysis indicated considerable interaction between the drug and beta-cyclodextrin. A 2(3) factorial design was employed to prepare hydroxypropyl methylcellulose (HPMC) matrix tablets containing the drug or its complex. The effect of the total polymer loads (X1), levels of HPMC K100LV (X9), and complexation (X3) on release at first hour (Y1), 24 h (Y2), time taken for 50% release (Y3), and diffusion exponent (Y4) was systematically analyzed using the F test. Mathematical models containing only the significant terms (P < 0.05) were generated for each parameter by multiple linear regression analysis and analysis of variance. Complexation was found to exert a significant effect on Y1, Y2, and Y3, whereas total polymer loads significantly influenced all the responses. The models generated were validated by developing two new formulations with a combination of factors within the experimental domain. The experimental values of the response parameters were in close agreement with the predicted values, thereby proving-the validity of the generated mathematical models.

Preparation, characterization and molecular modeling studies of the inclusion complex of Caffeine with Beta-cyclodextrin

NASA Astrophysics Data System (ADS)

Prabu, Samikannu; Swaminathan, Meenakshisundaram; Sivakumar, Krishnamoorthy; Rajamohan, Rajaram

2015-11-01

The formation through supramolecular interaction of a host-guest inclusion complex of caffeine (CA) with nano-hydrophobic cavity beta-cyclodextrin (β-CD) is achieved by a physical mixture, a kneading method and a co-precipitation method. The formation of the inclusion complex of CA with β-CD in solution state is confirmed by UV-visible spectrophotometer, fluorescence spectrophotometer and time-resolved fluorescence spectrophotometer. The stoichiometry of the inclusion complex is 1:1; the imidazole ring and pyrimidine ring of caffeine is deeply entrapped in the beta-cyclodextrin as confirmed by spectral shifts. The Benesi-Hildebrand plot is used to calculate the binding constant of the inclusion complex of CA with β-CD at room temperature. The Gibbs free energy change of the inclusion complex process is calculated and the process is found to be spontaneous. The thermal stability of the inclusion complex of CA with β-CD is analyzed using differential scanning calorimetry. The crystal structure modification of a solid inclusion complex is confirmed by scanning electron microscopy image analysis. The formation of the inclusion complex of CA with β-CD in the solid phase is also confirmed by FT-IR and XRD. The formation of the inclusion complex between CA and β-CD, as confirmed by molecular docking studies, is in good relationship with the results obtained through different experimental methods.

Modified β-Cyclodextrin Inclusion Complex to Improve the Physicochemical Properties of Albendazole. Complete In Vitro Evaluation and Characterization

PubMed Central

García, Agustina; Leonardi, Darío; Salazar, Mario Oscar; Lamas, María Celina

2014-01-01

The potential use of natural cyclodextrins and their synthetic derivatives have been studied extensively in pharmaceutical research and development to modify certain properties of hydrophobic drugs. The ability of these host molecules of including guest molecules within their cavities improves notably the physicochemical properties of poorly soluble drugs, such as albendazole, the first chosen drug to treat gastrointestinal helminthic infections. Thus, the aim of this work was to synthesize a beta cyclodextrin citrate derivative, to analyze its ability to form complexes with albendazole and to evaluate its solubility and dissolution rate. The synthesis progress of the cyclodextrin derivative was followed by electrospray mass spectrometry and the acid-base titration of the product. The derivative exhibited an important drug affinity. Nuclear magnetic resonance experiments demonstrated that the tail and the aromatic ring of the drug were inside the cavity of the cyclodextrin derivative. The inclusion complex was prepared by spray drying and full characterized. The drug dissolution rate displayed exceptional results, achieving 100% drug release after 20 minutes. The studies indicated that the inclusion complex with the cyclodextrin derivative improved remarkably the physicochemical properties of albendazole, being a suitable excipient to design oral dosage forms. PMID:24551084

Cyclodextrin-based microsensor for volatile organic compounds

DOE Office of Scientific and Technical Information (OSTI.GOV)

Swanson, B.I.; Li, D.Q.

1996-12-31

The direct covalent attachment of modified {alpha}- and {beta}-cyclodextrin on oxide surfaces has been studied for application in chemical sensors. First, oxide surfaces were treated with a silane coupling layer followed by the addition of cyclodextrin to form a self-assembled monolayer (SAM) of host receptors. Second, the oxide surfaces were reacted with a sol-gel (SG) precursor based on cyclodextrin structure to form a thick film with defined hydrophobic cyclodextrin cavities. The sensing properties of both films (SAM and SG) were examined with surface acoustic wave (SAW) measurement platform. Molecular interactions between an organic guest and a host thin-film on amore » 200 MHZ SAW resonator are being studied as a method of tracking and recognizing the presence of volatile organics. Surface acoustic wave sensors based on the inclusion chemistry of the bucket-type (cyclodextrin) molecules, were capable of detecting volatile organic compounds (VOCs) down to ppb levels. Because the nature of the interactions is moderate but noncovalent, detection of these VOCs was possible using a reversible real-time mode. Pattern recognition with an array of complementary microsensors appears to be a viable approach for identifying and quantifying VOCs. Recent results using optical waveguides for sensor transduction will also be discussed.« less

[Effects of penetration enhancers on curcumin transdermal drug delivery].

PubMed

Gao, Zhen-Shen; Wang, Lan; Zhang, Mei

2012-01-01

To study the effects of penetration enhancers and their combinations on the curcumine transdermal drug delivery (CUR-TDDS). The penetration rate of curcumin through rat skin in vitro was measured using Valia-Chien diffusion cells, and orthogonal design method was set up for experimental design. The optimum penetration enhancers were: 3% hydroxypropyl beta cyclodextrins (HP-beta-CD), 9% borneol and 3% peppermint oil. The HP-beta-CD has the most potent enhancing effect.

Supramolecular self-assemblies of beta-cyclodextrins with aromatic tethers: factors governing the helical columnar versus linear channel superstructures.

PubMed

Liu, Yu; Fan, Zhi; Zhang, Heng-Yi; Yang, Ying-Wei; Ding, Fei; Liu, Shuang-Xi; Wu, Xue; Wada, Takehiko; Inoue, Yoshihisa

2003-10-31

A series of 6-O-(p-substituted phenyl)-modified beta-cyclodextrin derivatives, i.e., 6-O-(4-bromophenyl)-beta-CD (1), 6-O-(4-nitrophenyl)-beta-CD (2), 6-O-(4-formylphenyl)-beta-CD (3), 6-phenylselenyl-6-deoxy-beta-CD (4), and 6-O-(4-hydroxybenzoyl)-beta-CD (5), were synthesized, and their inclusion complexation behavior in aqueous solution and self-assembling behavior in the solid state were comparatively studied by NMR spectroscopy, microcalorimetry, crystallography, and scanning tunneling microscopy. Interestingly, (seleno)ethers 1-4 and ester 5 displayed distinctly different self-assembling behavior in the solid state, affording a successively threading head-to-tail polymeric helical structure for the (seleno)ethers or a mutually penetrating tail-to-tail dimeric columnar channel structure for the ester. Combining the present and previous structures reported for the relevant beta-CD derivatives, we further deduce that the pivot heteroatom, through which the aromatic substituent is tethered to beta-CD, plays a critical role in determining the helix structure, endowing the 2-fold and 4-fold axes to the N/O- and S/Se-pivoted beta-CD aggregates, respectively. This means that one can control the self-assembling orientation, alignment, and helicity in the solid state by finely tuning the pivot atom and the tether length. Further NMR and calorimetric studies on the self-assembling behavior in aqueous solution revealed that the dimerization step is the key to the formation of linear polymeric supramolecular architecture, which is driven by favorable entropic contributions.

Effects of beta-cyclodextrin on the structure of sphingomyelin/cholesterol model membranes.

PubMed

Jablin, Michael S; Flasiński, Michał; Dubey, Manish; Ratnaweera, Dilru R; Broniatowski, Marcin; Dynarowicz-Łatka, Patrycja; Majewski, Jarosław

2010-09-08

The interaction of beta-cyclodextrin (beta-CD) with mixed bilayers composed of sphingomylein and cholesterol (Chol) above and below the accepted stable complexation ratio (67:33) was investigated. Membranes with the same (symmetric) and different (asymmetric) compositions in their inner and outer leaflets were deposited at surface pressures of 20, 30, and 40 mN/m at the solid-liquid interface. Using neutron reflectometry, membranes of various global molar ratios (defined as the sum of the molar ratios of the inner and outer leaflets), were characterized before and after beta-CD was added to the subphase. The structure of bilayers with global molar ratios at or above the stable complexation ratio was unchanged by beta-CD, indicating that beta-CD is unable to remove sphingomyelin or complexed Chol. However, beta-CD removed all uncomplexed Chol from bilayers composed of global molar ratios below the stable complexation ratio. The removal of Chol by beta-CD was independent of the initial structure of the membranes as deposited, suggesting that asymmetric membranes homogenize by the exchange of molecules between leaflets. The interaction of beta-CD with the aforementioned membranes was independent of the deposition surface pressure except for a symmetric 50:50 membrane deposited at 40 mN/m. The scattering from 50:50 bilayers with higher packing densities (deposited at 40 mN/m) was unaffected by beta-CD, suggesting that the removal of Chol can depend on both the composition and packing density of the membrane. Copyright 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Analysis of repaglinide enantiomers in pharmaceutical formulations by capillary electrophoresis using 2,6-di-o-methyl-β-cyclodextrin as a chiral selector.

PubMed

Li, Cen; Jiang, Ye

2012-09-01

This study used the general applicability of 2,6-didi-o-methyl-β-cyclodextrin (DM-β-CD) as the chiral selector in capillary electrophoresis for fast and efficient chiral separation of repaglinide enantiomers. A systematic study of the parameters affecting separation was performed with UV detection at 243 nm. The optimum conditions were determined to be 1.25% (w/v) DM-β-CD in 20 mM sodium phosphate (pH 2.5) as the running buffer and separation voltage at 20 kV. DM-β-CD had the best enantiomer resolution properties under the tested conditions, whereas other β-cyclodextrins showed inferior performances or no performance. The proposed method had a linear calibration curve in the concentration range of 12.5-400 µg/mL. The limit of detection was 100 ng/mL. The intra-day and inter-day precisions were 2.8 and 3.2%, respectively. Recoveries of 97.9-100.9% were obtained. The proposed method was fast and convenient, and was determined to be efficient for separating enantiomers and applicable for analyzing repaglinide enantiomers in quality control of pharmaceutical production.

Sulfobutyl ether β-cyclodextrin (Captisol(®) ) and methyl β-cyclodextrin enhance and stabilize fluorescence of aqueous indocyanine green.

PubMed

DeDora, Daniel J; Suhrland, Cassandra; Goenka, Shilpi; Mullick Chowdhury, Sayan; Lalwani, Gaurav; Mujica-Parodi, Lilianne R; Sitharaman, Balaji

2016-10-01

As the only FDA-approved near-infrared fluorophore, indocyanine green (ICG) is commonly used to image vasculature in vivo. ICG degrades rapidly in solution, which limits its usefulness in certain applications, including time-sensitive surgical procedures. We propose formulations that address this shortcoming via complexation with β-cyclodextrin derivatives (β-CyD), which are known to create stabilizing inclusion complexes with hydrophobic molecules. Here, we complexed ICG with highly soluble methyl β-CyD and FDA-approved sulfobutyl ether β-CyD (Captisol(®) ) in aqueous solution. We measured the fluorescence of the complexes over 24 h. We found that both CyD+ICG complexes exhibit sustained fluorescence increases of >2.0× versus ICG in water and >20.0× in PBS. Using transmission electron microscopy, we found evidence of reduced aggregation in complexes versus ICG alone. We thus conclude that this reduction in aggregation helps mitigate fluorescence autoquenching of CyD+ICG complexes compared in ICG alone. We also found that while ICG complexed with methyl β-CyD severely reduced the viability of MRC-5 fibroblasts, ICG complexed with sulfobutyl ether β-CyD had no effect on viability. These results represent an important first step toward enhancing the utility of aqueous ICG by reducing aggregation-dependent fluorescence degradation. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1457-1464, 2016. © 2015 Wiley Periodicals, Inc.

Cholesterol binding, efflux, and a PDZ-interacting domain of scavenger receptor–BI mediate HDL-initiated signaling

PubMed Central

Assanasen, Chatchawin; Mineo, Chieko; Seetharam, Divya; Yuhanna, Ivan S.; Marcel, Yves L.; Connelly, Margery A.; Williams, David L.; de la Llera-Moya, Margarita; Shaul, Philip W.; Silver, David L.

2005-01-01

The binding of HDL to scavenger receptor–BI (SR-BI) mediates cholesterol movement. HDL also induces multiple cellular signals, which in endothelium occur through SR-BI and converge to activate eNOS. To determine the molecular basis of a signaling event induced by HDL, we examined the proximal mechanisms in HDL activation of eNOS. In endothelial cells, HDL and methyl-β-cyclodextrin caused comparable eNOS activation, whereas cholesterol-loaded methyl-β-cyclodextrin had no effect. Phosphatidylcholine-loaded HDL caused greater stimulation than native HDL, and blocking antibody against SR-BI, which prevents cholesterol efflux, prevented eNOS activation. In a reconstitution model in COS-M6 cells, wild-type SR-BI mediated eNOS activation by both HDL and small unilamellar vesicles (SUVs), whereas the SR-BI mutant AVI, which is incapable of efflux to SUV, transmitted signal by only HDL. In addition, eNOS activation by methyl-β-cyclodextrin was SR-BI dependent. Studies of mutant and chimeric class B scavenger receptors revealed that the C-terminal cytoplasmic PDZ-interacting domain and the C-terminal transmembrane domains of SR-BI are both necessary for HDL signaling. Furthermore, we demonstrated direct binding of cholesterol to the C-terminal transmembrane domain using a photoactivated derivative of cholesterol. Thus, HDL signaling requires cholesterol binding and efflux and C-terminal domains of SR-BI, and SR-BI serves as a cholesterol sensor on the plasma membrane. PMID:15841181

Two-photon absorption properties of cationic 1,4-bis(styryl)benzene derivative and its inclusion complexes with cyclodextrins.

PubMed

Nag, Okhil Kumar; Nayak, Rati Ranjan; Lim, Chang Su; Kim, In Hong; Kyhm, Kwangseuk; Cho, Bong Rae; Woo, Han Young

2010-07-29

Two-photon absorption properties of 1,4-bis{4'-[N,N-bis(6''-trimethylammoniumhexyl)amino]styryl}benzene tetrabromide (C1) and its inclusion complexes (ICs) with cyclodextrins (CDs) have been studied. Upon complexation with CDs, the absorption spectra of C1 showed a slight red shift, whereas the emission spectra showed a blue shift with concomitant increase in the fluorescence quantum efficiency. A Stern-Volmer study using K(3)Fe(CN)(6) as a quencher revealed significant reduction in the photoinduced charge transfer quenching, in accord with the IC formation. Comparison of the spectroscopic results reveals that C1 forms increasingly more stable ICs in the order C1/beta-CD < C1/gamma-CD < C1/(3gamma:beta)-CD (gamma-CD/beta-CD 3:1, mole ratio). Moreover, the two-photon action cross section of C1 increased from 200 GM for C1 to 400 GM for C1/beta-CD, 460 GM for C1/gamma-CD, and 650 GM for C1/(3gamma:beta)-CD, respectively. Furthermore, the two-photon microscopy images of HeLa cells stained with C1 emitted strong two-photon excited fluorescence in the plasma membrane. These results provide a useful guideline for the development of efficient two-photon materials for bioimaging applications.

Effect of hydroxypropyl-beta-cyclodextrin on the degradation of pentachlorophenol by potassium monopersulfate catalyzed with iron(III)-porphyrin complex.

PubMed

Fukushima, Masami; Tatsumi, Kenji

2005-12-01

A novel biomimetic catalytic system containing a supramolecular complex between iron(III)-tetrakis(p-sulfonatophenyl)porphyrin [Fe(III)-TPPS] and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was examined for the potassium monopersulfate catalyzed oxidation of pentachlorophenol (PCP). In the absence of HP-beta-CD, the percentage of PCP disappearance and the numbers of chlorine atoms released from PCP increased to 50% and 1.5 for a 1-day reaction period, respectively. However, in the presence of HP-beta-CD, the PCP completely disappeared and the number of chlorine atoms from PCP was increased to 3.1. o-Tetrachloroquinone, 2- and 4-hydroxyl-nonachlorodiphenyl ethers, and octachlorodibenzo-p-dioxin were detected among the oxidation products. In the absence of HP-beta-CD, the percentage of PCP conversion to oxidation products increased and then reached plateau. In the presence of HP-beta-CD, the amount of oxidation products produced initially increased for the first 10 min and thereafter decreased gradually. These results suggest that the addition of HP-beta-CD results in the further degradation of oxidation products. In addition, the mineralization of PCP to CO2 was investigated using 14C6-labeled PCP. After a 1-day reaction period, 24% of the 14C6-labeled PCP was converted to 14CO2 in the presence of HP-beta-CD, although significant 14CO2 generation was not observed in its absence. The effect of HP-beta-CD on the facilitation of PCP degradation can be attributed to the fact that the self-oxidation of Fe(III)-TPPS is prevented by the formation of a stable supramolecular complex between HP-beta-CD and Fe(III)-TPPS.

Enantiomeric separation of 2-arylpropionic acid nonsteroidal anti-inflammatory drugs by HPLC with hydroxypropyl-beta-cyclodextrin as chiral mobile phase additive.

PubMed

Ye, Jincui; Yu, Wenying; Chen, Guosheng; Shen, Zhengrong; Zeng, Su

2010-08-01

The enantio-separations of eight 2-arylpropionic acid nonsteroidal anti-inflammatory drugs (2-APA NSAIDs) were established using reversed-phase high-performance liquid chromatography with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) as chiral mobile phase additive for studying the stereoselective skin permeation of suprofen, ketoprofen, naproxen, indoprofen, fenoprofen, furbiprofen, ibuprofen and carprofen. The effects of the mobile phase composition, concentration of HP-beta-CD and column temperature on retention and enantioselective separation were investigated. With 2-APA NSAIDs as acidic analytes, the retention times and resolutions of the enantiomers were strongly related to the pH of the mobile phase. In addition, both the concentration of HP-beta-CD and temperature had a great effect on retention time, but only a slight or almost no effect on resolutions of the analytes. Enantioseparations were achieved on a Shimpack CLC-ODS (150 x 4.6 mm i.d., 5 microm) column. The mobile phase was a mixture of methanol and phosphate buffer (pH 4.0-5.5, 20 mM) containing 25 mM HP-beta-CD. This method was flexible, simple and economically advantageous over the use of chiral stationary phase, and was successfully applied to the enantioselective determination of the racemic 2-APA NSAIDs in an enantioselective skin permeation study.

Sol-gel coated polydimethylsiloxane/beta-cyclodextrin as novel stationary phase for stir bar sorptive extraction and its application to analysis of estrogens and bisphenol A.

PubMed

Hu, Yuling; Zheng, Yanjie; Zhu, Fei; Li, Gongke

2007-04-27

A sol-gel technique was used for the preparation of a stir bar coated with a composite composed of polydimethysiloxane and beta-cyclodextrin (PDMS/beta-CD). The sol-gel mechanism during coating procedure was discussed and successful binding of beta-CD to the sol-gel network was confirmed by the IR spectra. Scanning electron micrographs of the stir bars revealed a homogeneous surface with a film thickness of 30-150 microm attributing to different coating times. Good thermal stability and solvent-resistance of the stir bar were found thanks to chemical binding formed between the stationary phase and the glass substrate. The PDMS/beta-CD coated stir bar was proved to have better selectivity to polar compounds compared to the PDMS coated stir bar, and higher extraction capacity compared to the corresponding PDMS/beta-CD coated fiber. Methods for the determinations of estrogens in environmental water, bisphenol A in drinking water and in leachate of one-off dishware by the PDMS/beta-CD coated stir bar coupled with high-performance liquid chromatography (HPLC) were developed. The limits of detection were within the range of 0.04-0.11 microg l(-1) for estrogens using UV detection and 8 ngl(-1) for bisphenol A using fluorescence detection. Reproducibility with RSD less than 9.7% for extractions of real water samples at microg l(-1) or ngl(-1) level was obtained.

Clinical Significance of Retinoic Acid Receptor Beta Promoter Methylation in Prostate Cancer: A Meta-Analysis.

PubMed

Dou, MengMeng; Zhou, XueLiang; Fan, ZhiRui; Ding, XianFei; Li, LiFeng; Wang, ShuLing; Xue, Wenhua; Wang, Hui; Suo, Zhenhe; Deng, XiaoMing

2018-01-01

Retinoic acid receptor beta (RAR beta) is a retinoic acid receptor gene that has been shown to play key roles during multiple cancer processes, including cell proliferation, apoptosis, migration and invasion. Numerous studies have found that methylation of the RAR beta promoter contributed to the occurrence and development of malignant tumors. However, the connection between RAR beta promoter methylation and prostate cancer (PCa) remains unknown. This meta-analysis evaluated the clinical significance of RAR beta promoter methylation in PCa. We searched all published records relevant to RAR beta and PCa in a series of databases, including PubMed, Embase, Cochrane Library, ISI Web of Science and CNKI. The rates of RAR beta promoter methylation in the PCa and control groups (including benign prostatic hyperplasia and normal prostate tissues) were summarized. In addition, we evaluated the source region of available samples and the methods used to detect methylation. To compare the incidence and variation in RAR beta promoter methylation in PCa and non-PCa tissues, the odds ratio (OR) and 95% confidence interval (CI) were calculated accordingly. All the data were analyzed with the statistical software STATA 12.0. Based on the inclusion and exclusion criteria, 15 articles assessing 1,339 samples were further analyzed. These data showed that the RAR beta promoter methylation rates in PCa tissues were significantly higher than the rates in the non-PCa group (OR=21.65, 95% CI: 9.27-50.57). Subgroup analysis according to the source region of samples showed that heterogeneity in Asia was small (I2=0.0%, P=0.430). Additional subgroup analysis based on the method used to detect RAR beta promoter methylation showed that the heterogeneity detected by MSP (methylation-specific PCR) was relatively small (I2=11.3%, P=0.343). Although studies reported different rates for RAR beta promoter methylation in PCa tissues, the total analysis demonstrated that RAR beta promoter methylation may be correlated with PCa carcinogenesis and that the RAR beta gene is particularly susceptible. Additional studies with sufficient data are essential to further evaluate the clinical features and prognostic utility of RAR beta promoter methylation in PCa. © 2018 The Author(s). Published by S. Karger AG, Basel.

Preparation of acryloyl β-cyclodextrin-silica hybrid monolithic column and its application in pipette tip solid-phase extraction and HPLC analysis of methyl parathion and fenthion.

PubMed

Chen, Ling; Dang, Xueping; Ai, Youhong; Chen, Huaixia

2018-05-07

An acryloyl β-cyclodextrin-silica hybrid monolithic column for pipette tip solid-phase extraction and high-performance liquid chromatography determination of methyl parathion and fenthion have been prepared through a sol-gel polymerization method. The synthesis conditions, including the volume of cross-linker and the ratio of inorganic solution to organic solution, were optimized. The prepared monolithic column was characterized by thermogravimetric analysis, scanning electron microscopy and Fourier transform infrared spectroscopy. The eluent type, volume and flow rate, sample volume, flow rate, acidity and ionic strength were optimized in detail. Under the optimized conditions, a simple and sensitive pipette tip solid-phase extraction with high-performance liquid chromatography method was developed for the determination of methyl parathion and fenthion in lettuce. The method yielded a linear calibration curve in the concentration ranges of 15-400 μg/kg for methyl parathion and 20-400 μg/kg for fenthion with correlation coefficients of above 0.9957. The limits of detection were 4.5 μg/kg for methyl parathion and 6.0 μg/kg for fenthion, respectively. The recoveries of methyl parathion and fenthion spiked in lettuce ranged from 96.0 to 104.2% with relative standard deviations less than 8.4%. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Influence of chirality on vibrational and relaxational properties of (S)- and (R,S)-ibuprofen/methyl-β-cyclodextrin inclusion complexes: an INS and QENS study.

PubMed

Crupi, Vincenza; Guella, Graziano; Longeville, Stéphane; Majolino, Domenico; Mancini, Ines; Paciaroni, Alessandro; Rossi, Barbara; Venuti, Valentina

2013-10-03

In this paper, we analyze the internal picosecond dynamics of enantiomeric ((S)-) and racemic ((R,S)-) ibuprofen (IBP), when forming inclusion complexes, in solid state, with methyl-β-cyclodextrin (Me-β-CD), by inelastic and quasi elastic neutron scattering. The study was aimed at understanding, by the analysis of the vibrational and relaxational properties of the inclusion complexes also with respect to the single components, if and how the differences in the structural properties of the hydrogen bond (HB) network of (S)- and (R,S)-IBP can have influence on the complexation process triggered by "host-guest" interactions, whose detailed knowledge is retained as a prerequisite for enantiodiscrimination. From the results, a similar complexation mechanism for (S)- and (R,S)-IBP is argued, with a preferred penetration mode involving the isopropyl group of IBP.

Prolonged absorption of antimony(V) by the oral route from non-inclusion meglumine antimoniate-beta-cyclodextrin conjugates.

PubMed

Ribeiro, Raul R; Ferreira, Weverson A; Martins, Patricia S; Neto, Rubens L M; Rocha, Olguita G F; Le Moyec, Laurence; Demicheli, Cynthia; Frézard, Frédéric

2010-03-01

The orally active composition comprising meglumine antimoniate (MA) and beta-cyclodextrin (beta-CD) differs markedly from conventional drug-CD complexes, since it combines a water-soluble drug and a hydrophilic CD. In order to obtain insights into the mechanism(s) responsible for the improved oral delivery of the drug, physicochemical and pharmacokinetic studies were carried out. The composition investigated here was prepared at a 7:1 antimony(Sb)/beta-CD molar ratio, a condition that improves its solubility in water and allows the oral administration of a high dose of Sb in large animals. It was characterized by circular dichroism, (1)H-NMR, ESI-MS and photon correlation spectroscopy. Pharmacokinetic data were obtained in Beagle dogs after oral administration of the composition at 100 mg Sb/kg. (1)H-NMR and ESI-MS data supported the formation of non-inclusion complexes between MA and beta-CD. Sub-micron assemblies were also evidenced that slowly dissociate and presumably release the MA drug, upon reconstitution of the composition in water. Pharmacokinetic studies of MA and MA/beta-CD in dogs showed a prolongation of the serum mean residence time of Sb from 4.1 to 6.8 h, upon complexation of MA with beta-CD. Evidence was also obtained that Sb remains essentially under the form of pentavalent Sb-meglumine complex, following gastro-intestinal absorption from the MA/beta-CD composition. In conclusion, the present data support the model that the sustained drug release property of 7:1 MA/beta-CD composition resulted in the prolongation of MA absorption by the oral route and, consequently, in the increase of the drug mean residence time in serum. Copyright (c) 2009 John Wiley & Sons, Ltd.

Identification and quantification of metabolites common to 17alpha-methyltestosterone and mestanolone in horse urine.

PubMed

Yamada, Masayuki; Aramaki, Sugako; Okayasu, Toshimasa; Hosoe, Tomoo; Kurosawa, Masahiko; Kijima-Suda, Isao; Saito, Koichi; Nakazawa, Hiroyuki

2007-09-21

Anabolic steroids with the 17alpha-methyl,17beta-hydroxyl group, which were developed as oral formulations for therapeutic purposes, have been abused in the field of human sports. These anabolic steroids are also used to enhance racing performance in racehorses. In humans, structurally related 17alpha-methyltestosterone (MTS) and mestanolone (MSL), which are anabolic steroids with the 17alpha-methyl,17beta-hydroxyl group, have metabolites in common. The purpose of this study was to determine metabolites common to these two steroids in horses, which may serve as readily available screening targets for the doping test of these steroids in racehorses. Urine sample collected after administering MTS and MSL to horses was treated to obtain unconjugated steroid, glucuronide, and sulfate fractions. The fractions were subjected to gas chromatography/mass spectrometry (GC/MS), and 17alpha-methyl-5alpha-androstan-3beta,17beta-diol, 17alpha-hydroxymethyl-5alpha-androstan-3beta,17beta-diol, 17alpha-methyl-5alpha-androstan-3beta,16beta,17beta-triol, and 17alpha-methyl-5alpha-androstan-3beta,16alpha,17beta-triol were detected as the common metabolites by comparison with synthesized reference standards. The urinary concentrations of these metabolites after dosing were determined by GC/MS. 17Alpha-methyl-5alpha-androstan-3beta,16beta,17beta-triol was mainly detected in the sulfate fractions of urine samples after administration. This compound was consistently detected for the longest time in the urine samples after dosing with both steroids. The results suggest that 17alpha-methyl-5alpha-androstan-3beta,16beta,17beta-triol is a very useful screening target for the doping test of MTS and MSL in racehorses.

Molecular Modeling and Physicochemical Properties of Supramolecular Complexes of Limonene with α- and β-Cyclodextrins.

PubMed

Dos Passos Menezes, Paula; Dos Santos, Polliana Barbosa Pereira; Dória, Grace Anne Azevedo; de Sousa, Bruna Maria Hipólito; Serafini, Mairim Russo; Nunes, Paula Santos; Quintans-Júnior, Lucindo José; de Matos, Iara Lisboa; Alves, Péricles Barreto; Bezerra, Daniel Pereira; Mendonça Júnior, Francisco Jaime Bezerra; da Silva, Gabriel Francisco; de Aquino, Thiago Mendonça; de Souza Bento, Edson; Scotti, Marcus Tullius; Scotti, Luciana; de Souza Araujo, Adriano Antunes

2017-02-01

This study evaluated three different methods for the formation of an inclusion complex between alpha- and beta-cyclodextrin (α- and β-CD) and limonene (LIM) with the goal of improving the physicochemical properties of limonene. The study samples were prepared through physical mixing (PM), paste complexation (PC), and slurry complexation (SC) methods in the molar ratio of 1:1 (cyclodextrin:limonene). The complexes prepared were evaluated with thermogravimetry/derivate thermogravimetry, infrared spectroscopy, X-ray diffraction, complexation efficiency through gas chromatography/mass spectrometry analyses, molecular modeling, and nuclear magnetic resonance. The results showed that the physical mixing procedure did not produce complexation, but the paste and slurry methods produced inclusion complexes, which demonstrated interactions outside of the cavity of the CDs. However, the paste obtained with β-cyclodextrin did not demonstrate complexation in the gas chromatographic technique because, after extraction, most of the limonene was either surface-adsorbed by β-cyclodextrin or volatilized during the procedure. We conclude that paste complexation and slurry complexation are effective and economic methods to improve the physicochemical character of limonene and could have important applications in pharmacological activities in terms of an increase in solubility.

Characterization of aspartame-cyclodextrin complexation.

PubMed

Sohajda, Tamás; Béni, Szabolcs; Varga, Erzsébet; Iványi, Róbert; Rácz, Akos; Szente, Lajos; Noszál, Béla

2009-12-05

The inclusion complex formation of aspartame (guest) and various cyclodextrins (host) were examined using 1H NMR titration and capillary electrophoresis. Initially the protonation constants of aspartame were determined by NMR-pH titration with in situ pH measurement to yield log K1=7.83 and log K2=2.96. Based on these values the stability of the complexes formed by aspartame and 21 different cyclodextrins (CDs) were studied at pH 2.5, pH 5.2 and pH 9.0 values where aspartame exists predominantly in monocationic, zwitterionic and monoanionic form, respectively. The host cyclodextrin derivatives differed in various sidechains, degree of substitution, charge and purity so that the effect of these properties could be examined systematically. Concerning size, the seven-membered beta-cyclodextrin and its derivatives have been found to be the most suitable host molecules for complexation. Highest stability was observed for the acetylated derivative with a degree of substitution of 7. The purity of the CD enhanced the complexation while the degree of substitution did not provide obvious consequences. Finally, geometric aspects of the inclusion complex were assessed by 2D ROESY NMR and molecular modelling which proved that the guest's aromatic ring enters the wider end of the host cavity.

Rotavirus RRV associates with lipid membrane microdomains during cell entry.

PubMed

Isa, Pavel; Realpe, Mauricio; Romero, Pedro; López, Susana; Arias, Carlos F

2004-05-01

Rotavirus cell entry is a multistep process, not completely understood, which requires at least four interactions between the virus and cell surface molecules. In this work, we investigated the role of the sphingolipid- and cholesterol-enriched lipid microdomains (rafts) in the entry of rotavirus strain RRV to MA104 cells. We found that ganglioside GM1, integrin subunits alpha2 and beta3, and the heat shock cognate protein 70 (hsc70), all of which have been implicated as rotavirus receptors, are associated with TX-100 and Lubrol WX detergent-resistant membranes (DRMs). Integrin subunits alpha2 and beta3 were found to be particularly enriched in DRMs resistant to lysis by Lubrol WX. When purified RRV particles were incubated with cells at 4 degrees C, about 10% of the total infectious virus was found associated with DRMs, and the DRM-associated virus increased to 37% in Lubrol-resistant membrane domains after 60-min incubation at 37 degrees C. The virus was excluded from DRMs if the cells were treated with methyl-beta-cyclodextrin (MbetaCD). Immunoblot analysis of the viral proteins showed that the virus surface proteins became enriched in DRMs upon incubation at 37 degrees C, being almost exclusively localized in Lubrol-resistant DRMs after 60 min. These data suggest that detergent-resistant membrane domains play an important role in the cell entry of rotaviruses, which could provide a platform to facilitate the efficient interaction of the rotavirus receptors with the virus particle.

Unimolecular Micelles of Amphiphilic Cyclodextrin-Core Star-Like Copolymers with Covalent pH-Responsive Linkage of Anticancer Prodrugs.

PubMed

Jia, Tao; Huang, Shuo; Yang, Cangjie; Wang, Mingfeng

2017-08-07

Multifunctional stable and stimuli-responsive drug delivery systems are important for efficient cancer treatment due to their advantages such as enhanced cancer-targeting efficiency, improved pharmacokinetics, minimized drug leaching, and reduced undesirable side effects. Here we report a robust and pH-responsive anticancer drug delivery system based on unimolecular micelles of star-like amphiphilic copolymers. The polymers (denoted as CPOFs) were facilely synthesized via one-step atom transfer radical polymerization of functionalizable benzoaldehyde and hydrophilic poly[(oligo ethylene glycol) methyl ether methacrylate] as comonomers from the core of heptakis [2,3,6-tri-o-(2-bromo-2-methyl propionyl]-β-cyclodextrin as the initiator. Doxorubicin (DOX) as an anticancer drug was covalently linked to the benzoaldehyde groups of CPOFs through pH-sensitive Schiff-base bonds. The DOX-conjugated polymers, denoted as CPOF-DOX, formed robust unimolecular micelles with an average diameter of 18 nm in aqueous media. More importantly, these unimolecular micelles showed higher drug loading capacity and more controllable drug release characteristics, compared to our previous unimolecular micelles of β-cyclodextrin-poly(lactic acid)-b-poly[(oligo ethylene glycol) methyl ether methacrylates] that physically encapsulated DOX via hydrophobic interaction. Moreover, the CPOF-DOX unimolecular micelles could be internalized by human cervical cancer HeLa cells in a stepwise way and showed less cytotoxicity compared to carrier-free DOX. We foresee that CPOF-DOX would provide a promising robust and controllable anticancer drug delivery system for future animal study and clinical trials for cancer treatment.

Induction of mitophagy-mediated antitumor activity with folate-appended methyl-β-cyclodextrin.

PubMed

Kameyama, Kazuhisa; Motoyama, Keiichi; Tanaka, Nao; Yamashita, Yuki; Higashi, Taishi; Arima, Hidetoshi

2017-01-01

Mitophagy is the specific autophagic elimination system of mitochondria, which regulates cellular survival via the removal of damaged mitochondria. Recently, we revealed that folate-appended methyl-β-cyclodextrin (FA-M-β-CyD) provides selective antitumor activity in folate receptor-α (FR-α)-expressing cells by the induction of autophagy. In this study, to gain insight into the detailed mechanism of this antitumor activity, we focused on the induction of mitophagy by the treatment of FR-α-expressing tumor cells with FA-M-β-CyD. In contrast to methyl-β-cyclodextrin, FA-M-β-CyD entered KB cells, human epithelial cells from a fatal cervical carcinoma (FR-α (+)) through FR-α-mediated endocytosis. The transmembrane potential of isolated mitochondria after treatment with FA-M-β-CyD was significantly elevated. In addition, FA-M-β-CyD lowered adenosine triphosphate (ATP) production and promoted reactive oxygen species production in KB cells (FR-α (+)). Importantly, FA-M-β-CyD enhanced light chain 3 (LC3) conversion (LC3-I to LC3-II) in KB cells (FR-α (+)) and induced PTEN-induced putative kinase 1 (PINK1) protein expression, which is involved in the induction of mitophagy. Furthermore, FA-M-β-CyD had potent antitumor activity in BALB/c nu/nu mice xenografted with KB cells (FR-α (+)) without any significant side effects. Taken together, these findings demonstrate that the autophagic cell death elicited by FA-M-β-CyD could be associated with mitophagy induced by an impaired mitochondrial function.

Enantiomeric composition of (3R)-(-)- and (3S)-(+)-linalool in various essential oils of Indian origin by enantioselective capillary gas chromatography-flame ionization and mass spectrometry detection methods.

PubMed

Chanotiya, Chandan S; Yadav, Anju

2009-04-01

Enantiomeric ratios of linalool have been determined in various authentic essential oils of Indian origin using 10% heptakis(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-beta-cyclodextrin as a chiral stationary phase. A complete enantiomeric excess (ee) for (3S)-(+)-linalool was characteristic of Lippia alba and Cinnamomum tamala leaf oils while less than 90% excess was noticed in Zanthoxylum armatum leaf, Zingiber roseum root/rhizome and Citrus sinensis leaf oils. On the contrary, an enantiomeric excess of (3R)-(-)-linalool characterizes essential oils of basil (100% for Ocimum basilicum) and bergamot mint (72 to 75% for Mentha citrata). Notably, some essential oils containing both enantiomers in equal ratios or in racemic forms are rose, geranium, lemongrass and Origanum. The enantiomeric composition studies are discussed as indicators of origin authenticity and quality of essential oil of Indian origin.

Comparison of chiral electrophoretic separation methods for phenethylamines and application on impurity analysis.

PubMed

Borst, Claudia; Holzgrabe, Ulrike

2010-12-15

A chiral microemulsion electrokinetic chromatography method has been developed for the separation of the enantiomers of the phenethylamines ephedrine, N-methylephedrine, norephedrine, pseudoephedrine, adrenaline (epinephrine), 2-amino-1-phenylethanol, diethylnorephedrine, and 2-(dibutylamino)-1-phenyl-1-propanol, respectively. The separations were achieved using an oil-in-water microemulsion consisting of the oil-component ethyl acetate, the surfactant sodium dodecylsulfate, the cosurfactant 1-butanol, the organic modifier propan-2-ol and 20mM phosphate buffer pH 2.5 as aqueous phase. For enantioseparation sulfated beta-cyclodextrin was added. The method was compared to an already described CZE method, which made use of heptakis(2,3-di-O-diacetyl-6-O-sulfo)-beta-cyclodextrin (HDAS) as chiral selector. Additionally, the developed method was successfully applied to the related substances analysis of noradrenaline, adrenaline, dipivefrine, ephedrine and pseudoephedrine monographed in the European Pharmacopoeia 6. Copyright 2010 Elsevier B.V. All rights reserved.

Cleaning efficacy of hydroxypropyl-beta-cyclodextrin for biofouling reduction on reverse osmosis membranes.

PubMed

Alayande, Abayomi Babatunde; Kim, Lan Hee; Kim, In S

2016-01-01

In this study, an environmentally friendly compound, hydroxypropyl-beta-cyclodextrin (HP-β-CD) was applied to clean reverse osmosis (RO) membranes fouled by microorganisms. The cleaning with HP-β-CD removed the biofilm and resulted in a flux recovery ratio (FRR) of 102%. As cleaning efficiency is sometimes difficult to determine using flux recovery data alone, attached bacterial cells and extracellular polymeric substances (EPS) were quantified after cleaning the biofouled membrane with HP-β-CD. Membrane surface characterization using scanning electron microscopy (SEM), attenuated total reflectance Fourier transform infrared (ATR-FTIR) and atomic force microscopy (AFM) confirmed the effectiveness of HP-β-CD in removal of biofilm from the RO membrane surface. Finally, a comparative study was performed to investigate the competitiveness of HP-β-CD with other known cleaning agents such as sodium dodecyl sulfate (SDS), ethylenediaminetetraacetic acid (EDTA), Tween 20, rhamnolipid, nisin, and surfactin. In all cases, HP-β-CD was superior.

Synthesis, self-assembly, and drug-loading capacity of well-defined cyclodextrin-centered drug-conjugated amphiphilic A(14)B(7) Miktoarm star copolymers based on poly(epsilon-caprolactone) and poly(ethylene glycol).

PubMed

Gou, Peng-Fei; Zhu, Wei-Pu; Shen, Zhi-Quan

2010-04-12

Novel drug-conjugated amphiphilic A(14)B(7) miktoarm star copolymers composed of 14 poly(epsilon-caprolactone) (PCL) arms and 7 poly(ethylene glycol) (PEG) arms with beta-cyclodextrin (beta-CD) as core moiety were synthesized by the combination of controlled ring-opening polymerization (CROP) and "click" chemistry. (1)H NMR, FT-IR, and SEC-MALLS analyses confirmed the well-defined A(14)B(7) miktoarm star architecture. These amphiphilic miktoarm star copolymers could self-assemble into multimorphological aggregates in aqueous solution, which were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Moreover, the drug-loading efficiency and drug-encapsulation efficiency of the drug-conjugated miktoarm star copolymers were higher than those of the corresponding non-drug-conjugated miktoarm star copolymers.

Kinetic study of the activation of banana juice enzymatic browning by the addition of maltosyl-beta-cyclodextrin.

PubMed

López-Nicolás, José M; Pérez-López, Antonio J; Carbonell-Barrachina, Angel; García-Carmona, Francisco

2007-11-14

In recent years, the use of cyclodextrins (CDs) as antibrowning agents in fruit juices has received growning attention. However, there has been no detailed study of the behavior of these molecules as substances, which can lead to the darkening of foods. In this paper, when the color of fresh banana juice was evaluated in the presence of different CDs, the evolution of several color parameters was the opposite of that observed in other fruit juices. Moreover, a kinetic model based on the complexation by CDs of the natural browning inhibitors present in banana is developed for the first time to clarify the enzymatic browning activation of banana juice. Finally, the apparent complexation constant between the natural polyphenoloxidase inhibitors present in banana juice and maltosyl-beta-CD was calculated (Kci = 27.026 +/- 0.212 mM (-1)).

Intestinal Permeability of β-Lapachone and Its Cyclodextrin Complexes and Physical Mixtures.

PubMed

Mangas-Sanjuan, Victor; Gutiérrez-Nieto, Jorge; Echezarreta-López, Magdalena; González-Álvarez, Isabel; González-Álvarez, Marta; Casabó, Vicente-Germán; Bermejo, Marival; Landin, Mariana

2016-12-01

β-Lapachone (βLAP) is a promising, poorly soluble, antitumoral drug. βLAP combination with cyclodextrins (CDs) improves its solubility and dissolution but there is not enough information about the impact of cyclodextrins on βLAP intestinal permeability. The objectives of this work were to characterize βLAP intestinal permeability and to elucidate cyclodextrins effect on the dissolution properties and on the intestinal permeability. The final goal was to evaluate CDs influence on the oral absorption of βLAP. Binary systems (physical mixtures and inclusion complexes) including βLAP and CDs (β-cyclodextrin: βCD, random-methyl-β-cyclodextrin: RMβCD and sulfobutylether-β-cyclodextrin: SBEβCD) have been prepared and analysed by differential scanning calorimetry. βLAP (and its combinations with CDs) absorption rate coefficients and effective permeability values have been determined in vitro in MDCK or MDCK-Mdr1 monolayers and in situ in rat by a closed loop perfusion technique. DSC results confirmed the formation of the inclusion complexes. βLAP-CDs inclusion complexes improve drug solubility and dissolution rate in comparison with physical mixtures. βLAP presented a high permeability value which can provide complete oral absorption. Its oral absorption is limited by its low solubility and dissolution rate. Cyclodextrin (both as physical mixtures and inclusion complexes) showed a positive effect on the intestinal permeability of βLAP. Complexation with CDs does not reduce βLAP intestinal permeability in spite of the potential negative effect of the reduction in free fraction of the drug. The use of RMβCD or SBEβCD inclusion complexes could benefit βLAP oral absorption by enhancing its solubility, dissolution rate and permeability.

Stable supersaturated aqueous solutions of silatecan 7-t-butyldimethylsilyl-10-hydroxycamptothecin via chemical conversion in the presence of a chemically modified beta-cyclodextrin.

PubMed

Xiang, Tian-Xiang; Anderson, Bradley D

2002-08-01

A method for obtaining clear supersaturated aqueous solutions for parenteral administration of the poorly soluble experimental anti-cancer drug silatecan 7-t-butyldimethylsilyl-10-hydroxycamptothecin (DB-67) has been developed. Equilibrium solubilities of DB-67 were determined in various solvents and pH values, and in the presence of chemically modified water-soluble beta-cyclodextrins. The stoichiometry and binding constants for complexes of the lactone form of DB-67 and its ring-opened carboxylate with sulfobutyl ether and 2-hydroxypropyl substituted beta-cyclodextrins (SBE-CD and HP-CD) were obtained by solubility and circular dichroism spectroscopy, respectively. Kinetics for the reversible ring-opening of DB-67 in aqueous solution and for lactone precipitation were determined by HPLC with UV detection. Solubilities of DB-67 lactone in various injectable solvent systems were found to be at least one order of magnitude below the target concentration (2 mg/ml). DB-67 forms inclusion complexes with SBE-CD and HP-CD but the solubilization attainable is substantially less than the target concentration. Slow addition of DB-67/ DMSO into 22.2% (w/v) SBE-CD failed to yield stable supersaturated solutions due to precipitation. Stable supersatured solutions were obtained, however, by mixing a concentrated alkaline aqueous solution of DB-67 carboxylate with an acidified 22.2% (w/v) SBE-CD solution. Ring-closure yielded supersaturated solutions that could be lyophilized and reconstituted to clear, stable, supersaturated solutions. The method developed provides an alternative to colloidal dispersions (e.g., liposomal suspensions, emulsions, etc.) for parenteral administration of lipophilic camptothecin analogs.

Sorption of benzimidazole anthelmintics to dissolved organic matter surrogates and sewage sludge.

PubMed

Kim, Hyo-Jung; Lee, Dong Soo; Kwon, Jung-Hwan

2010-06-01

The sorption coefficients of four rarely studied zwitterionic pharmaceuticals (benzimidazoles: fenbendazole, albendazole, thiabendazole and flubendazole) and four metabolites of fenbendazole to various dissolved organic matter surrogates (humic acid, sodium dodecyl sulfate micelle, hydroxypropyl-beta-cyclodextrin and liposomes made of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), and sewage sludge) were measured to extend the available sorption coefficients and eventually to evaluate their environmental fate in soil and water environment. For the entire range of dissolved organic matters, the more hydrophobic fenbendazole and albendazole had higher sorption coefficients than thiabendazole and flubendazole, indicating that the traditional hypothesis of hydrophobic interaction holds for zwitterionic benzimidazole anthelmintics. However, the sorption coefficients of a given benzimidazole to selected dissolved organic matters (DOMs) varied within an order of magnitude. The measured K(oc) values decreased in the order of fenbendazole, albendazole, thiabendazole and flubendazole for sewage sludge and hydroxypropyl-beta-cyclodextrin whereas the orders were different for the other DOM surrogates, implying the hydrophilic nature of sewage sludge. This was also supported by the (N+O)/C elemental ratio of the sewage sludge sample used in this study. The correlations between log K(oc) and log K(ow) were weak (r(2)=0.28-0.64) and the magnitude of the sorption coefficients to the hydrophilic organic matters (hydroxypropyl-beta-cyclodextrin and sewage sludge) were similar to or slightly smaller than those for the hydrophobic organic matters (humic acids and liposome). This suggests that specific hydrophilic interactions also play a significant role in the sorption of moderately hydrophobic benzimidazoles to organic matters. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Enhancement of selectivity and resolution in the enantioseparation of uncharged compounds using mixtures of oppositely charged cyclodextrins in capillary electrophoresis.

PubMed

Abushoffa, Adel M; Fillet, Marianne; Servais, Anne-Catherine; Hubert, Philippe; Crommen, Jacques

2003-01-01

The enantiomeric separation of some nonsteroidal anti-inflammatory drugs (NSAIDs) was investigated in capillary electrophoresis (CE) using dual systems with mixtures of charged cyclodextrin (CD) derivatives. A significant enhancement of selectivity and resolution could be achieved in the enantioseparation of these analytes in their uncharged form by the simultaneous addition of two oppositely charged CD derivatives to the background electrolyte. The combination of the single-isomer cationic CD, permethyl-6-monoamino-6-monodeoxy-beta-CD (PMMAbetaCD) and the single-isomer polyanionic CD, heptakis-6-sulfato-beta-cyclodextrin (HSbetaCD) in a pH 2.5 phosphoric acid-triethanolamine buffer, was designed and employed for the enantioseparation of profens. The improvement in selectivity and resolution can be attributed to the fact that the two CDs, which lead to independent and enantioselective complexation with the analyte enantiomers, have not only opposite effects on the electrophoretic mobility of these compounds but also opposite affinity patterns towards the enantiomers of these compounds. Binding constants for these enantiomers with each CD were determined using linear regression approach, in order to be able to predict the effect of the concentrations of the two CDs on enantiomeric selectivity and resolution in such dual systems.

Preparation of polydimethylsiloxane/beta-cyclodextrin/divinylbenzene coated "dumbbell-shaped" stir bar and its application to the analysis of polycyclic aromatic hydrocarbons and polycyclic aromatic sulfur heterocycles compounds in lake water and soil by high performance liquid chromatography.

PubMed

Yu, Chunhe; Yao, Zhimin; Hu, Bin

2009-05-08

A "dumbbell-shaped" stir bar was proposed to prevent the friction loss of coating during the stirring process, and thus prolonged the lifetime of stir bars. The effects of the coating components, including polydimethylsiloxane (PDMS), beta-cyclodextrin (beta-CD) and divinylbenzene (DVB) were investigated according to an orthogonal experimental design, using three polycyclic aromatic hydrocarbons (PAHs) and four polycyclic aromatic sulfur heterocycles (PASHs) as model analytes. Four kinds of stir bars coated with PDMS, PDMS/beta-CD, PDMS/DVB and PDMS/beta-CD/DVB were prepared and their extraction efficiencies for the target compounds were compared. It was demonstrated that PDMS/beta-CD/DVB-coated stir bar showed the best affinity to the studied compounds. The preparation reproducibility of PDMS/beta-CD/DVB-coated stir bar ranged from 3.2% to 15.2% (n = 6) in one batch, and 5.2% to 13.4% (n = 6) among batches. The "dumbbell-shaped" stir bar could be used for about 40 times, which were 10 extractions more than a normal stir bar. The prepared PDMS/beta-CD/DVB-coated "dumbbell-shaped" stir bar was used for stir bar sorptive extraction (SBSE) of PAHs and PASHs and the desorbed solution was introduced into HPLC-UV for subsequent analysis. The limits of detection of the proposed method for seven target analytes ranged from 0.007 to 0.103 microg L(-1), the relative standard deviations were in the range of 6.3-12.9% (n = 6, c = 40 microg L(-1)), and the enrichment factors were 19-86. The proposed method was successfully applied to the analysis of seven target analytes in lake water and soil samples.

Sustained inhibition of intimal thickening. In vitro and in vivo effects of polymeric beta-cyclodextrin sulfate.

PubMed Central

Bachinsky, W B; Barnathan, E S; Liu, H; Okada, S S; Kuo, A; Raghunath, P N; Muttreja, M; Caron, R J; Tomaszewski, J E; Golden, M A

1995-01-01

Intimal thickening after vascular injury may be modulated in part by heparin binding growth factors. We hypothesized that placement of a therapeutic polymer in the periadventitial space capable of tightly binding growth factors might alter the vascular response to injury. We first demonstrated that incubation of rat aortic smooth muscle cells with an insoluble, sulfated polymer of beta-cyclodextrin (P-CDS) was associated with a dose-dependent inhibition of proliferation induced by fetal calf serum, fibroblast growth factor-2 (FGF-2), platelet-derived growth factor BB, or epidermal growth factor. Preincubation studies of P-CDS with FGF-2 revealed a very rapid removal of mitogenic activity. Using radiolabeled FGF-2 (0.25 microg/ml), we observed a very rapid association rate (0.34 +/- 0.07 min-1, n=4) and a very slow dissociation rate (3.3 +/- 0.2 X 10(-7) min-1) at 37 degrees C, suggesting a high affinity interaction. Using both Transwell and linear under-agarose assays, we demonstrated a significant inhibition of random migration (chemokinesis) by P-CDS. Unsulfated polymeric beta-cyclodextrin (P-CD) had little if any of these effects, suggesting that the high negative charge density of P-CDS was important for the effects. Finally, rats undergoing carotid artery balloon injury were randomized to treatment with periadventitial P-CDS or no treatment, and were killed at 4 (n=20), 14 (n=59), and 88 d (n=14). Morphometric analysis demonstrated significant and sustained inhibition of intimal thickening in P-CDS-treated rats at 14 (P < 0.01) and 88 d (P < 0.05) using absolute intimal area or intima/media area ratios. No inhibition was seen in a group of rats treated with P-CD. In P-CDS-treated rats, bromodeoxyuridine labeling studies revealed fewer labeled smooth muscle cells in the intima at 14 d (P=0.01), while staining with Evans blue revealed enhanced late endothelial cell regrowth. Thus, periadventitially applied sulfated beta-cyclodextrin polymer, which can tightly bind heparin binding growth factors, inhibits intimal thickening in vivo in a sustained fashion without using an additional delivery system. These studies suggest that cellular processes mediated by heparin binding growth factors may be modulated by P-CDS. Images PMID:8675622

Determination of the glass transition temperature of cyclodextrin polymers.

PubMed

Tabary, Nicolas; Garcia-Fernandez, Maria Jose; Danède, Florence; Descamps, Marc; Martel, Bernard; Willart, Jean-François

2016-09-05

The aim of this work was to determine the main physical characteristics of β-cyclodextrin polymers, well known for improving complexation capacities and providing enhanced and sustained release of a large panel of drugs. Two polymers were investigated: a polymer of β-cyclodextrin (polyβ-CD) and a polymer of partially methylated (DS=0.57) β-cyclodextrin (polyMe-β-CD). The physical characterizations were performed by powder X-ray diffraction and differential scanning calorimetry. The results indicate that these polymers are amorphous and that their glass transition is located above the thermal degradation point of the materials preventing their direct observation and thus their full characterization. We could however estimate the virtual glass transition temperatures by mixing the polymers with different plasticizers (trehalose and mannitol) which decreases Tg sufficiently to make the glass transition observable. Extrapolation to zero plasticizer concentration then yield the following Tg values: Tg (polyMe-β-CD)=317°C±5°C and Tg (polyβ-CD)=418°C±6°C. Copyright © 2016 Elsevier Ltd. All rights reserved.

Extracellular chromone derivatives in cell cultures of Pimpinella anisum. Influence of elicitation with methyl jasmonate and 2β-methyl cyclodextrins.

PubMed

Soto-Argel, Camilo; Hidalgo, Diego; Palazon, Javier; Corchete, Purificación

2018-02-01

To explore the potentiality of undifferentiated Pimpinella anisum L. cell cultures for the production of secondary metabolites by means of elicitation. Two chromone compounds were secreted to the medium of undifferentiated cultures of P. anisum: 4-methoxyfuro[3,2-g]chromen-7-one, known as bergapten, which is constitutive to anise, and 5-hydroxy-7-methoxy-2-methylchromen-4-one, the rare chromone eugenin, not yet described in P. anisum. Caffeoyl quinic acid species were also identified in the biomass. Elicitation with methyl jasmonate enhanced chromone accumulation in the medium and stimulated phenolic acid metabolism in the biomass (11 mg caffeoyl quinic acids g -1 DW cells). The application of 2,6-dimethyl-β-cyclodextrins to cultures led to an intense accumulation of chromones, with nearly 10 mg l -1 bergapten and 150 mg l -1 eugenin being accumulated extracellularly after optimal elicitation conditions. The significant amounts of eugenin obtained in the anise cultures and the stability of production over long periods of time can be of interest for its biotechnological production and for future studies on biosynthesis regulation.

Egg Yolk and Glycerol Requirements for Freezing Boar Spermatozoa Treated with Methyl β-Cyclodextrin or Cholesterol-loaded Cyclodextrin

PubMed Central

BLANCH, Eva; TOMÁS, Cristina; HERNÁNDEZ, Marta; ROCA, Jordi; MARTÍNEZ, Emilio A.; VÁZQUEZ, Juan M.; MOCÉ, Eva

2014-01-01

Egg yolk (EY) and glycerol are common constituents of extenders used for sperm cryopreservation. It has been demonstrated that using cholesterol-loaded cyclodextrins (CLC) improves sperm cryosurvival in several species. However, standard freezing extenders might not be the most appropriate for CLC-treated sperm. This study evaluated the EY and glycerol requirements for freezing CLC-treated boar spermatozoa. Semen samples from 34 ejaculates coming from 4 boars were used. Each ejaculate was split into three aliquots: one was used untreated (control), and the other two were treated with 1 mg of CLC or methyl-β-cyclodextrin/120 × 106 sperm for 15 min at 22 C prior to cryopreservation. Our results indicated that reducing the concentration of EY was detrimental for sperm viability after thawing (31.57 ± 2 vs. 19.89% ± 2 for 20 and 10% EY, respectively; P <0.05), even in semen treated with CLC. On the other hand, it was observed that the traditional concentration of glycerol (3%) was not the appropriate for freezing CLC-treated sperm (61.10 ± 3 vs. 47.87% ± 3 viable sperm for control and CLC-treated sperm, respectively; P <0.05). Thus, CLC-treated sperm showed a higher tolerance to high glycerol concentrations (5%) in terms of sperm viability (59.19% ± 3) than non-treated sperm (45.58% ± 3; P<0.05). Therefore, it could be necessary to modify the freezing extenders for CLC-treated sperm. Nevertheless, additional studies will be needed to evaluate alternative cryoprotectants and to determine the effect of high glycerol concentrations on sperm functionality. PMID:24492655

Egg yolk and glycerol requirements for freezing boar spermatozoa treated with methyl β-cyclodextrin or cholesterol-loaded cyclodextrin.

PubMed

Blanch, Eva; Tomás, Cristina; Hernández, Marta; Roca, Jordi; Martínez, Emilio A; Vázquez, Juan M; Mocé, Eva

2014-04-24

Egg yolk (EY) and glycerol are common constituents of extenders used for sperm cryopreservation. It has been demonstrated that using cholesterol-loaded cyclodextrins (CLC) improves sperm cryosurvival in several species. However, standard freezing extenders might not be the most appropriate for CLC-treated sperm. This study evaluated the EY and glycerol requirements for freezing CLC-treated boar spermatozoa. Semen samples from 34 ejaculates coming from 4 boars were used. Each ejaculate was split into three aliquots: one was used untreated (control), and the other two were treated with 1 mg of CLC or methyl-β-cyclodextrin/120 × 10(6) sperm for 15 min at 22 C prior to cryopreservation. Our results indicated that reducing the concentration of EY was detrimental for sperm viability after thawing (31.57 ± 2 vs. 19.89% ± 2 for 20 and 10% EY, respectively; P <0.05), even in semen treated with CLC. On the other hand, it was observed that the traditional concentration of glycerol (3%) was not the appropriate for freezing CLC-treated sperm (61.10 ± 3 vs. 47.87% ± 3 viable sperm for control and CLC-treated sperm, respectively; P <0.05). Thus, CLC-treated sperm showed a higher tolerance to high glycerol concentrations (5%) in terms of sperm viability (59.19% ± 3) than non-treated sperm (45.58% ± 3; P<0.05). Therefore, it could be necessary to modify the freezing extenders for CLC-treated sperm. Nevertheless, additional studies will be needed to evaluate alternative cryoprotectants and to determine the effect of high glycerol concentrations on sperm functionality.

An Alginate/Cyclodextrin Spray Drying Matrix to Improve Shelf Life and Antioxidant Efficiency of a Blood Orange By-Product Extract Rich in Polyphenols: MMPs Inhibition and Antiglycation Activity in Dysmetabolic Diseases.

PubMed

Lauro, Maria Rosaria; Crascì, Lucia; Giannone, Virgilio; Ballistreri, Gabriele; Fabroni, Simona; Sansone, Francesca; Rapisarda, Paolo; Panico, Anna Maria; Puglisi, Giovanni

2017-01-01

Alginate and β -cyclodextrin were used to produce easily dosable and spray-dried microsystems of a dried blood orange extract with antidysmetabolic properties, obtained from a by-product fluid extract. The spray-dried applied conditions were able to obtain a concentrate dried extract without the loss of AOA and with TPC and TMA values of 35-40% higher than that of the starting material. They were also effective in producing microparticles with 80-100% of encapsulation efficiency. The 2% sodium alginate was capable of improving the extract shelf life , while the beta-cyclodextrin (1 : 1 molar ratio with dried extract) prolonged the extract antioxidant efficiency by 6 hours. The good inhibition effect of the dried extract on the AGE formation and the MMP-2 and MMP-9 activity is presumably due to a synergic effect exerted by both anthocyanin and bioflavonoid extract compounds and was improved by the use of alginate and cyclodextrin.

An Alginate/Cyclodextrin Spray Drying Matrix to Improve Shelf Life and Antioxidant Efficiency of a Blood Orange By-Product Extract Rich in Polyphenols: MMPs Inhibition and Antiglycation Activity in Dysmetabolic Diseases

PubMed Central

Giannone, Virgilio; Ballistreri, Gabriele; Fabroni, Simona; Rapisarda, Paolo; Panico, Anna Maria; Puglisi, Giovanni

2017-01-01

Alginate and β-cyclodextrin were used to produce easily dosable and spray-dried microsystems of a dried blood orange extract with antidysmetabolic properties, obtained from a by-product fluid extract. The spray-dried applied conditions were able to obtain a concentrate dried extract without the loss of AOA and with TPC and TMA values of 35–40% higher than that of the starting material. They were also effective in producing microparticles with 80–100% of encapsulation efficiency. The 2% sodium alginate was capable of improving the extract shelf life, while the beta-cyclodextrin (1 : 1 molar ratio with dried extract) prolonged the extract antioxidant efficiency by 6 hours. The good inhibition effect of the dried extract on the AGE formation and the MMP-2 and MMP-9 activity is presumably due to a synergic effect exerted by both anthocyanin and bioflavonoid extract compounds and was improved by the use of alginate and cyclodextrin. PMID:29230268

Solid microparticles based on chitosan or methyl-β-cyclodextrin: a first formulative approach to increase the nose-to-brain transport of deferoxamine mesylate

PubMed Central

Rassu, Giovanna; Soddu, Elena; Cossu, Massimo; Brundu, Antonio; Cerri, Guido; Marchetti, Nicola; Ferraro, Luca; Regan, Raymond F.; Giunchedi, Paolo; Gavini, Elisabetta; Dalpiaz, Alessandro

2015-01-01

We propose the formulation and characterization of solid microparticles as nasal drug delivery systems able to increase the nose-to-brain transport of deferoxamine mesylate (DFO), a neuroprotector unable to cross the blood brain barrier and inducing negative peripheral impacts. Spherical chitosan chloride and methyl-β-cyclodextrin microparticles loaded with DFO (DCH and MCD, respectively) were obtained by spray drying. Their volume-surface diameters ranged from 1.77 ± 0.06 μm (DCH) to 3.47 ± 0.05 μm (MCD); the aerodynamic diameters were about 1.1 μm and their drug content was about 30%. In comparison with DCH, MCD enhanced the in vitro DFO permeation across lipophilic membranes, similarly as shown by ex vivo permeation studies across porcine nasal mucosa. Moreover, MCD were able to promote the DFO permeation across monolayers of PC 12 cells (neuron like), but like DCH did not modify the DFO permeation pattern across Caco-2 monolayers (epithelial like). Nasal administration to rats of 200 μg DFO encapsulated in the microparticles resulted in its uptake into the cerebrospinal fluid (CSF) with peak values ranging from 3.83 ± 0.68 μg/mL (DCH) and 14.37 ± 1.69 μg/mL (MCD) 30 min after insufflation of microparticles. No drug CSF uptake was detected after nasal administration of a DFO water solution. The DFO systemic absolute bioavailabilities obtained by DCH and MCD nasal administration were 6% and 15%, respectively. Chitosan chloride and methyl-β-cyclodextrins appear therefore suitable to formulate solid microparticles able to promote the nose to brain uptake of DFO and to limit its systemic exposure. PMID:25620068

Bioadhesive tablets containing cyclodextrin complex of itraconazole for the treatment of vaginal candidiasis.

PubMed

Cevher, Erdal; Açma, Ayşe; Sinani, Genada; Aksu, Buket; Zloh, Mire; Mülazımoğlu, Lütfiye

2014-08-01

Itraconazole (ITR) is commonly used in the treatment of Candida infections. It has a nephrotoxic effect and low bioavailability in patients who suffer from renal insufficiency, and its poor solubility in water makes ITR largely unavailable. Cyclodextrins (CyDs) are used to form inclusion complexes with drugs to improve their aqueous solubility and to reduce their side effects. In this study, ITR was complexed with γ-cyclodextrin (γ-CyD), hydroxypropyl-β-cyclodextrin (HP-β-CyD), methyl-β-cyclodextrin (Met-β-CyD) and sulphobutyl ether-β-cyclodextrin (SBE7-β-CyD) to increase its water solubility and to reduce the side effects of the drug without decreasing antifungal activity. Complex formation between ITR and CyDs was evaluated using SEM, (1)H NMR and XRD studies. The antifungal activity of the complexes was analyzed on Candida albicans strains, and the susceptibility of the strains was found to be higher for the ITR-SBE7-β-CyD complex than for the complexes that were prepared with other CyDs. Vaginal bioadhesive sustained release tablet formulations were developed using the ITR-SBE7-β-CyD inclusion complex to increase the residence time of ITR in the vagina, thereby boosting the efficacy of the treatment. The swelling, matrix erosion and bioadhesion properties of formulations and the drug release rate of these tablets were analyzed, and the most therapeutically effective vaginal formulation was determined. Copyright © 2014 Elsevier B.V. All rights reserved.

Efficient synthesis of pure monotosylated beta-cyclodextrin and its dimers.

PubMed

Tripodo, Giuseppe; Wischke, Christian; Neffe, Axel T; Lendlein, Andreas

2013-11-15

6-O-Monotosyl-β-cyclodextrin (mono-Ts-βCD) is one of the most important intermediates in the production of substituted βCD. So far, performing the monotosylation reaction and, in particular, the purification steps was challenging, relied on toxic solvents, and resulted in long and expensive procedures at, importantly, low yields. Here, the reaction of cyclodextrin with p-toluenesulfonyl chloride in aqueous environment is described to obtain a highly pure mono-Ts-βCD, for which a single-step purification with a cation exchange resin was applied. With this synthetic route and purification, yields could be increased from typically <10-15% to 35%, and organic solvents could be avoided. As characterized by FTIR, mass spectrometry, elemental analysis, and NMR, mono-Ts-βCD was obtained with a molar purity of >98mol%. From mono-Ts-βCD, β-cyclodextrin dimers linked by ethylenediamine (bis-Et-βCD) were successfully prepared (yield 93%, purity 96mol%) in a one-step approach using an anion exchange resin to trap leaving groups that typically interfere in the reaction. This synthesis procedure with a direct collection of side-products may be a general strategy applicable for nucleophilic substitution of tosylated cyclodextrins. Copyright © 2013 Elsevier Ltd. All rights reserved.

Enhancement of ibuprofen dissolution via wet granulation with beta-cyclodextrin.

PubMed

Ghorab, M K; Adeyeye, M C

2001-08-01

The purpose was to investigate the effect of wet granulation with beta-cyclodextrin (betaCD) on the enhancement of ibuprofen (IBU) dissolution. The effect of the granulation variables on the physical properties as well as the dissolution of tablets prepared from these granules was also examined. Granulation was performed using three granulating solvents: water, ethanol (95 vol%), and isopropanol. Granules were either oven-dried for 2 h or air-dried for 3 days. The granules or respective physical mixtures were compressed into tablets. Powder X-ray diffraction showed that oven-dried granulation resulted in less amorphous entities thatfacilitated IBU-betaCD complexation in solution and enhanced the dissolution of the corresponding tablets compared to the physical mixture with or without oven drying. In contrast, air-dried granulation did not cause any differences in the X-ray diffraction pattern (crystallinity) or the dissolution compared to the physical mixture without drying. Isopropanol and water, as granulating solvents, enhanced the dissolution of the oven-dried batches more than ethanol. The Differential scanning calorimetry (DSC) and Thermogravimetric analysis (TGA) data showed that tablets prepared from oven-dried granules, but not air-dried granules, had lower AH values and percent loss in weight, respectively, than those prepared from the physical mixture as a result of the expulsion of the water molecules from the betaCD cavity and enhancement of the complexation in solution. These results showed that oven-dried granulation of IBU and betaCD provided faster IBU dissolution than the physical mixture; air-dried granulation did not substantially affect the dissolution of IBU.

Analysis of the phase solubility diagram of a phenacetin/competitor/beta-cyclodextrin ternary system, involving competitive inclusion complexation.

PubMed

Ono, N; Hirayama, F; Arima, H; Uekama, K

2001-01-01

The competitive inclusion complexations in the ternary phenacetin/competitors/beta-cyclodextrin (beta-CyD) systems were investigated by the solubility method, where m-bromobenzoic acid (m-BBA) and o-toluic acid (o-TA) were used as competitors. The solubility changes of the drug and competitors as a function of beta-CyD concentration in the ternary systems were formulated using their stability constants and intrinsic solubilities. The decrease in solubility of phenacetin by the addition of competitors could be quantitatively simulated by the formulation, when both drug and competitor give A(L) type solubility diagrams. On the other hand, when one of the guests gives a B(S) type solubility diagram, its solubility change was clearly reflected in that of the another guest, i.e., phenacetin gave an A(L) type solubility diagram in the binary phenacetin/beta-CyD system and o-TA gave a B(S) type diagram in the binary o-TA/beta-CyD system, but in the ternary phenacetin/o-TA/beta-CyD system, a new plateau region appeared in the original A(L) type diagram of phenacetin. This was explained by the solubilization theory of Higuchi and Connors. The solubility analysis of the ternary drug/competitor/CyD systems may be particularly useful for determination of the stability constant of a drug whose physicochemical and spectroscopic analyses are difficult, because they can be calculated by monitoring the solubility change of a competitor, without monitoring that of a drug. Furthermore, the present results suggest that attention should be paid to the type of the phase solubility diagram, as well as the magnitude of the stability constant and the solubility of the complex, for a rational formulation design of CyD complexes.

[Preparation of coated tablets of glycyrrhetic acid-HP-beta-cyclodextrin tablets for colon-specific release].

PubMed

Cui, Qi-Hua; Cui, Jing-Hao; Zhang, Jin-Jin

2008-10-01

To prepare coated tablets of glycyrrhetinic acid and hydroxypropyl-beta-cyclodextrin (GTA-HP-beta-CYD) inclusion complex tablets for colon-specific release. In order to improve the solubility of GTA, the GTA-HP-beta-CYD inclusion complex was prepared by ultrasonic-lyophilization technique and its formation were characterized by X-ray powder diffraction profiles and infrared spectrometry. The effects of inclusion condition on the inclusion efficiency and stability coefficient of inclusion complex were investigated, respectively. After prepared GTA-HP-beta-CYD tablets by powder direct compression, the pH dependant polymer Eudragit III and/or mixed with Eudragit II were used for further coating materials in fluid-bed coater. The influences of coating weight on the GTA release in different pH conditions were evaluated to establish the method for prepering colon specific delivery tablets with pulsed release properties. The formation of inclusion complexes were proved by X-ray powder diffraction profile and phase solubility curve. The effect of pH value of solvent was played critical role on the preparation of GTA- HP-beta-CYD inclusion complex. And the inclusion efficiency of GTA was 9. 3% and the solubility was increased to 54. 6 times at optimized method. The Eudragit III coated GTA- HP-beta-CYD tablets with coating weight 10% and 16% were showed pH dependant colon specific release profiles with slow release rate. The release profile of tablets coated with the mixture of Eudragit II and Eudragit III (1:2) were indicated typical pH dependant colon specific and pulsed release properties while the coating weight was 17%. The preliminary method for preparation of colon specific release tablets containing glycyrrhetinic acid with improved solubility was established for further in vivo therapeutic experiment.

Remediation of organochlorine pesticides (OCPs) contaminated site by successive methyl-β-cyclodextrin (MCD) and sunflower oil enhanced soil washing - Portulaca oleracea L. cultivation.

PubMed

Ye, Mao; Sun, Mingming; Hu, Feng; Kengara, Fredrick Orori; Jiang, Xin; Luo, Yongming; Yang, Xinlun

2014-06-01

An innovative ex situ soil washing technology was developed in this study to remediate organochlorine pesticides (OCPs)-contaminated site. Elevated temperature (50 °C) combined with ultrasonication (35 kHz, 30 min) at 25 g L(-1) methyl-β-cyclodextrin and 100 mL L(-1) sunflower oil were effective in extracting OCPs from the soil. After four successive washing cycles, the removal efficiency for total OCPs, DDTs, endosulfans, 1,2,3,4,5,6-hexachlorocyclohexanes, heptachlors, and chlordanes were all about 99%. The 4th washed soil with 3 months cultivation of Portulaca oleracea L. and nutrient addition significantly increase (p<0.05) the number, biomass carbon, nitrogen, and functioning diversity of soil microorganisms. This implied that the microbiological functioning of the soil was at least partially restored. This combined cleanup strategy proved to be effective and environmental friendly. Copyright © 2014 Elsevier Ltd. All rights reserved.

Improvement of dissolution behavior of poorly water soluble drugs by biodegradable polymeric submicron carriers containing sparingly methylated β-cyclodextrin.

PubMed

Singhavi, Dilesh J; Khan, Shagufta; Yeole, Pramod G

2013-04-01

The objective of this study was to develop submicron carriers of two drugs that are practically insoluble in water, i.e. meloxicam and aceclofenac, to improve their dissolution behavior. The phase solubility of the drugs was studied using different concentrations of sparingly methylated β-cyclodextrin, Kleptose(®) Crysmeβ (Crysmeb), in the presence and absence of 0.2 % w/v water-soluble chitosan. Drug-loaded submicron particles (SMPs) were prepared using chitosan chlorhydrate and Crysmeb by the ionotropic gelation method. The SMPs were characterized in terms of powder X-ray diffraction, Fourier transforms infrared spectroscopy, size determination, process yield, drug loading, encapsulation efficiency, surface morphology and in vitro release. The drug loading in the SMPs was enhanced in the presence of Crysmeb. The in vitro drug release was found to be enhanced with SMPs prepared using higher concentrations of Crysmeb. These results indicate that SMPs formed from chitosan chlorhydrate and Crysmeb are promising submicron carriers for enhancing the dissolution of meloxicam and aceclofenac.

Host-guest interaction induced supramolecular amphiphilic star architecture and uniform nanovesicle formation for anticancer drug delivery

NASA Astrophysics Data System (ADS)

Zhu, Jing-Ling; Liu, Kerh Li; Wen, Yuting; Song, Xia; Li, Jun

2016-01-01

A star polymer of poly[(R,S)-3-hydroxybutyrate] (PHB) with adamantyl end-terminals extended from an α-cyclodextrin (α-CD) core is designed. It subsequently self-assembles to form controllable and uniform nanovesicles induced by host-guest interactions between heptakis(2,6-di-O-methyl)-β-CD and the adamantyl ends. The nanovesicles are suitable for loading and intracellular delivery of the anticancer drug doxorubicin.A star polymer of poly[(R,S)-3-hydroxybutyrate] (PHB) with adamantyl end-terminals extended from an α-cyclodextrin (α-CD) core is designed. It subsequently self-assembles to form controllable and uniform nanovesicles induced by host-guest interactions between heptakis(2,6-di-O-methyl)-β-CD and the adamantyl ends. The nanovesicles are suitable for loading and intracellular delivery of the anticancer drug doxorubicin. Electronic supplementary information (ESI) available: Polymer synthesis, characterization, preparation of drug-loaded nanovesicles, intracellular drug release and cytotoxicity assays, TEM and DLS measurements. See DOI: 10.1039/c5nr06744h

Cholesterol-dependent balance between evoked and spontaneous synaptic vesicle recycling

PubMed Central

Wasser, Catherine R; Ertunc, Mert; Liu, Xinran; Kavalali, Ege T

2007-01-01

Cholesterol is a prominent component of nerve terminals. To examine cholesterol's role in central neurotransmission, we treated hippocampal cultures with methyl-β-cyclodextrin, which reversibly binds cholesterol, or mevastatin, an inhibitor of cholesterol biosynthesis, to deplete cholesterol. We also used hippocampal cultures from Niemann-Pick type C1-deficient mice defective in intracellular cholesterol trafficking. These conditions revealed an augmentation in spontaneous neurotransmission detected electrically and an increase in spontaneous vesicle endocytosis judged by horseradish peroxidase uptake after cholesterol depletion by methyl-β-cyclodextrin. In contrast, responses evoked by action potentials and hypertonicity were severely impaired after the same treatments. The increase in spontaneous vesicle recycling and the decrease in evoked neurotransmission were reversible upon cholesterol addition. Cholesterol removal did not impact on the low level of evoked neurotransmission seen in the absence of synaptic vesicle SNARE protein synaptobrevin-2 whereas the increase in spontaneous fusion remained. These results suggest that synaptic cholesterol balances evoked and spontaneous neurotransmission by hindering spontaneous synaptic vesicle turnover and sustaining evoked exo-endocytosis. PMID:17170046

Influence of wet granulation and lubrication on the powder and tableting properties of codried product of microcrystalline cellulose with beta-cyclodextrin.

PubMed

Wu, J; Ho, H; Sheu, M

2001-01-01

The individual influence of wet granulation and lubrication on the powder and tableting properties of codried product of microcrystalline cellulose (MCC) with beta-cyclodextrin (beta-CD) was examined in this study. Avicel PH 101 and 301 were included for comparison. The codried product, Avicel PH 101 and 301 were granulated with water, and the granules were milled to retain three different size fractions: 37-60 microm, 60-150 microm, and 150-420 microm. The original Avicels and codried product were lubricated with magnesium stearate in three different percentages (0.2, 0.5, and 1.0%). The results showed that the powder flowability and disintegration of codried product and Avicels were significantly improved after wet granulation. However, the compactibility of codried product and Avicels decreased with increasing particle size. Nevertheless, the compactibility of the codried excipient after granulation was still better than the non-granulated Avicel PH 101 and 301. On the other hand, codried product and Avicels were sensitive to lubrication and resulted in decreasing compactibility and increasing disintegration. Because of the rounder shape of particles, the codried excipient was more sensitive to magnesium stearate and produced weaker tablets than did Avicels.

Analysis of optical purity and impurity of synthetic D-phenylalanine products using sulfated beta-cyclodextrin as chiral selector by reversed-polarity capillary electrophoresis.

PubMed

Zhao, Yan; Yang, Xing-Bin; Jiang, Ru; Sun, Xiao-Li; Li, Xiao-Ye; Liu, Wen-Min; Zhang, Sheng-Yong

2006-02-01

A new capillary electrophoresis (CE) method has been achieved for simultaneous separation and quantification of phenylalanine, N-acetylphenylalanine enantiomers, and prochiral N-acetylaminocinnamic acid, possibly co-existent in reaction systems or synthesized products of D-phenylalanine. The separation was carried out in an uncoated capillary under reversed-electrophoretic mode. Among the diverse charged cyclodextrins (CDs) examined, highly sulfated (HS)-beta-CD as the chiral selector exhibited the best enantioselectivity. The complete separation of the analytes was obtained under the optimum conditions of pH 2.5, 35 mM Tris buffer containing 4% HS-beta-CD, applied voltage -15 kV, and capillary temperature 25 degrees C. Furthermore, the proposed method was applied to the determination of optical purity and trace impurities in three batches of the asymmetric synthetic samples of D-phenylalanine, and satisfactory results were obtained. The determination recoveries of the samples were in the range of 97.8-103.8%, and precisions fell within 2.3-5.0% (RSD). The results demonstrate that this CE method is a useful, simple technique and is applicable to purity assays of D-phenylalanine. (c) 2005 Wiley-Liss, Inc.

Enhanced absorption of cyclosporin A by complexation with dimethyl-beta-cyclodextrin in bile duct-cannulated and -noncannulated rats.

PubMed

Miyake, K; Arima, H; Irie, T; Hirayama, F; Uekama, K

1999-01-01

The enhancing effects of dimethyl-beta-cyclodextrin (DM-beta-CyD) on the absorption of cyclosporin A (CsA) after oral administration to rats under bile duct-cannulated and -noncannulated conditions were investigated. The dissolution rate of CsA was markedly augmented by complexation with DM-beta-CyD. In a closed loop in situ study, DM-beta-CyD considerably increased the cumulative amounts of CsA in the mesenteric venous blood after injection of the aqueous CsA suspension into the small intestinal sac of rats. In addition, the cumulative amount ratio of M1, the dominant metabolite of CsA in rats, to CsA in the mesenteric venous blood for up to 40 min after the injection of the CsA-DM-beta-CyD suspension into the sac was lower than that of the CsA suspension alone. DM-beta-CyD inhibited the bioconversion of CsA in the small intestinal microsomes of rats. These results indicate that the bioconversion of CsA was abated by complexation with DM-beta-CyD. An in vivo study revealed that DM-beta-CyD increased the transfer of CsA to blood, not lymph, with low variability in the absorption after oral administration of the CsA suspension to rats. The variability of bioavailability of DM-beta-CyD complex was lower than that of Sandimmune, although the extent of bioavailability of DM-beta-CyD was only a little higher than that of Sandimmune. The bioavailability of CsA or its DM-beta-CyD complex was appreciably decreased by the cannulation of the bile duct of rats, and the extent of the lowering in the bioavailability in the presence of DM-beta-CyD was much less serious than that of CsA alone. The present results suggest that DM-beta-CyD is particularly useful in designing oral preparations of CsA with an enhanced bioavailability and a reduced variability in absorption.

Development and In Vitro Evaluation of an Innovative “Dietary Flavonoid Supplement” on Osteoarthritis Process

PubMed Central

Panico, Anna Maria; Puglisi, Giovanni

2017-01-01

The aim of this study was to evaluate the antidegenerative effect in osteoarthritis damage of eriocitrin alone and eriocitrin formulated as innovative “dietary flavonoid supplement.” A complexation between eriocitrin and hydroxypropyl β-cyclodextrin by solubilization/freeze-drying method was performed. The complex in solution was evaluated by phase solubility studies and the optimal 1 : 2 flavanone/cyclodextrin molar ratio was selected. Hydroxypropyl β-cyclodextrin was able to complex eriocitrin as confirmed by UV-Vis absorption, DSC, and FTIR studies. The complex formed increased the eriocitrin water solubility (from 4.1 ± 0.2 g·L−1 to 11.0 ± 0.1 g·L−1) and dissolution rate (from 37.0% to 100%) in 30 min. The in vitro studies exhibit the notion that eriocitrin and its complex inhibit AGEs in a similar manner because hydroxypropyl β-cyclodextrin does not interfere with the flavanone intrinsic property. Instead, the presence of cyclodextrin improves eriocitrin antioxidant stability maintaining a high fluorescence value until 8 hours with respect to the pure materials. Moreover, hydroxypropyl β-cyclodextrin showed moderate GAGs restoration acting synergistically with the complexed compound to maintain the structural chondrocytes integrity. The results point out that ERT/HP-betaCD complex possesses technological and biological characteristics able to obtain an easily soluble nutraceutical product, which reduces the degenerative and oxidative damage which occurs in osteoarthritis, and improve the patient compliance. PMID:28367273

Use of Carboxymethyl-beta-cyclodextrin (CMCD) as Flushing Agent for Remediation of Metal Contaminated Soil

NASA Astrophysics Data System (ADS)

Skold, M. E.; Thyne, G. D.; McCray, J. E.; Drexler, J. W.

2005-12-01

One of the major challenges in remediating soil and ground water is the presence of mixed organic and inorganic contaminants. Due to their very different behavior, research has to a large extent focused on remediation of either organic or inorganic contaminants rather than mixed waste. Cyclodextrins (CDs) are a group of non-toxic sugar based molecules that do not sorb to soil particles and do not experience pore size exclusion. Thus, they have good hydraulic properties. CDs enhance the solubility of organic compounds by forming inclusion complexes between organic contaminants and the non-polar cavity at the center of the CD. By substituting functional groups to the cyclodextrin molecule it can form complexes with heavy metals. Previous studies have shown that carboxymethyl-beta-cyclodextrin (CMCD) can simultaneously complex organic and inorganic contaminants. The aim of this study is to compare how strongly CMCD complexes several common heavy metals, radioactive elements and a common divalent cation. Results from batch experiments show that CMCD has the ability to complex a wide array of heavy metals and radioactive elements. The solubility of metal oxalates and metal oxides clearly increased in the presence of CMCD. Logarithmic conditional formation constants ranged from 3.5 to 6 for heavy metals and from 3 to 6 for radioactive elements. Calcium, which may compete for binding sites, has a logarithmic conditional formation constant of 3.1. Batch experiments performed at 10 and 25 degrees C showed little temperature effect on conditional formation constants. Results from batch experiments were compared to results from column experiments where Pb was sorbed onto hydrous ferric oxide coated sand and subsequently removed by a CMCD solution. The results indicate that CMCD is a potential flushing agent for remediation of mixed waste sites.

Influence of hydroxypropyl-beta-cyclodextrin on the transdermal permeation and skin accumulation of oxybenzone.

PubMed

Felton, Linda A; Wiley, Cody J; Godwin, Donald A

2002-10-01

The objective of the present study was to determine the effects of hydroxypropyl-beta-cyclodextrin (HPCD) concentration on the transdermal permeation and skin accumulation of a model ultraviolet (UV) absorber, oxybenzone. The concentration of oxybenzone was held constant at 2.67 mg/mL for all formulations, while the HPCD concentrations varied from 0 to 20% (w/w). Complexation of oxybenzone by HPCD was demonstrated by differential scanning calorimetry. A modified Franz cell apparatus was used in the transdermal experiments, with aliquots of the receptor fluid assayed for oxybenzone by high-performance liquid chromatography. From the permeation data, flux of the drug was calculated. Skins were removed from the diffusion cells at specified time points over a 24-hr period and the oxybenzone content in the skin determined. The aqueous solubility of oxybenzone increased linearly with increasing HPCD concentration, following a Higuchi AL-type complexation. The stability constant of the reaction was calculated from the phase-solubility diagram and found to be 2047 M-1. As the concentration of HPCD was increased from 0 to 10%, transdermal permeation and skin accumulation of oxybenzone increased. Maximum flux occurred at 10% HPCD, where sufficient cyclodextrin was added to completely solubilize all oxybenzone. When the concentration of HPCD was increased to 20%, both transdermal permeation and skin accumulation decreased. These data suggest the formation of a drug reservoir on the surface of the skin.

Size-exclusive Nanosensor for Quantitative Analysis of Fullerene C60: A Concept Paper

EPA Science Inventory

This paper presents the first development of a mass-sensitive nanosensor for the isolation and quantitative analyses of engineered fullerene (C₆₀) nanoparticles, while excluding mixtures of structurally similar fullerenes. Amino-modified beta cyclodextrin (β-CD-NH

Hydroxypropyl-beta-cyclodextrin as non-exhaustive extractant for organochlorine pesticides and polychlorinated biphenyls in muck soil.

PubMed

Wong, Fiona; Bidleman, Terry F

2010-05-01

Hydroxypropyl-beta-cyclodextrin (HPCD) was used as a non-exhaustive extractant for organochlorine pesticides (OCs) and polychlorinated biphenyls (PCBs) in muck soil. An optimized extraction method was developed which involved using a HPCD to soil mass ratio of 5.8 with a single extraction period of 20 h. An aging experiment was performed by spiking a muck soil with (13)C-labeled OCs and non-labeled PCBs. The soil was extracted with the optimized HPCD method and Soxhlet apparatus with dichloromethane over 550 d periodically. The HPCD extractability of the spiked OCs was greater than of the native OCs. A decreased in HPCD extractability was observed for the spiked OCs after 550 d of aging and their extractability approached those of the natives. The partition coefficient between HPCD and soil (logK(CD-Soil)) was negatively correlated with the octanol-water partition coefficient (logK(OW)) with r(2)=0.67 and p<0.05. Crown Copyright 2010. Published by Elsevier Ltd. All rights reserved.

High enantiomeric excess of the flavor relevant 4-alkyl-branched Fatty acids in milk fat and subcutaneous adipose tissue of sheep and goat.

PubMed

Kaffarnik, Stefanie; Heid, Carolina; Kayademir, Yasemin; Eibler, Dorothee; Vetter, Walter

2015-01-21

Volatile 4-alkyl-branched fatty acids are characteristic flavor compounds of sheep and goat. Due to the methyl branch, the carbon C-4 represents a stereogenic center with the possible presence of one or both enantiomers in the respective samples. In this study, we used enantioselective gas chromatography to study the enantiomeric composition of 4-methyloctanoic acid (4-Me-8:0) and 4-ethyloctanoic acid (4-Et-8:0) in milk and dairy products from sheep and goat as well as in goat subcutaneous tissue. Different columns coated with modified cyclodextrins were tested to resolve racemic 4-alkyl-branched fatty acid methyl ester standards. The best enantiomer resolution was obtained on 25% octakis(2,3,6-tri-O-ethyl)-γ-cyclodextrin (γ-TECD) diluted in OV-1701. For analysis of the food samples, the lipids were extracted and fatty acids in the extracts were converted into fatty acid methyl esters. Non-aqueous reversed-phase high-performance liquid chromatography was used to fractionate the samples in order to gain one solution enriched in 4-Me-8:0 methyl ester and one solution enriched with 4-Et-8:0 methyl ester. Subsequent analysis by enantioselective gas chromatography with mass spectrometry allowed only the detection of one enantiomer of 4-Me-8:0 and 4-Et-8:0 in the samples. By means of a non-racemic standard of 4-Me-8:0, it was found that the predominant enantiomer was (R)-4-Me-8:0.

Supramolecular hydrogel formation between chitosan and hydroxypropyl β-cyclodextrin via Diels-Alder reaction and its drug delivery.

PubMed

Zhang, Mengke; Wang, Jinpeng; Jin, Zhengyu

2018-07-15

Chitosan-cyclodextrin hydrogel (CFCD) was prepared via Diels-Alder reaction between furfural functionalized chitosan (CF) and N-maleoyl alanine functionalized hydroxypropyl β-cyclodextrin (HPCD-AMI) in aqueous media without any catalyst or initiator. The CF and HPCD-AMI were confirmed by Fourier transform infrared spectroscopy and 1 H nuclear magnetic resonance spectroscopy. The resultant CFCD hydrogel was characterized in terms of thermal peripteries, microstructure, rheology behavior, and swelling capacity. The rheology analysis found that the storage modulus G' ranged from 1pa to 1200pa as the degree of furfural substitute on chitosan increased from 2.6% to 28.3%, indicating the hydrogel strength can be tuned readily by reaction stoichiometry. The swelling behaviors proved that CFCD hydrogel was pH-responsive with low swelling capacity, which would be preferable for drug delivery. Drug adsorption analysis showed the introduction of cyclodextrin into CFCD hydrogels promoted drug adsorption capacity. In addition, methyl orange cumulative release in PBS buffer was only 48.85% after 24h, suggesting CFCD hydrogel had good sustained release capacity on the loaded drug. Copyright © 2018 Elsevier B.V. All rights reserved.

Enhanced bioavailability of process-induced fast-dissolving ibuprofen cogranulated with beta-cyclodextrin.

PubMed

Ghorab, Mohamed K; Adeyeye, Moji Christianah

2003-08-01

The objectives of this study were to evaluate the bioavailability of cogranulated and oven-dried ibuprofen (IBU) and beta-cyclodextrin (betaCD), in comparison to a physical mixture, and to examine the effect of endogenous bile on the bioavailability of the drug. In vitro dissolution studies were performed using USP type 2 apparatus. The granules and physical mixture were administered perorally in a crossover fashion, to male Wistar bile duct-nonligated rats. The granules were also perorally administered to bile duct-ligated rats. Blood samples were taken at different time intervals and the plasma analyzed for IBU. Dissolution of granules was faster than the physical mixture due to faster IBU-betaCD complex formation in solution from the former than the latter. The in vivo study showed that C(max), AUC(0-8), and the absolute bioavailability for the granules (49.0 microg/mL, 57.0 h x microg/mL and 80.6%, respectively) were almost one and half times that of the physical mixture (32.2 microg/mL, 38.4 h x microg/mL and 53.1%, respectively). However, in bile duct-ligated rats, lower C(max) and AUC(0-8) (15.9 microg/mL and 14.4 h x microg/mL, respectively) were obtained for the granules. Phase solubility study of IBU in an aqueous betaCD solution in the presence of the bile salt (sodium cholate), showed an increase in the solubility of IBU. Moreover, the stability constant value for the IBU-betaCD complex was also found to decrease as the sodium cholate concentration increased. These results indicated that the enhancement in the bioavailability of IBU was due to faster in-solution complex formation, and micelllar solubilization by the bile salt. Copyright 2003 Wiley-Liss, Inc.

Interscience Conference on Antimicrobial Agents and Chemotherapy--49th annual meeting. Part 1. 11-15 September 2009, San Francisco, CA, USA.

PubMed

Turner, Ben; Murch, Lisa

2009-11-01

The Interscience Conference on Antimicrobial Agents and Chemotherapy held in San Francisco included topics covering new therapeutic developments for the treatment of infectious diseases. This conference report highlights selected presentations on a beta-cyclodextrin derivative for the treatment of Staphylococcus aureus infections, a type 3 secretion system inhibitor for the treatment of Pseudomonas aeruginosa infections, a small-molecule inhibitor of the fungal Hos2 HDAC, a TLR9 agonist used as an adjuvant, a CMV vaccine, a glycopeptide-cephalosporin heterodimer antibiotic, a topical quinolone for the treatment of complicated skin and skin structure infections, a broad-spectrum glycylcycline antibiotic and an HCV RNA replication inhibitor. Investigational drugs discussed include IB-201 (Innovative Biologics Inc), MBX-1641 (Microbiotix Inc), MGCD-290 (MethylGene Inc), agatolimod (Coley Pharmaceutical Group Inc/Pfizer Inc/GlaxoSmithKline plc/Merck & Co Inc/Dynavax Technologies Corp/Novartis AG/Emergent BioSolutions Inc), TD-1792 (Theravance Inc), ozenoxacin (Ferrer Internacional SA/Maruho Co Ltd/Toyama Chemical Co Ltd) and ATI-0810 (Arisyn Therapeutics Inc).

Characterization of a single-isomer carboxymethyl-beta-cyclodextrin in chiral capillary electrophoresis.

PubMed

Fejős, Ida; Varga, Erzsébet; Benkovics, Gábor; Malanga, Milo; Sohajda, Tamás; Szemán, Julianna; Béni, Szabolcs

2017-08-01

In this work, the synthesis, characterization, and chiral capillary electrophoretic study of heptakis-(2,3-di-O-methyl-6-O-carboxymethyl)-β-CD (HDMCM), a single-isomer carboxymethylated CD, are presented. The pH-dependent and selector concentration-dependent enantiorecognition properties of HDMCM were investigated and discussed herein. The enantioseparation was assessed applying a structurally diverse set of noncharged, basic, and zwitterionic racemates. The increase in the selector concentration and gross negative charge of HDMCM improved the enantioseparation that could be observed in the majority of the cases. HDMCM was also successfully applied as BGE additive in NACE using a methanol-based system in order to prove the separation selectivity features and to highlight the broad applicability of HDMCM. Over 25 racemates showed partial or baseline separation with HDMCM under the conditions investigated, among which optimal enantiomer migration order was found for the four stereoisomers of tadalafil, tapentadol, and dapoxetine, offering the possibility of a chiral CE method development for chiral purity profiling of these drugs. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis of Anomeric Methyl Fructofuranosides and Their Separation on an Ion-Exchange Resin

ERIC Educational Resources Information Center

Nurminen, Erkki; Poijarvi, Paivi; Koskua, Katja; Hovinen, Jari

2007-01-01

Treatment of d-fructose with methanol in the presence of acid as a catalyst gives a mixture of methyl-[beta]-d-fructopyranoside, methyl-[alpha]-D-fructofuranoside, and methyl-[beta]-d-fructofuranoside, which were separated on an ion exchange column and characterized polarimetrically.

Bridging the gap between protein carboxyl methylation and phospholipid methylation to understand glucose-stimulated insulin secretion from the pancreatic beta cell.

PubMed

Kowluru, Anjaneyulu

2008-01-15

Recent findings have implicated post-translational modifications at C-terminal cysteines [e.g., methylation] of specific proteins [e.g., G-proteins] in glucose-stimulated insulin secretion [GSIS]. Furthermore, methylation at the C-terminal leucine of the catalytic subunit of protein phosphatase 2A [PP2Ac] has also been shown to be relevant for GSIS. In addition to these two classes of protein methyl transferases, a novel class of glucose-activated phospholipid methyl transferases have also been identified in the beta cell. These enzymes catalyze three successive methylations of phosphatidylethanolamine to yield phosphatidylcholine. The "newly formed" phosphatidylcholine is felt to induce alterations in the membrane fluidity, which might favor vesicular fusion with the plasma membrane for the exocytosis of insulin. The objectives of this commentary are to: (i) review the existing evidence on the regulation, by glucose and other insulin secretagogues, of post-translational carboxylmethylation [CML] of specific proteins in the beta cell; (ii) discuss the experimental evidence, which implicates regulation, by glucose and other insulin secretagogues, of phosphatidylethanolamine methylation in the islet beta cell; (iii) propose a model for potential cross-talk between the protein and lipid methylation pathways in the regulation of GSIS and (iv) highlight potential avenues for future research, including the development of specific pharmacological inhibitors to further decipher regulatory roles for these methylation reactions in islet beta cell function.

Eudragit RS 100 microparticles containing 2-hydroxypropyl-beta-cyclodextrin and glutathione: physicochemical characterization, drug release and transport studies.

PubMed

Trapani, Adriana; Laquintana, Valentino; Denora, Nunzio; Lopedota, Angela; Cutrignelli, Annalisa; Franco, Massimo; Trapani, Giuseppe; Liso, Gaetano

2007-01-01

The aim of this study was to encapsulate glutathione (GSH) alone or in combination with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) in Eudragit RS 100 microparticles (MPs), and to evaluate these novel delivery systems for oral administration of the considered tripeptide. The MPs were prepared by an O/O emulsion-solvent evaporation method according to a multilevel experimental design involving the volume of liquid paraffin, the HP-beta-CD amount, and the drug/polymer ratio as independent variables. The effects of these parameters on particle size, entrapment efficiency, and drug release were investigated. Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) analysis and differential scanning calorimetry (DSC) studies were performed to evaluate possible interactions between GSH and Eudragit RS 100 polymer and to characterize the physical state of drug within the MPs. The release profiles of GSH from MPs were examined in vitro at pH 1.2, 6.8. and 7.4 using the USP III (BioDis) dissolution apparatus. In general, a slow and zero-order release of GSH from MPs at pH 1.2 occurred, while at higher pH values considerable amounts of glutathione disulfide (i.e., GSSG) were observed. The enzymatic stability and the intestinal permeability of some GSH-containing MPs were assessed by using pepsin, alpha-chymotrypsin, gamma-glutamyl-transpeptidase and everted frog intestinal sac methodology, respectively. The results suggest that GSH-loaded Eudragit RS 100 MPs containing HP-beta-CD represent a new sustained GSH delivery system useful for the oral administration of the examined tripeptide.

Structure-activity relationships of sandalwood odorants: synthesis and odour of methyl-beta-santalol.

PubMed

Buchbauer, G; Zechmeister-Machhart, F; Weiss-Greiler, P; Wolschann, P

1997-04-01

The synthesis and odour properties of the new santalol analogue, methyl-beta-santalol, are described. The additional methyl group adjacent to the hydroxyl function of the standard molecule, beta-santalol, deprives the new compound of the sandalwood note. The synthesis and the odour evaluation of this compound supports the proposed model for sandalwood fragrance as it shows that the methyl group located at the osmophoric center prevents association of the molecule with the hypothetical receptor.

N.m.r. studies of the conformation of analogues of methyl beta-lactoside in methyl sulfoxide-d6.

PubMed

Rivera-Sagredo, A; Jiménez-Barbero, J; Martín-Lomas, M

1991-12-16

The 1H- and 13C-n.m.r. spectra of solutions of methyl beta-lactoside (1), all of its monodeoxy derivatives (2, 3, 6-10), the 3-O-methyl derivative (4), and methyl 4-O-beta-D-galactopyranosyl-D-xylopyranoside (5) in methyl sulfoxide-d6 have been analysed. The n.O.e.'s and specific desheildings indicate similar distributions of low-energy conformers, comparable to those in aqueous solution. The major conformer has torsion angles phi H and psi H of 49 degrees and 5 degrees, respectively, with contributions of conformers with phi/psi 24 degrees/-59 degrees, 22 degrees/32 degrees, and 6 degrees/44 degrees.

Functional Nanofibers via Electospinning: New Materials and Processes

NASA Astrophysics Data System (ADS)

Manasco, Joshua Lee

Cyclodextrins are fascinating, amphiphilic molecules that are of considerable interest due to their ability to be used in a variety of applications ranging from pharmaceuticals and cosmetics to foods and agriculture. These are ring-shaped sugar molecules possess a hydrophobic cavity and a hydrophilic exterior which imparts them water solubility. There are three main types of naturally occurring cyclodextrins namely alpha-, beta- and gamma- CD which have 6, 7 and 8 member rings, respectively. Owing to their hydrophobic interior, cyclodextrin molecules encapsulate hydrophobic guest molecules (from small to macromolecules) to form host-guest supermolecular structures. Chemically modified CDs are often preferred to the natural forms, particularly methylated (MbetaCD) and hydroxypropylated (HPbetaCD) cyclodextrins, for their enhanced solubility and chemical stability. Electrostatic spinning (electrospinning) of nanofibers has drawn significant research attention in recent decades. This technique involves the stretching of a polymer solution or melt in a high electric field to produce fibers on the nanoscale. These 1-Dimensional nanostructures possess extraordinary surface-to-weight ratio and find applications that vary from filtration membranes and tissue scaffolding materials to drug delivery and many others. The scope of this research attempts to leverage the unique features of CDs with the high aspect ratio of nanofibers to create functional nanomaterials. The present study can be divided into three sections. In the first part, we establish that CDs can be electrospun without the need for a "carrier" polymer. This discovery may serve to extend the horizon of what is currently considered "electrospinnable" from macromolecules now to small molecules. The ability to electrospin CDs led to their incorporation of other polymers to create bicomponent fibers with poly (vinyl alcohol) (PVA) and polyacrylonitrile (PAN). In the case of PVA we demonstrate the ability to not only to control the fiber properties based on PVA/CD ratio, but also crosslink these fibers to create water resistant fiber mats. Furthermore, the use of these fibers as rapid dissolving membranes for drug delivery is explored. Additionally, CDs are investigated for use as a porogen for PAN and carbon fibers. We find that CDs are particularly good candidates for us as porogens due to their amorphous nature and versatility to be dissolved in various solvent system. By nature, solution electrospinning is a low-throughput, solvent intensive process. In the last part we attempt to alleviate this issue by designing an extrusion based melt electrospinning device. We show that submicron fibers of polycaprolactone are possible through this technique without the use of organic solvents.

Low-molecular-weight poly(alpha-methyl beta,L-malate) of microbial origin: synthesis and crystallization.

PubMed

Fernández, Carlos E; Mancera, Manuel; Holler, Eggehard; Bou, Jordi J; Galbis, Juan A; Muñoz-Guerra, Sebastián

2005-02-23

Low-molecular-weight poly(alpha-methyl beta,L-malate) made of approximately 25-30 units was prepared from microbial poly(beta,L-malic acid) by treatment with diazomethane. The thermal characterization of the polymalate methyl ester was carried out and its crystalline structure was preliminary examined. Its ability to crystallize both from solution and from the melt was comparatively evaluated.

Sustained-releasing hollow microparticles with dual-anticancer drugs elicit greater shrinkage of tumor spheroids.

PubMed

Baek, Jong-Suep; Choo, Chee Chong; Tan, Nguan Soon; Loo, Say Chye Joachim

2017-10-06

Polymeric particulate delivery systems are vastly explored for the delivery of chemotherapeutic agents. However, the preparation of polymeric particulate systems with the capability of providing sustained release of two or more drugs is still a challenge. Herein, poly (D, L-lactic-co-glycolic acid, 50:50) hollow microparticles co-loaded with doxorubicin and paclitaxel were developed through double-emulsion solvent evaporation technique. Hollow microparticles were formed through the addition of an osmolyte into the fabrication process. The benefits of hollow over solid microparticles were found to be higher encapsulation efficiency and a more rapid drug release rate. Further modification of the hollow microparticles was accomplished through the introduction of methyl-β-cyclodextrin. With this, a higher encapsulation efficiency of both drugs and an enhanced cumulative release were achieved. Spheroid study further demonstrated that the controlled release of the drugs from the methyl-β-cyclodextrin -loaded hollow microparticles exhibited enhanced tumor regressions of MCF-7 tumor spheroids. Such hollow dual-drug-loaded hollow microparticles with sustained releasing capabilities may have a potential for future applications in cancer therapy.

Characterization of Albendazole-Randomly Methylated-β-Cyclodextrin Inclusion Complex and In Vivo Evaluation of Its Antihelmitic Activity in a Murine Model of Trichinellosis

PubMed Central

García, Agustina; Leonardi, Darío; Vasconi, María D.; Hinrichsen, Lucila I.; Lamas, María C.

2014-01-01

Albendazole is a benzimidazole carbamate extensively used in oral chemotherapy against intestinal parasites, due to its broad spectrum activity, good tolerance and low cost. However, the drug has the disadvantage of poor bioavailability due to its very low solubility in water; as a consequence, a very active area of research focuses on the development of new pharmaceutical formulations to increase its solubility, dissolution rate, and bioavailability. The primary objective of this study was to prepare randomly methylated β-cyclodextrins inclusion complexes to increase albendazole dissolution rate, in order to enhance its antiparasitic activity. This formulation therapeutic efficacy was contrasted with that of the pure drug by treating Trichinella spiralis infected mice during the intestinal phase of the parasite cycle, on days five and six post-infection. This protocol significantly decreased muscle larval burden measured in the parenteral stage on day 30 post-infection, when compared with the untreated control. Thus, it could be demonstrated that the inclusion complexes improve the in vivo therapeutic activity of albendazole. PMID:25406084

Role of cosubstrate and bioaccessibility played in the enhanced anaerobic biodegradation of organochlorine pesticides (OCPs) in a paddy soil by nitrate and methyl-β-cyclodextrin amendments.

PubMed

Ye, Mao; Sun, Mingming; Ni, Ni; Chen, Yinwen; Liu, Zongtang; Gu, Chengang; Bian, Yongrong; Hu, Feng; Li, Huixin; Kengara, Fredrick Orori; Jiang, Xin

2014-01-01

The present study was conducted to investigate the anaerobic biodegradation potential of biostimulation by nitrate (KNO3) and methyl-β-cyclodextrin (MCD) addition on an aged organochlorine pesticide (OCP)-contaminated paddy soil. After 180 days of incubation, total OCP biodegradation was highest in soil receiving the addition of nitrate and MCD simultaneously and then followed by nitrate addition, MCD addition, and control. The highest biodegradation of chlordanes, hexachlorocyclohexanes, endosulfans, and total OCPs was 74.3, 63.5, 51.2, and 65.1%, respectively. Meanwhile, MCD addition significantly increased OCP bioaccessibility (p < 0.05) evaluated by Tenax TA extraction and a three-compartment model method. Moreover, the addition of nitrate and MCD also obtained the highest values of soil microbial activities, including soil microbial biomass carbon and nitrogen, ATP production, denitrifying bacteria count, and nitrate reductase activity. Such similar trend between OCP biodegradation and soil-denitrifying activities suggests a close relationship between OCP biodegradation and N cycling and the indirect/direct involvement of soil microorganisms, especially denitrifying microorganisms in the anaerobic biodegradation of OCPs.

Methyl-β-cyclodextrins preferentially remove cholesterol from the liquid disordered phase in giant unilamellar vesicles.

PubMed

Sanchez, Susana A; Gunther, German; Tricerri, Maria A; Gratton, Enrico

2011-05-01

Methyl-β-cyclodextrins (MβCDs) are molecules that are extensively used to remove and to load cholesterol (Chol) from artificial and natural membranes; however, the mechanism of Chol extraction by MβCD from pure lipids or from complex mixtures is not fully understood. One of the outstanding questions in this field is the capability of MβCD to remove Chol from lipid domains having different packing. Here, we investigated the specificity of MβCD to remove Chol from coexisting macrodomains with different lipid packing. We used giant unilamellar vesicles (GUVs) made of 1,2-dioleoylphosphatidylcholine:1,2-dipalmitoylphatidylcholine:free cholesterol, 1:1:1 molar ratio at 27°C. Under these conditions, individual GUVs present Chol distributed into lo and ld phases. The two phases can be distinguished and visualized using Laurdan generalized polarization and two-photon excitation fluorescence microscopy. Our data indicate that MβCD removes Chol preferentially from the more disordered phase. The process of selective Chol removal is dependent on the MβCD concentration. At high concentrations, MβCD also removes phospholipids.

High shear mixing granulation of ibuprofen and beta-cyclodextrin: effects of process variables on ibuprofen dissolution.

PubMed

Ghorab, Mohamed K; Adeyeye, Moji Christianah

2007-10-19

The aims of the study were to evaluate the effect of high shear mixer (HSM) granulation process parameters and scale-up on wet mass consistency and granulation characteristics. A mixer torque rheometer (MTR) was employed to evaluate the granulating solvents used (water, isopropanol, and 1:1 vol/vol mixture of both) based on the wet mass consistency. Gral 25 and mini-HSM were used for the granulation. The MTR study showed that the water significantly enhanced the beta-cyclodextrin (beta CD) binding tendency and the strength of liquid bridges formed between the particles, whereas the isopropanol/water mixture yielded more suitable agglomerates. Mini-HSM granulation with the isopropanol/water mixture (1:1 vol/vol) showed a reduction in the extent of torque value rise by increasing the impeller speed as a result of more breakdown of agglomerates than coalescence. In contrast, increasing the impeller speed of the Gral 25 resulted in higher torque readings, larger granule size, and consequently, slower dissolution. This was due to a remarkable rise in temperature during Gral granulation that reduced the isopropanol/water ratio in the granulating solvent as a result of evaporation and consequently increased the beta CD binding strength. In general, the HSM granulation retarded ibuprofen dissolution compared with the physical mixture because of densification and agglomeration. However, a successful HSM granulation scale-up was not achieved due to the difference in the solvent mixture's effect from 1 scale to the other.

Drug loading into beta-cyclodextrin granules using a supercritical fluid process for improved drug dissolution.

PubMed

Hussein, Khaled; Türk, Michael; Wahl, Martin A

2008-03-03

To improve dissolution properties of drugs, a supercritical fluid (SCF) technique was used to load these drugs into a solid carrier. In this study, granules based on beta-cyclodextrin (betaCD) were applied as a carrier for poor water-soluble drug and loaded with a model drug (ibuprofen) using two different procedures: controlled particle deposition (CPD), SCF process and solution immersion (SI) as a conventional method for comparison. Using the CPD technique, 17.42+/-2.06wt.% (n=3) ibuprofen was loaded into betaCD-granules, in contrast to only 3.8+/-0.15wt.% (n=3) in the SI-product. The drug loading was confirmed as well by reduction of the BET surface area for the CPD-product (1.134+/-0.07m(2)/g) compared to the unloaded-granules (1.533+/-0.031m(2)/g). Such a reduction was not seen in the SI-product (1.407+/-0.048m(2)/g). The appearance of an endothermic melting peak at 77 degrees C and X-ray patterns representing ibuprofen in drug-loaded granules can be attributed to the amount of ibuprofen loaded in its crystalline form. A significant increase in drug dissolution was achieved by either drug-loading procedures compared to the unprocessed ibuprofen. In this study, the CPD technique, a supercritical fluid process avoiding the use of toxic or organic solvents was successfully applied to load drug into solid carriers, thereby improving the water-solubility of the drug.

Genome-wide analysis of DNA methylation variations caused by chronic glucolipotoxicity in beta-cells.

PubMed

Hu, Y; Xu, X-H; He, K; Zhang, L-L; Wang, S-K; Pan, Y-Q; He, B-S; Feng, T-T; Mao, X-M

2014-02-01

There is a growing body of literature suggesting the role of interactions between genes and the environment in development of type 2 diabetes mellitus (T2DM). However, the interplay between environment and genetic in developing and progressing T2MD is not fully understood. To determine the effects of high-glucose-lipid on the status of DNA methylation in beta cells, and clarify the mechanism of glucolipotoxicity on beta-cell deterioration, the DNA methylation profile was detected in beta-cells cultured with high-glucose-lipid medium.We utilized a high throughput NimbleGen RN34 CpG Island & Promoter Microarray to investigate the DNA methylation profile in beta-cells cultured with high-glucose-lipid medium. To validate the results of microarray, the immunoprecipitation (MeDIP) PCR was used to test the methylation status of some selected genes. The mRNA and protein expression of insulin and Tcf7l2 in these cells were quantified by RT-PCR and western blot, respectively.We have identified a lot of loci which experienced aberrant DNA methylation in beta-cells cultured with high-glucose-lipid medium. The results of MeDIP PCR were consistency to the microarray. An opposite regulation in transcription and translation of Tcf7l2 gene was found. Furthermore, the insulin mRNA and protein expression in beta-cells also decreased after cultured with high-glucose-lipid medium compared with the control cells.We conclude that chronic glucolipotoxicity could induce aberrant DNA methylation of some genes and may affect these genes expression in beta-cells, which might contribute to beta-cell function failure in T2DM and be helpful to explain, at least partially, the mechanism of glucolipotoxicity on beta-cells deterioration. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

40 CFR 180.157 - Methyl 3-[(dimethoxyphos-phinyl) oxy]butenoate, alpha and beta isomers; tolerances for residues.

Code of Federal Regulations, 2010 CFR

2010-07-01

...]butenoate, alpha and beta isomers; tolerances for residues. 180.157 Section 180.157 Protection of...]butenoate, alpha and beta isomers; tolerances for residues. (a) General. Tolerances are established for residues of the insecticide methyl 3-[(dimethoxyphosphinyl)oxy]butenoate, alpha and beta isomers, in or on...

40 CFR 180.157 - Methyl 3-[(dimethoxyphos-phinyl) oxy]butenoate, alpha and beta isomers; tolerances for residues.

Code of Federal Regulations, 2011 CFR

2011-07-01

...]butenoate, alpha and beta isomers; tolerances for residues. 180.157 Section 180.157 Protection of...]butenoate, alpha and beta isomers; tolerances for residues. (a) General. Tolerances are established for residues of the insecticide methyl 3-[(dimethoxyphosphinyl)oxy]butenoate, alpha and beta isomers, in or on...

Purification and characterization of the glycogen-bound protein phosphatase from rat liver.

PubMed

Wera, S; Bollen, M; Stalmans, W

1991-01-05

Glycogen-bound protein phosphatase G from rat liver was transferred from glycogen to beta-cyclodextrin (cycloheptaamylose) linked to Sepharose 6B. After removal of the catalytic subunit and of contaminating proteins with 2 M NaCl, elution with beta-cyclodextrin yielded a single protein on native polyacrylamide gel electrophoresis and two polypeptides (161 and 54 kDa) on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Several lines of evidence indicate that the latter polypeptides are subunits of the protein phosphatase G holoenzyme. First, these polypeptides were also present, together with the catalytic subunit, in the extensively purified holoenzyme. Also, polyclonal antibodies against these polypeptides were able to bind the holoenzyme. Further, while bound to cyclodextrin-Sepharose, the polypeptides were able to recombine with separately purified type-1 (AMD) catalytic subunit, but not with type-2A (PCS) catalytic subunit. The characteristics of the reconstituted enzyme resembled those of the nonpurified protein phosphatase G. At low dilutions, the spontaneous phosphorylase phosphatase activity of the reconstituted enzyme was about 10 times lower than that of the catalytic subunit, but it was about 1000-fold more resistant to inhibition by the modulator protein (inhibitor-2). In contrast with the free catalytic subunit, the reconstituted enzyme co-sedimented with glycogen, and it was able to activate purified liver glycogen synthase b. Also, the synthase phosphatase activity was synergistically increased by a cytosolic phosphatase and inhibited by physiological concentrations of phosphorylase alpha and of Ca2+.

Methylation of insulin DNA in response to proinflammatory cytokines during the progression of autoimmune diabetes in NOD mice.

PubMed

Rui, Jinxiu; Deng, Songyan; Lebastchi, Jasmin; Clark, Pamela L; Usmani-Brown, Sahar; Herold, Kevan C

2016-05-01

Type 1 diabetes is caused by the immunological destruction of pancreatic beta cells. Preclinical and clinical data indicate that there are changes in beta cell function at different stages of the disease, but the fate of beta cells has not been closely studied. We studied how immune factors affect the function and epigenetics of beta cells during disease progression and identified possible triggers of these changes. We studied FACS sorted beta cells and infiltrating lymphocytes from NOD mouse and human islets. Gene expression was measured by quantitative real-time RT-PCR (qRT-PCR) and methylation of the insulin genes was investigated by high-throughput and Sanger sequencing. To understand the role of DNA methyltransferases, Dnmt3a was knocked down with small interfering RNA (siRNA). The effects of cytokines on methylation and expression of the insulin gene were studied in humans and mice. During disease progression in NOD mice, there was an inverse relationship between the proportion of infiltrating lymphocytes and the beta cell mass. In beta cells, methylation marks in the Ins1 and Ins2 genes changed over time. Insulin gene expression appears to be most closely regulated by the methylation of Ins1 exon 2 and Ins2 exon 1. Cytokine transcription increased with age in NOD mice, and these cytokines could induce methylation marks in the insulin DNA by inducing methyltransferases. Similar changes were induced by cytokines in human beta cells in vitro. Epigenetic modification of DNA by methylation in response to immunological stressors may be a mechanism that affects insulin gene expression during the progression of type 1 diabetes.

Ethanol Inhibits High-Affinity Immunoglobulin E Receptor (FcεRI) Signaling in Mast Cells by Suppressing the Function of FcεRI-Cholesterol Signalosome

PubMed Central

Draberova, Lubica; Paulenda, Tomas; Halova, Ivana; Potuckova, Lucie; Bugajev, Viktor; Bambouskova, Monika; Tumova, Magda; Draber, Petr

2015-01-01

Ethanol has multiple effects on biochemical events in a variety of cell types, including the high-affinity immunoglobulin E receptor (FcεRI) signaling in antigen-activated mast cells. However, the underlying molecular mechanism remains unknown. To get better understanding of the effect of ethanol on FcεRI-mediated signaling we examined the effect of short-term treatment with non-toxic concentrations of ethanol on FcεRI signaling events in mouse bone marrow-derived mast cells. We found that 15 min exposure to ethanol inhibited antigen-induced degranulation, calcium mobilization, expression of proinflammatory cytokine genes (tumor necrosis factor-α, interleukin-6, and interleukin-13), and formation of reactive oxygen species in a dose-dependent manner. Removal of cellular cholesterol with methyl-β-cyclodextrin had a similar effect and potentiated some of the inhibitory effects of ethanol. In contrast, exposure of the cells to cholesterol-saturated methyl-β-cyclodextrin abolished in part the inhibitory effect of ethanol on calcium response and production of reactive oxygen species, supporting lipid-centric theories of ethanol action on the earliest stages of mast cell signaling. Further studies showed that exposure to ethanol and/or removal of cholesterol inhibited early FcεRI activation events, including tyrosine phosphorylation of the FcεRI β and γ subunits, SYK kinases, LAT adaptor protein, phospholipase Cγ, STAT5, and AKT and internalization of aggregated FcεRI. Interestingly, ethanol alone, and particularly in combination with methyl-β-cyclodextrin, enhanced phosphorylation of negative regulatory tyrosine 507 of LYN kinase. Finally, we found that ethanol reduced passive cutaneous anaphylactic reaction in mice, suggesting that ethanol also inhibits FcεRI signaling under in vivo conditions. The combined data indicate that ethanol interferes with early antigen-induced signaling events in mast cells by suppressing the function of FcεRI-cholesterol signalosomes at the plasma membrane. PMID:26658290

Differential subcellular membrane recruitment of Src may specify its downstream signalling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Diesbach, Philippe de; Medts, Thierry; Carpentier, Sarah

2008-04-15

Most Src family members are diacylated and constitutively associate with membrane 'lipid rafts' that coordinate signalling. Whether the monoacylated Src, frequently hyperactive in carcinomas, also localizes at 'rafts' remains controversial. Using polarized MDCK cells expressing the thermosensitive v-Src/tsLA31 variant, we here addressed how Src tyrosine-kinase activation may impact on its (i) membrane recruitment, in particular to 'lipid rafts'; (ii) subcellular localization; and (iii) signalling. The kinetics of Src-kinase thermoactivation correlated with its recruitment from the cytosol to sedimentable membranes where Src largely resisted solubilisation by non-ionic detergents at 4 deg. C and floated into sucrose density gradients like caveolin-1 andmore » flotillin-2, i.e. 'lipid rafts'. By immunofluorescence, activated Src showed a dual localization, at apical endosomes/macropinosomes and at the apical plasma membrane. The plasma membrane Src pool did not colocalize with caveolin-1 and flotillin-2, but extensively overlapped GM1 labelling by cholera toxin. Severe ({approx} 70%) cholesterol extraction with methyl-{beta}-cyclodextrin (M{beta}CD) did not abolish 'rafts' floatation, but strongly decreased Src association with floating 'rafts' and abolished its localization at the apical plasma membrane. Src activation independently activated first the MAP-kinase - ERK1/2 pathway, then the PI3-kinase - Akt pathway. MAP-kinase - ERK1/2 activation was insensitive to M{beta}CD, which suppressed Akt phosphorylation and apical endocytosis induced by Src, both depending on the PI3-kinase pathway. We therefore suggest that activated Src is recruited at two membrane compartments, allowing differential signalling, first via ERK1/2 at 'non-raft' domains on endosomes, then via PI3-kinase-Akt on a distinct set of 'rafts' at the apical plasma membrane. Whether this model is applicable to c-Src remains to be examined.« less

Characterization of mitotane (o,p'-DDD)--cyclodextrin inclusion complexes: phase-solubility method and NMR.

PubMed

Alfonsi, R; Attivi, D; Astier, A; Socha, M; Morice, S; Gibaud, S

2013-05-01

Mitotane (o,p'-dichlorodimethyl dichloroethane [o,p'-DDD]) is used for the treatment of adrenocortical cancer and occasionally Cushing's syndrome. This drug is very poorly soluble in water, and following oral administration, approximately 60% of the dose is recovered in the feces unaltered. The preparation of a soluble formulation (i.e. by complexation with cyclodextrins) with improved bioavailability is the aim of this work. The inclusion of mitotane in methyl-ß-cyclodextrins was studied using both phase-solubility methods and NMR experiments. To elucidate the inclusion mechanism, o,p'-DDD was compared to its regioisomer (i.e. p,p'-DDD). It was demonstrated that two dimethyl-ß-cyclodextrins (DMßCD) can complex with the aromatic rings. From the phase-solubility diagrams, we observe that both cases are very different: K(1:1) is between 37 000 and 85 000 mol.l(-1), whereas K(1:2) is between 5.3 and 32 mol.l(-1). The NMR experiments confirmed the inclusion but it also gave an insight into the kinetics of the dissociation: the ortho-chloro moiety is in slow exchange on the NMR time scale, whereas the para-chloro moiety is in fast exchange rate. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Surfactant Dysfunction in ARDS and Bronchiolitis is Repaired with Cyclodextrins.

PubMed

Al-Saiedy, Mustafa; Gunasekara, Lasantha; Green, Francis; Pratt, Ryan; Chiu, Andrea; Yang, Ailian; Dennis, John; Pieron, Cora; Bjornson, Candice; Winston, Brent; Amrein, Matthias

2018-03-01

Acute respiratory distress syndrome (ARDS) is caused by many factors including inhalation of toxicants, acute barotrauma, acid aspiration, and burns. Surfactant function is impaired in ARDS and acute airway injury resulting in high surface tension with alveolar and small airway collapse, edema, hypoxemia, and death. In this study, we explore the mechanisms whereby surfactant becomes dysfunctional in ARDS and bronchiolitis and its repair with a cyclodextrin drug that sequesters cholesterol. We used in vitro model systems, a mouse model of ARDS, and samples from patients with acute bronchiolitis. Surface tension was measured by captive bubble surfactometry. Patient samples showed severe surfactant inhibition even in the absence of elevated cholesterol levels. Surfactant was also impaired in ARDS mice where the cholesterol to phospholipid ratio (W/W%) was increased. Methyl-β-cyclodextrin (MβCD) restored surfactant function to normal in both human and animal samples. Model studies showed that the inhibition of surfactant was due to both elevated cholesterol and an interaction between cholesterol and oxidized phospholipids. MβCD was also shown to have anti-inflammatory effects. Inhaled cyclodextrins have potential for the treatment of ARDS. They could be delivered in a portable device carried in combat and used following exposure to toxic gases and fumes or shock secondary to hemorrhage and burns.

Separations on water-ice. Final report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dasgupta, P.K.

1998-07-01

This report focuses on processes to separate water frozen into ice. Research topics include the following: normal phase columnar chromatography; electrophoresis in a planar format; and zone melting type separations on a solid column of ice. Attempts were made to dope the emulsion with {beta}-cyclodextrin in order to separate commercially important chiral drugs such as Inderal.

Cyclodextrin inclusion complex formation and solid-state characterization of the natural antioxidants alpha-tocopherol and quercetin.

PubMed

Koontz, John L; Marcy, Joseph E; O'Keefe, Sean F; Duncan, Susan E

2009-02-25

Cyclodextrin (CD) complexation procedures are relatively simple processes, but these techniques often require very specific conditions for each individual guest molecule. Variations of the coprecipitation from aqueous solution technique were optimized for the CD complexation of the natural antioxidants alpha-tocopherol and quercetin. Solid inclusion complex products of alpha-tocopherol/beta-CD and quercetin/gamma-CD had molar ratios of 1.7:1, which were equivalent to 18.1% (w/w) alpha-tocopherol and 13.0% (w/w) quercetin. The molar reactant ratios of CD/antioxidant were optimized at 8:1 to improve the yield of complexation. The product yields of alpha-tocopherol/beta-CD and quercetin/gamma-CD complexes from their individual reactants were calculated as 24 and 21% (w/w), respectively. ATR/FT-IR, 13C CP/MAS NMR, TGA, and DSC provided evidence of antioxidant interaction with CD at the molecular level, which indicated true CD inclusion complexation in the solid state. Natural antioxidant/CD inclusion complexes may serve as novel additives in controlled-release active packaging to extend the oxidative stability of foods.

Core-shell nanosized assemblies mediated by the alpha-beta cyclodextrin dimer with a tumor-triggered targeting property.

PubMed

Quan, Chang-Yun; Chen, Jing-Xiao; Wang, Hui-Yuan; Li, Cao; Chang, Cong; Zhang, Xian-Zheng; Zhuo, Ren-Xi

2010-07-27

In this paper, the alpha-beta cyclodextrin dimer is designed via "click" chemistry to connect the hydrophilic and hydrophobic segments to form self-assembled noncovalently connected micelles (NCCMs) through host-guest interactions. A peptide containing the Arg-Gly-Asp (RGD) sequence was introduced to NCCMs as a target ligand to improve the cell uptake efficacy, while PEGylated technology was employed via benzoic-imine bonds to protect the ligands in normal tissues and body fluid. In addition, two fluorescent dyes were conjugated to different segments to track the formation of the micelles as well as the assemblies. It was found that the targeting property of NCCMs was switched off before reaching the tumor sites and switched on after removing the poly(ethylene glycol) (PEG) segment in the tumor sites, which was called "tumor-triggered targeting". With deshielding of the PEG segment, the drugs loaded in NCCMs could be released rapidly due to the thermoinduced phase transition. The new concept of "tumor-triggered targeting" proposed here has great potential for cancer treatment.

Synthesis, Characterization, In Vitro Evaluation, and Preclinical Profiling of beta-Cyclodextrin Polyrotaxane Families for Use As Potential Niemann-Pick Type C Therapeutics

NASA Astrophysics Data System (ADS)

Collins, Christopher J.

Niemann-Pick Disease Type C (NPC) is a rare, autosomal recessive genetic disorder featuring a loss of proteins responsible for unesterified cholesterol (UC) trafficking through the late endosomes/lysosomes (LE/LY) of every cell of the body. Disruption of this pathway leads to abnormal accumulation and storage of UC and other lipids. A broad range of visceral and neurological symptoms result from this accumulation exhibiting a variable age of onset and a disease progression that is ultimately fatal. The disease has an incidence of approximately 1 in 120,000 live births and has no known effective treatment. beta-Cyclodextrin (beta-CD) are natural small molecules macrocycles composed of glucose units with a hydrophobic inner cavity and hydrophilic outer rims. beta-CD derivatives have recently been shown to be effective therapeutics for NPC in cellular and animal models. In the mouse model of the disease, beta-CD therapy increases overall lifetime by as much as 50% and slows the progression of neurodegeneration. The progress has led to the initiation of a National Institutes of Health phase I clinical trial. A main drawback of beta-CD administration is the poor pharmacokinetic profile characterized by rapid renal clearance of the drug through the urine. Libraries of beta-CD derivative carrying high molecular weight polyrotaxane (PR) systems have been designed to prevent glomerular filtration of the injected beta-CD dose. An initial family of unmodified beta-CD PRs was synthesized, characterized, and their therapeutic efficacy was tested in NPC fibroblasts. This was followed by screening of PRs consisting of mixed beta-CD derivative threading featuring charged sulfobutylether beta-CD. Finally, we sought to define PR structure-property effects on in vivo pharmacokinetics, biodistribution, toxicity, immunogenicity, and protein hard corona composition. This was accomplished using a family of gadolinium carrying PRs composed of triblock Pluronic co-polymers of varying molecular weights and hydrophilic/lipophilic ratios. The effect of varying threaded beta-CD derivative surface chemistry on PR mediated hemolysis and hard protein corona was also studied. Knowing if structure-property relationships exist in the in vivo performances of PR materials will help with building pre-clinical profile, selecting candidate materials for a given application, and understanding therapeutic outcomes.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fujimoto, Michiko; Hayashi, Teruo, E-mail: thayashi@mail.nih.gov; Su, Tsung-Ping, E-mail: tsu@intra.nida.nih.gov

Highlights: Black-Right-Pointing-Pointer The endoplasmic reticulum subdomain termed MAM associates with mitochondria. Black-Right-Pointing-Pointer The biophysical role of lipids in the MAM-mitochondria association is unknown. Black-Right-Pointing-Pointer The in vitro membrane association assay was used to examine the role of lipids. Black-Right-Pointing-Pointer Cholesterol was found to negatively regulate the association. -- Abstract: The unique endoplasmic reticulum (ER) subdomain termed the mitochondria-associated ER membrane (MAM) engages the physical connection between the ER and the mitochondrial outer membrane and plays a role in regulating IP{sub 3} receptor-mediated Ca{sup 2+} influx and the phospholipid transport between the two organelles. The MAM contains certain signaling and membrane-tetheringmore » proteins but also lipids including cholesterol. The biophysical role of lipids at the MAM, specifically in the physical interaction between the MAM of the ER and mitochondria, remains not totally clarified. Here we employed the in vitro membrane association assay to investigate the role of cholesterol in the association between MAMs and mitochondria. The purified MAMs and mitochondria were mixed in vitro in a test tube and then the physical association of the two subcellular organelles was quantified indirectly by measuring the presence of the MAM-specific protein sigma-1 receptors in the mitochondria fraction. Purified MAMs contained free cholesterol approximately 7 times higher than that in microsomes. We found that depletion of cholesterol in MAMs with methyl-{beta}-cyclodextrin (M{beta}C) significantly increases the association between MAMs and mitochondria, whereas M{beta}C saturated with cholesterol does not change the association. {sup 14}C-Serine pulse-labeling demonstrated that the treatment of living cells with M{beta}C decreases the level of de novo synthesized {sup 14}C-phosphatidylserine (PtSer) and concomitantly increases greatly the synthesis of {sup 14}C-phosphatidylethanolamine (PtEt). Apparently, cholesterol depletion increased the PtSer transport from MAMs to mitochondria. Our findings suggest that cholesterol is an important substrate in regulating the association between MAMs of the ER and mitochondria.« less

Metabolism of methyltestosterone in the greyhound.

PubMed

Biddle, S T B; O'Donnell, A; Houghton, E; Creaser, C

2009-03-01

Gas chromatography/mass spectrometry and selective derivatisation techniques have been used to identify urinary metabolites of methyltestosterone following oral administration to the greyhound. Several metabolites were identified including reduced, mono-, di- and trihydroxylated steroids. The major metabolites observed were 17alpha-methyl-5beta-androstane-3alpha-17beta-diol, 17alpha-methyl-5beta-androstane-3alpha,16alpha,17beta-triol, and a further compound tentatively identified as 17alpha-methyl-5z-androstane-6z,17beta-triol. The most abundant of these was the 17alpha-methyl-5beta-androstane-3alpha,16alpha,17beta-triol. This metabolite was identified by comparison with a reference standard synthesised using a Grignard procedure and characterised using trimethylsilyl (TMS) and acetonide-TMS derivatisation techniques. There did not appear to be any evidence for 16beta-hydroxylation as a phase I metabolic transformation in the greyhound. However, significant quantities of 16alpha-hydroxy metabolites were detected. Selective enzymatic hydrolysis procedures indicated that the major metabolites identified were excreted as glucuronic acid conjugates. Metabolic transformations observed in the greyhound have been compared with those of other mammalian species and are discussed here. John Wiley & Sons, Ltd

Influence of organic matter, nutrients, and cyclodextrin on microbial and chemical herbicide and degradate dissipation in subsurface sediment slurries.

PubMed

Kerminen, Kaisa; Le Moël, Romain; Harju, Vilhelmiina; Kontro, Merja H

2018-03-15

Pesticides leaching from soil to surface and groundwater are a global threat for drinking water safety, as no cleaning methods occur for groundwater environment. We examined whether peat, compost-peat-sand (CPS) mixture, NH 4 NO 3 , NH 4 NO 3 with sodium citrate (Na-citrate), and the surfactant methyl-β-cyclodextrin additions enhance atrazine, simazine, hexazinone, dichlobenil, and the degradate 2,6-dichlorobenzamide (BAM) dissipations in sediment slurries under aerobic and anaerobic conditions, with sterilized controls. The vadose zone sediment cores were drilled from a depth of 11.3-14.6m in an herbicide-contaminated groundwater area. The peat and CPS enhanced chemical atrazine and simazine dissipation, and the peat enhanced chemical hexazinone dissipation, all oxygen-independently. Dichlobenil dissipated under all conditions, while BAM dissipation was fairly slow and half-lives could not be calculated. The chemical dissipation rates could be associated with the chemical structures and properties of the herbicides, and additive compositions, not with pH. Microbial atrazine degradation was only observed in the Pseudomonas sp. ADP amended slurries, although the sediment slurries were known to contain atrazine-degrading microorganisms. The bioavailability of atrazine in the water phase seemed to be limited, which could be due to complex formation with organic and inorganic colloids. Atrazine degradation by indigenous microbes could not be stimulated by the surfactant methyl-β-cyclodextrin, or by the additives NH 4 NO 3 and NH 4 NO 3 with Na-citrate, although the nitrogen additives increased microbial growth. Copyright © 2017 Elsevier B.V. All rights reserved.

Host-guest complex formation in cyclotrikis-(1-->6).

PubMed

Cescutti, P; Utille, J P; Rizzo, R

2000-11-17

The possibility that cyclotrikis-(1-->6)-[alpha-D-glucopyranosyl-(1-->4)-beta-D-glucopyranosyl] (CGM6) forms inclusion complexes, like cycloamyloses (cyclodextrins), was investigated by means of electrospray mass spectrometry and fluorescence spectroscopy. The complexing ability of both 1-anilinonaphthalene-8-sulfonate (ANS) and 2-p-toluidinylnaphthalene-6-sulfonate (TNS), which were already used with cyclodextrins, was investigated. The former showed very little or no tendency to be complexed by CGM6, while the latter produced detectable adducts with CGM6. Fixed 90 degree angle light scattering experiments supported the findings obtained by molecular modelling calculations, which indicated a polar character for the CGM6 internal cavity. CGM6-TNS complexes were probably formed throughout interaction of the polar regions of the two molecules.

Electrospinning of nanofibers from non-polymeric systems: polymer-free nanofibers from cyclodextrin derivatives

NASA Astrophysics Data System (ADS)

Celebioglu, Asli; Uyar, Tamer

2012-01-01

High molecular weight polymers and high polymer concentrations are desirable for the electrospinning of nanofibers since polymer chain entanglements and overlapping are important for uniform fiber formation. Hence, the electrospinning of nanofibers from non-polymeric systems such as cyclodextrins (CDs) is quite a challenge since CDs are cyclic oligosaccharides. Nevertheless, in this study, we have successfully achieved the electrospinning of nanofibers from chemically modified CDs without using a carrier polymer matrix. Polymer-free nanofibers were electrospun from three different CD derivatives, hydroxypropyl-β-cyclodextrin (HPβCD), hydroxypropyl-γ-cyclodextrin (HPγCD) and methyl-β-cyclodextrin (MβCD) in three different solvent systems, water, dimethylformamide (DMF) and dimethylacetamide (DMAc). We observed that the electrospinning of these CDs is quite similar to polymeric systems in which the solvent type, the solution concentration and the solution conductivity are some of the key factors for obtaining uniform nanofibers. Dynamic light scattering (DLS) measurements indicated that the presence of considerable CD aggregates and the very high solution viscosity were playing a key role for attaining nanofibers from CD derivatives without the use of any polymeric carrier. The electrospinning of CD solutions containing urea yielded no fibers but only beads or splashes since urea caused a notable destruction of the self-associated CD aggregates in their concentrated solutions. The structural, thermal and mechanical characteristics of the CD nanofibers were also investigated. Although the CD derivatives are amorphous small molecules, interestingly, we observed that these electrospun CD nanofibers/nanowebs have shown some mechanical integrity by which they can be easily handled and folded as a free standing material.

β-cyclodextrin in personal care formulations: role on the complexation of malodours causing molecules.

PubMed

Lopedota, A; Cutrignelli, A; Laquintana, V; Franco, M; Donelli, D; Ragni, L; Tongiani, S; Denora, N

2015-08-01

The aim of this study was to prove the capability of β-cyclodextrin (β-CD) to interact with some representative molecules responsible to cause body malodour, such as carboxylic acids, thiols and steroids, present in sweat and body secretions. The association constants in guest-CD were determined by (1) H-NMR spectroscopy for thiols and steroids such as 3-mercapto-1-hexanol, androstenone, androstenol and androsterone, and pH-potentiometric titration for acetic acid, l(+) lactic acid, isobutyric acid, isovaleric acid and 3-hydroxy-3-methyl-hexanoic acid. All considered systems are able to interact with relatively weak association constants with β-cyclodextrin, in a 1 : 1 host-guest ratio. From these findings, it is possible to conclude that β-CD is capable to interact with different components present in the sweat and body secretion, forming inclusion complexes. For this reason, β-CD could be a component of body care formulations, such as deodorants. © 2015 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

9-Methyl-beta-carboline has restorative effects in an animal model of Parkinson's disease.

PubMed

Wernicke, Catrin; Hellmann, Julian; Zieba, Barbara; Kuter, Katarzyna; Ossowska, Krystyna; Frenzel, Monika; Dencher, Norbert A; Rommelspacher, Hans

2010-01-01

In a previous study, a primary culture of midbrain cells was exposed to 9-methyl-beta-carboline for 48 h, which caused an increase in the number of tyrosine hydroxylase-positive cells. Quantitative RT-PCR revealed increased transcription of genes participating in the maturation of dopaminergic neurons. These in vitro findings prompted us to investigate the restorative actions of 9-methyl-beta-carboline in vivo. The compound was delivered for 14 days into the left cerebral ventricle of rats pretreated with the neurotoxin 1-methyl-4-phenyl-pyridinium ion (MPP+) for 28 days applying a dose which lowered dopamine by approximately 50%. Interestingly, 9-methyl-beta-carboline reversed the dopamine-lowering effect of the neurotoxin in the left striatum. Stereological counts of tyrosine hydroxylase-immunoreactive cells in the substantia nigra revealed that the neurotoxin caused a decrease in the number of those cells. However, when treated subsequently with 9-methyl-beta-carboline, the number reached normal values. In search of an explanation for the restorative activity, we analyzed the complexes that compose the respiratory chain in striatal mitochondria by 2-dimension gel electrophoresis followed by MALDI-TOF peptide mass fingerprinting.We found no changes in the overall composition of the complexes. However, the activity of complex I was increased by approximately 80% in mitochondria from rats treated with MPP+ and 9-methyl-beta-carboline compared to MPP+ and saline and to sham-operated rats, as determined by measurements of nicotinamide adenine dinucleotide dehydrogenase activity. Microarray technology and single RT-PCR revealed the induction of neurotrophins: brain-derived neurotrophic factor, conserved dopamine neurotrophic factor, cerebellin 1 precursor protein, and ciliary neurotrophic factor. Selected western blots yielded consistent results. The findings demonstrate restorative effects of 9-methyl-beta-carboline in an animal model of Parkinson's disease that improve the effectiveness of the respiratory chain and promote the transcription and expression of neurotrophin-related genes.

Investigation of Cyclodextrin-Based Nanosponges for Solubility and Bioavailability Enhancement of Rilpivirine.

PubMed

Rao, Monica R P; Chaudhari, Jagruti; Trotta, Francesco; Caldera, Fabrizio

2018-06-04

Rilpivrine is BCS class II drug used for treatment of HIV infection. The drug has low aqueous solubility (0.0166 mg/ml) and dissolution rate leading to low bioavailability (32%). Aim of this work was to enhance solubility and dissolution of rilpivirine using beta-cyclodextrin-based nanosponges. These nanosponges are biocompatible nanoporous particles having high loading capacity to form supramolecular inclusion and non-inclusion complexes with hydrophilic and lipophilic drugs for solubility enhancement. Beta-cyclodextrin was crosslinked with carbonyl diimidazole and pyromellitic dianhydride to prepare nanosponges. The nanosponges were loaded with rilpivirine by solvent evaporation method. Binary and ternary complexes of drug with β-CD, HP-β-CD, nanosponges, and tocopherol polyethylene glycol succinate were prepared and characterized by phase solubility, saturation solubility in different media, in vitro dissolution, and in vivo pharmacokinetics. Spectral analysis by Fourier transform infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry was performed. Results obtained from spectral characterization confirmed inclusion complexation. Phase solubility studies indicated stable complex formation. Saturation solubility was found to be 10-13-folds higher with ternary complexes in distilled water and 12-14-fold higher in 0.1 N HCl. Solubility enhancement was evident in biorelevant media. Molecular modeling studies revealed possible mode of entrapment of rilpivirine within β-CD cavities. A 3-fold increase in dissolution with ternary complexes was observed. Animal studies revealed nearly 2-fold increase in oral bioavailability of rilpivirine. It was inferred that electronic interactions, hydrogen bonding, and van der Waals forces are involved in the supramolecular interactions.

A convenient synthesis of a novel nucleoside analogue: 4-(alpha-diformyl-methyl)-1-(beta-D-ribofuranosyl)-2-pyrimidinone.

PubMed

Gao, K; Orgel, L E

2000-01-01

The nucleoside analogue 4-(alpha-diformyl-methyl)-1-(beta-D-ribofuranosyl)-2-pyrimidinone (5) was prepared from the corresponding 4-methyl pyrimidinone nucleoside by means of the Vilsmeier reaction. The unprotected nucleoside can be phosphorylated directly with phosphorus oxychloride in triethyl phosphate.

A convenient synthesis of a novel nucleoside analogue: 4-(alpha-diformyl-methyl)-1-(beta-D-ribofuranosyl)-2-pyrimidinone

NASA Technical Reports Server (NTRS)

Gao, K.; Orgel, L. E.; Bada, J. L. (Principal Investigator)

2000-01-01

The nucleoside analogue 4-(alpha-diformyl-methyl)-1-(beta-D-ribofuranosyl)-2-pyrimidinone (5) was prepared from the corresponding 4-methyl pyrimidinone nucleoside by means of the Vilsmeier reaction. The unprotected nucleoside can be phosphorylated directly with phosphorus oxychloride in triethyl phosphate.

DRME: Count-based differential RNA methylation analysis at small sample size scenario.

PubMed

Liu, Lian; Zhang, Shao-Wu; Gao, Fan; Zhang, Yixin; Huang, Yufei; Chen, Runsheng; Meng, Jia

2016-04-15

Differential methylation, which concerns difference in the degree of epigenetic regulation via methylation between two conditions, has been formulated as a beta or beta-binomial distribution to address the within-group biological variability in sequencing data. However, a beta or beta-binomial model is usually difficult to infer at small sample size scenario with discrete reads count in sequencing data. On the other hand, as an emerging research field, RNA methylation has drawn more and more attention recently, and the differential analysis of RNA methylation is significantly different from that of DNA methylation due to the impact of transcriptional regulation. We developed DRME to better address the differential RNA methylation problem. The proposed model can effectively describe within-group biological variability at small sample size scenario and handles the impact of transcriptional regulation on RNA methylation. We tested the newly developed DRME algorithm on simulated and 4 MeRIP-Seq case-control studies and compared it with Fisher's exact test. It is in principle widely applicable to several other RNA-related data types as well, including RNA Bisulfite sequencing and PAR-CLIP. The code together with an MeRIP-Seq dataset is available online (https://github.com/lzcyzm/DRME) for evaluation and reproduction of the figures shown in this article. Copyright © 2016 Elsevier Inc. All rights reserved.

Japan Report, Science and Technology.

DTIC Science & Technology

1987-02-06

cyclodextrin, which consists of natural cyclic oligosaccharides . Recently, the author and co-workers have found that methylated CD works as an effective...industry as catalysts for the production of olefin derivatives. This is quite interesting, when we compare it with the shitasu process . Research on...lasers in machin- ing and medicine, particularly in semiconductor processing . According to the Optoelectronic Industry and Technology Development

(-)-3 beta,4 beta-epoxyvalerenic acid from Valeriana officinalis.

PubMed

Dharmaratne, H Ranjith; Nanayakkara, N P; Khan, Ikhlas A

2002-07-01

Chemical investigation of the root extract of Valeriana officinalis afforded a new bicyclic sesquiterpene acid, (-)-3 beta,4 beta-epoxyvalerenic acid together with valerenic acid and hexadecanoic acid. The structure of the new compound was elucidated by spectroscopic data and confirmed by partial synthesis of its methyl ester from valerenic acid. Methyl (-)-3 alpha,4 alpha-epoxyvalerenate was obtained as a minor product from the above reaction.

Use of cyclodextrins in biotransformation reactions with cell cultures of Morus nigra: biosynthesis of prenylated chalcone isocordoin.

PubMed

Bolasco, Adriana; Fioravanti, Rossella; Rossi, Francesca; Rossi, Paola; Vitali, Alberto

2010-06-16

In vivo biotransformation experiments were performed by using a cell suspension culture of Morus nigra expressing a high PT (prenyltransferase) activity, fed with the target substrate 2',4'-dihydroxychalcone. In order to improve the reaction yields by enhancing the chalcone solubility, three different cyclodextrins have been used to host the substrate. The respective complexes have been studied by means of both spectroscopic and calorimetric techniques (Fourier-transform infrared, 1H-NMR and differential scanning calorimetry) and the solution behaviours have been characterized by solubility phase studies. The hydroxypropyl-beta-cyclodextrin complex was found to be the most suitable for biotransformation, and the reaction of prenylation resulted in a 6-fold higher yield of the final product when compared with the use of the free substrate. The reaction provided as the sole product the 3'-dimethylallyl derivative isocordoin, a biologically active plant compound. The results obtained allow the development of systems based on the use of biofermentors or the use of immobilized cells in order to enhance the biotransformation yields.

Cyclodextrin Complexes of Reduced Bromonoscapine in Guar Gum Microspheres Enhance Colonic Drug Delivery

PubMed Central

2015-01-01

Here, we report improved solubility and enhanced colonic delivery of reduced bromonoscapine (Red-Br-Nos), a cyclic ether brominated analogue of noscapine, upon encapsulation of its cyclodextrin (CD) complexes in bioresponsive guar gum microspheres (GGM). Phase–solubility analysis suggested that Red-Br-Nos complexed with β-CD and methyl-β-CD in a 1:1 stoichiometry, with a stability constant (Kc) of 2.29 × 103 M–1 and 4.27 × 103 M–1. Fourier transforms infrared spectroscopy indicated entrance of an O–CH2 or OCH3–C6H4–OCH3 moiety of Red-Br-Nos in the β-CD or methyl-β-CD cavity. Furthermore, the cage complex of Red-Br-Nos with β-CD and methyl-β-CD was validated by several spectral techniques. Rotating frame Overhauser enhancement spectroscopy revealed that the Ha proton of the OCH3–C6H4–OCH3 moiety was closer to the H5 proton of β-CD and the H3 proton of the methyl-β-CD cavity. The solubility of Red-Br-Nos in phosphate buffer saline (PBS, pH ∼ 7.4) was improved by ∼10.7-fold and ∼21.2-fold when mixed with β-CD and methyl-β-CD, respectively. This increase in solubility led to a favorable decline in the IC50 by ∼2-fold and ∼3-fold for Red-Br-Nos−β-CD-GGM and Red-Br-Nos–methyl-β-CD-GGM formulations respectively, compared to free Red-Br-Nos−β-CD and Red-Br-Nos–methyl-β-CD in human colon HT-29 cells. GGM-bearing drug complex formulations were found to be highly cytotoxic to the HT-29 cell line and further effective with simultaneous continuous release of Red-Br-Nos from microspheres. This is the first study to showing the preparation of drug-complex loaded GGMS for colon delivery of Red-Br-Nos that warrants preclinical assessment for the effective management of colon cancer. PMID:25350222

Roles of specific membrane lipid domains in EGF receptor activation and cell adhesion molecule stabilization in a developing olfactory system.

PubMed

Gibson, Nicholas J; Tolbert, Leslie P; Oland, Lynne A

2009-09-29

Reciprocal interactions between glial cells and olfactory receptor neurons (ORNs) cause ORN axons entering the brain to sort, to fasciculate into bundles destined for specific glomeruli, and to form stable protoglomeruli in the developing olfactory system of an experimentally advantageous animal species, the moth Manduca sexta. Epidermal growth factor receptors (EGFRs) and the cell adhesion molecules (IgCAMs) neuroglian and fasciclin II are known to be important players in these processes. We report in situ and cell-culture studies that suggest a role for glycosphingolipid-rich membrane subdomains in neuron-glia interactions. Disruption of these subdomains by the use of methyl-beta-cyclodextrin results in loss of EGFR activation, depletion of fasciclin II in ORN axons, and loss of neuroglian stabilization in the membrane. At the cellular level, disruption leads to aberrant ORN axon trajectories, small antennal lobes, abnormal arrays of olfactory glomerul, and loss of normal glial cell migration. We propose that glycosphingolipid-rich membrane subdomains (possible membrane rafts or platforms) are essential for IgCAM-mediated EGFR activation and for anchoring of neuroglian to the cytoskeleton, both required for normal extension and sorting of ORN axons.

Determination of total antioxidant capacity by oxygen radical absorbance capacity (ORAC) using fluorescein as the fluorescence probe: First Action 2012.23.

PubMed

Ou, Boxin; Chang, Tony; Huang, Dejian; Prior, Ronald L

2013-01-01

An improved method for the measurement of oxygen radical absorbance capacity (ORAC) was developed and validated using fluorescein (3',6'-dihydroxyspiro[isobenzofuran-1[3H], 9'[9H]-xanthen]-3-one) as a new fluorescence probe (ORAC(FL)). Randomly methylated beta-cyclodextrin (RMCD) was introduced as the water-solubility enhancer for lipophilic antioxidants. 7% RMCD (w/v) in 50% acetone-H2O mixture sufficiently solubilized vitamin E compounds and other lipophilic phenolic antioxidants in 75 mM phosphate buffer (pH 7.4). Results indicated that fluorescein shows excellent photostability under the plate reader conditions. This ORAC(FL) was validated through linearity, precision, accuracy, and ruggedness. The validation results demonstrated that the ORACFL assay is reliable and robust. The mean of intraday and interday CVs were <15%; for hydrophilic ORAC, LOD and LOQ are 5 and 6.25 microM, respectively; for lipophilic ORAC, LOD and LOQ are 6.25 and 12.5 microM, respectively. It is concluded that unlike other popular methods, the ORAC(FL) assay provides a direct measure of total antioxidant capacity against the peroxyl radicals.

Correlation of beta-catenin localization with cyclooxygenase-2 expression and CpG island methylator phenotype (CIMP) in colorectal cancer.

PubMed

Kawasaki, Takako; Nosho, Katsuhiko; Ohnishi, Mutsuko; Suemoto, Yuko; Kirkner, Gregory J; Dehari, Reiko; Meyerhardt, Jeffrey A; Fuchs, Charles S; Ogino, Shuji

2007-07-01

The WNT/beta-catenin (CTNNB1) pathway is commonly activated in the carcinogenic process. Cross-talks between the WNT and cyclooxygenase-2 (COX-2 or PTGS2)/prostaglandin pathways have been suggested. The relationship between beta-catenin activation and microsatellite instability (MSI) in colorectal cancer has been controversial. The CpG island methylator phenotype (CIMP or CIMP-high) with widespread promoter methylation is a distinct epigenetic phenotype in colorectal cancer, which is associated with MSI-high. However, no study has examined the relationship between beta-catenin activation and CIMP status. Using 832 population-based colorectal cancer specimens, we assessed beta-catenin localization by immunohistochemistry. We quantified DNA methylation in eight CIMP-specific promoters [CACNA1G, CDKN2A(p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1] by real-time polymerase chain reaction (MethyLight). MSI-high, CIMP-high, and BRAF mutation were associated inversely with cytoplasmic and nuclear beta-catenin expressions (i.e., beta-catenin activation) and associated positively with membrane expression. The inverse relation between beta-catenin activation and CIMP was independent of MSI. COX-2 overexpression correlated with cytoplasmic beta-catenin expression (even after tumors were stratified by CIMP status), but did not correlate significantly with nuclear or membrane expression. In conclusion, beta-catenin activation is inversely associated with CIMP-high independent of MSI status. Cytoplasmic beta-catenin is associated with COX-2 overexpression, supporting the role of cytoplasmic beta-catenin in stabilizing PTGS2 (COX-2) mRNA.

Hydration Differences Explain the Large Variations in the Complexation Thermodynamics of Modified γ-Cyclodextrins with Bile Salts.

PubMed

Køhler, Jonatan; Schönbeck, Christian; Westh, Peter; Holm, René

2016-01-28

The structure and thermodynamics of inclusion complexes of seven different γ-cyclodextrins (γCDs) and three biologically relevant bile salts (BS) were investigated in the present study. Natural γCD and six modified γCDs [two methyl-γCDs, one sulfobutyl ether-γCD (SBEγCD), and three 2-hydroxypropyl-γCDs (HPγCD)] and their complexes with BS were investigated by isothermal titration calorimetry, NMR, and molecular dynamics simulations. With the exception of the fully methylated γCD, which did not bind the BSs investigated, all of the γCDs formed 1:1 complexes with the BS, and the structures were similar to those with natural γCD; i.e., the modifications of the γCD had limited structural impact on the formation of complexes. Isothermal titration calorimetry was carried out over in the temperature interval 5-55 °C to enable the calculation of the stability constant (K) and the thermodynamic parameters enthalpy (ΔH°), entropy (ΔS°), and heat capacity (ΔCp°). The stability constants decreased with an increased degree of substitution (DS), with methyl substituents having a lower effect on the stability constant than the sulfobutyl ether and hydroxypropyl substituents on the stability constants. Enthalpy-entropy compensation was observed, since both enthalpy and entropy increased with the degree of substitution, which may reflect dehydration of the hydrophobic surface on both CD and BS. Calculations based on ΔCp° data suggested that each of the substituents dehydrated 10-20 (hydroxypropyl), 22-33 (sulfobutyl ether), and 10-15 Å(2) (methyl) of the BS surface area, in reasonable agreement with estimates from the molecular dynamics simulations. Combined with earlier investigations on modified βCDs, these results indicate general trends of the substituents on the thermodynamics of complex formation.

Bacterial production of methyl ketones

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beller, Harry R.; Goh, Ee-Been

The present invention relates to methods and compositions for increasing production of methyl ketones in a genetically modified host cell that overproduces .beta.-ketoacyl-CoAs through a re-engineered .beta.-oxidation pathway and overexpresses FadM.

Plasma Membrane Cholesterol as a Regulator of Human and Rodent P2X7 Receptor Activation and Sensitization*

PubMed Central

Robinson, Lucy E.; Shridar, Mitesh; Smith, Philip; Murrell-Lagnado, Ruth D.

2014-01-01

P2X7 receptors are nonselective cation channels gated by high extracellular ATP, but with sustained activation, receptor sensitization occurs, whereby the intrinsic pore dilates, making the cell permeable to large organic cations, which eventually leads to cell death. P2X7 receptors associate with cholesterol-rich lipid rafts, but it is unclear how this affects the properties of the receptor channel. Here we show that pore-forming properties of human and rodent P2X7 receptors are sensitive to perturbations of cholesterol levels. Acute depletion of cholesterol with 5 mm methyl-β-cyclodextrin (MCD) caused a substantial increase in the rate of agonist-evoked pore formation, as measured by the uptake of ethidium dye, whereas cholesterol loading inhibited this process. Patch clamp analysis of P2X7 receptor currents carried by Na+ and N-methyl-d-glucamine (NMDG+) showed enhanced activation and current facilitation following cholesterol depletion. This contrasts with the inhibitory effect of methyl-β-cyclodextrin reported for other P2X subtypes. Mutational analysis suggests the involvement of an N-terminal region and a proximal C-terminal region that comprises multiple cholesterol recognition amino acid consensus (CRAC) motifs, in the cholesterol sensitivity of channel gating. These results reveal cholesterol as a negative regulator of P2X7 receptor pore formation, protecting cells from P2X7-mediated cell death. PMID:25281740

Steroid catechol degradation: disecoandrostane intermediates accumulated by Pseudomonas transposon mutant strains.

PubMed

Leppik, R A

1989-07-01

Eleven transposon mutant strains affected in bile acid catabolism were each found to form yellow, muconic-like intermediates from bile acids. To characterize these unstable intermediates, media from the growth of one of these mutants with deoxycholic acid was treated with ammonia, then the crude product was methylated with diazomethane. Four compounds were subsequently isolated; spectral evidence suggested that they were methyl 12 alpha-hydroxy-3-oxo-23,24-dinorchola-1,4-dien-22-oate, methyl 4-aza-12 beta-hydroxy-9(10)-secoandrosta-1,3,5-triene-9,17-dione-3-carboxyl ate, 4-aza-9 alpha, 12 beta-dihydroxy-9(10)-secoandrosta-1,3,5-trien-17-one-3- methyl carboxylate and 4 alpha-[3'-propionic acid]-5-amino-7 beta-hydroxy-7 alpha beta-methyl- 3a alpha, 4,7,7a-tetrahydro-1-indanone-delta-lactam. It is proposed that the mutants are blocked in the utilization of such muconic-like compounds as the 3,12 beta-dihydroxy-5,9,17-trioxo-4(5),9(10)- disecoandrostal (10),2-dien-4-oic acid formed from deoxycholic acid. A further mutant was examined, which converted deoxycholic acid to 12 alpha-hydroxyandrosta-1,4-dien-3,17-dione, but accumulated yellow products from steroids which lacked a 12 alpha-hydroxy function, such as chenodeoxycholic acid. The products from the latter acid were treated as above; spectral evidence suggested that the two compounds isolated were methyl 4-aza-7-hydroxy-9(10)-secoandrosta-1,3,5- triene-9,17-dione-3-carboxylate and 4 alpha-[1'alpha-hydroxy-3'-propionic acid]-5-amino-7a beta-methyl-3a alpha,4,7,7a-tetrahydro-1-indanone-delta-lactam.

Pilot-scale electrokinetic movement of HCB and Zn in real contaminated sediments enhanced with hydroxypropyl-beta-cyclodextrin.

PubMed

Li, Taiping; Yuan, Songhu; Wan, Jinzhong; Lin, Li; Long, Huayun; Wu, Xiaofeng; Lu, Xiaohua

2009-08-01

This study deals with the efficiency of a pilot-scale electrokinetic (EK) treatment on real aged sediments contaminated with hexachlorobenzene (HCB) and Zn. A total of 0.5m(3) of sediments were treated under a constant voltage in a polyvinyl chloride reactor. The changes of sediment pH, electrical conductivity (EC), organic content (OC), the transport of contaminants in sediments and the consumption of electric energy were evaluated. After 100 d processing, sediment pH slightly increased compared with the initial values, particularly in the bottom layer close to cathodic section, while sediment EC in most sections significantly decreased. Sediment OC in all sections increased, which implied that hydroxypropyl-beta-cyclodextrin (HPCD) was successfully penetrated across sediments by electroosmosis. Significant movement of contaminants was observed across sediments with negligible removals. Both HCB and Zn generally moved from sections near anode and accumulated near cathode. Upon the completion of treatment, the electric energy consumption was calculated as 563 kWhm(-3). This pilot-scale EK test indicates that it is difficult to achieve great removal of hydrophobic organic compounds (HOCs), or HOCs and heavy metal mixed contaminants, by EK treatment in large scale with the use of HPCD.

A pilot study of direct delivery of hydroxypropyl-beta-cyclodextrin to the lung by the nasal route in a mouse model of Niemann-Pick C1 disease: motor performance is unaltered and lung disease is worsened.

PubMed

Erickson, Robert P; Deutsch, Gail; Patil, Ruturaj

2018-05-01

We have tested the efficacy of hydroxypropyl-beta-cyclodextrin (HPBCD) delivered by the nasal route in the mouse model of juvenile Niemann-Pick C1 disease (NPC1), as pulmonary disease has not responded to systemic therapy with this drug. Since mice have no gag reflex, coating of the nasal cavity, with possible access to the brain, would be followed by delivery of HPBCD to the lung. While foamy macrophages, containing stored cholesterol, were found in the Npc1 nmf164 homozygous mice, a marked inflammatory response was found with inhaled HPBCD, both in mutant and wild-type animals. Slight inflammation also occasionally occurred with saline inhalation. There was no difference between the saline-treated, HPBCD-treated, and untreated Npc1 nmf164 homozygous mice for weight, balance beam performance, or coat hanger performance. Interestingly, there was a trend to longer survival in the HPBCD-treated Npc1 nmf164 homozygous mice, which, when combined with the survival times of the saline-treated survivals (each of which was not different), became significant.

Chiral determination of cinchonine using an electrochemiluminescent sensor with molecularly imprinted membrane on the surfaces of magnetic particles.

PubMed

Yuan, Xingyi; Tan, Yanji; Wei, Xiaoping; Li, Jianping

2017-11-01

A novel molecular imprinting electrochemiluminescence sensor for detecting chiral cinchonine molecules was developed with a molecularly imprinted polymer membrane on the surfaces of magnetic microspheres. Fe 3 O 4 @Au nanoparticles modified with 6-mercapto-beta-cyclodextrin were used as a carrier, cinchonine as a template molecule, methacrylic acid as a functional monomer and N,N'-methylenebisacrylamide as a cross-linking agent. Cinchonine was specifically recognized by the 6-mercapto-beta-cyclodextrin functional molecularly imprinted polymer and detected based on enhancement of the electrochemiluminescence intensity caused by the reaction of tertiary amino structures of cinchonine molecules with Ru(bpy) 3 2+ . Cinchonine concentrations of 1 × 10 -10 to 4 × 10 -7  mol/L showed a good linear relationship with changes of the electrochemiluminescence intensity, and the detection limit of the sensor was 3.13 × 10 -11  mol/L. The sensor has high sensitivity and selectivity, and is easy to renew. It was designed for detecting serum samples, with recovery rates of 98.2% to 107.6%. Copyright © 2017 John Wiley & Sons, Ltd.

Conformation of methyl beta-lactoside bound to the ricin B-chain: Interpretation of transferred nuclear Overhauser effects facilitated by spin simulation and selective deuteration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bevilacqua, V.L.; Thomson, D.S.; Prestegard, J.H.

1990-06-12

Spin simulation and selective deuteration have been used to aid in the interpretation of 1D transferred nuclear Overhauser effect (TRNOE) NMR experiments on ricin B-chain/ligand systems. Application of these methods has revealed a change in the conformation of deuterated methyl beta-lactoside upon binding to the ricin B-chain which results in a slight change in glycosidic torsional angels which appear to dominate in the solution conformation. The combination of simulation and experiment also shows an important sensitivity of TRNOE magnitudes to dissociation rate constants and available spin-diffusion pathways for the ricin B-chain/ligand systems under study. The sensitivity to dissociation rates allowsmore » determination of rate constants for methyl beta-lactoside and methyl beta-galactoside of 50 and 300 s-1, respectively.« less

Host-guest complexes of 2-hydroxypropyl-β-cyclodextrin/β-cyclodextrin and nifedipine: 1H NMR, molecular modeling, and dissolution studies

NASA Astrophysics Data System (ADS)

de Araújo, Márcia Valéria Gaspar; Vieira, João Victor Francisco; da Silva, Caroline W. P.; Barison, Andersson; Andrade, George Ricardo Santana; da Costa, Nivan Bezerra; Barboza, Fernanda Malaquias; Nadal, Jessica Mendes; Novatski, Andressa; Farago, Paulo Vitor; Zawadzki, Sônia Faria

2017-12-01

Nifedipine (NIF) is a hydrophobic drug widely used for treating cardiovascular diseases. This calcium channel blocker can present a higher apparent solubility by its inclusion into different cyclodextrins (CDs) as host-guest complexes. This paper focused on the structural investigation and dissolution behavior of inclusion complexes prepared with 2-hydroxypropyl-β-cyclodextrin (HPβCD) or β-cyclodextrin (βCD) and NIF. Drug amorphization was observed for HPβCD/NIF and βCD/NIF inclusion complexes by X-ray diffractometry (XRD). The sharp endothermic peak of NIF was not observed for these both host-guest complexes by differential scanning calorimetry (DSC). These results of XRD and DSC provide evidences of complexation between drug and the investigated CDs. 1H and saturation transfer difference nuclear magnetic resonance studies revealed the enhancement in the signal at 2.27 ppm for HPβCD/NIF and βCD/NIF inclusion complexes that corresponded to the methyl groups of NIF from the non-aromatic ring. This result suggested that non-aromatic ring of NIF was inserted into HPβCD and βCD cavities. Considering the mathematical simulations, it was observed that the inclusion process can occur in the both NH-in or NH-out forms. However, since it was used aqueous medium, it is possible to indicate that the obtained host-guest complexes HPβCD/NIF and βCD/NIF are in NH-in form which corresponded to the previous results obtained by 1H NMR experiments. Dissolution assays demonstrated that NIF inclusion complexes improved the drug release nevertheless without changing its biexponential release behavior. These host-guest complexes can be further used as feasible NIF carriers in solid dosage forms.

Separation of 20 coumarin derivatives using the capillary electrophoresis method optimized by a series of Doehlert experimental designs.

PubMed

Woźniakiewicz, Michał; Gładysz, Marta; Nowak, Paweł M; Kędzior, Justyna; Kościelniak, Paweł

2017-05-15

The aim of this study was to develop the first CE-based method enabling separation of 20 structurally similar coumarin derivatives. To facilitate method optimization a series of three consequent Doehlert experimental designs with the response surface methodology was employed, using number of peaks and the adjusted time of analysis as the selected responses. Initially, three variables were examined: buffer pH, ionic strength and temperature (No. 1 Doehlert design). The optimal conditions provided only partial separation, on that account, several buffer additives were examined at the next step: organic cosolvents and cyclodextrin (No. 2 Doehlert design). The optimal cyclodextrin type was also selected experimentally. The most promising results were obtained for the buffers fortified with methanol, acetonitrile and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin. Since these additives may potentially affect acid-base equilibrium and ionization state of analytes, the third Doehlert design (No. 3) was used to reconcile concentration of these additives with optimal pH. Ultimately, the total separation of all 20 compounds was achieved using the borate buffer at basic pH 9.5 in the presence of 10mM cyclodextrin, 9% (v/v) acetonitrile and 36% (v/v) methanol. Identity of all compounds was confirmed using the in-lab build UV-VIS spectra library. The developed method succeeded in identification of coumarin derivatives in three real samples. It demonstrates a huge resolving power of CE assisted by addition of cyclodextrins and organic cosolvents. Our unique optimization approach, based on the three Doehlert designs, seems to be prospective for future applications of this technique. Copyright © 2017 Elsevier B.V. All rights reserved.

Development of a dual-analyte fluorescent sensor for the determination of bioactive nitrite and selenite in water samples.

PubMed

Martínez-Tomé, M J; Esquembre, R; Mallavia, R; Mateo, C R

2010-01-20

Nitrite and selenium are two bioactive compounds found in the environment which show beneficial effects for health at low levels but have toxic effects at higher doses. Consequently, quantification of both analytes in water samples results of great interest in areas such as biomedicine, food technology and environmental analysis. In a recent paper, we immobilized the inclusion complex formed between 2,3-diaminonaphthalene (DAN) and 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) in a sol-gel matrix, in order to prepare a highly sensitive reagentless fluorescence-based sensor for the specific measurement of nitrite. Here we have explored the possibility of using the sol-gel immobilized complex to quantify selenite (Se (IV)), the more toxic form of selenium, as well as to act as a dual-analyte chemical sensor for simultaneous quantification of both nitrite and selenite in aqueous samples. Results show that (a) inclusion of DAN in HP-beta-CD and its subsequent immobilization in a sol-gel matrix do not modify the reactivity of DAN against selenite, (b) the reaction product formed (4,5-benzopiazselenol) remains into the cyclodextrin increasing considerably its fluorescence quantum yield and avoiding, therefore, its extraction into organic solvents, (c) the developed sensor can detect selenite concentrations at submicromolar level with a minimum detection limit of 13 nM, (d) the immobilized system is able to simultaneously quantify nitrite and selenite at submicromolar concentrations in natural water samples with no further sample pre-treatment.

Synthesis and characterization of nano-encapsulated black pepper oleoresin using hydroxypropyl beta-cyclodextrin for antioxidant and antimicrobial applications.

PubMed

Teixeira, Bruna N; Ozdemir, Necla; Hill, Laura E; Gomes, Carmen L

2013-12-01

Previous studies have reported antimicrobial and antioxidant activity of black pepper oleoresin which is associated to its phenolic compounds and piperine. The ability of cyclodextrins to form an inclusion complex with a guest molecule could improve black pepper oleoresin application, bioavailability, and stability in foods. Hydroxypropyl beta-cyclodextrin (HPBCD) inclusion complex with black pepper olereosin were synthesized using the kneading method and characterized for its physico-chemical properties and its antioxidant and antimicrobial activities. Inclusion complex size was 103.9 ± 7.6 nm and indicated to be a polydisperse system. The entrapment efficiency was 78.3 ± 3.6%, which suggests that other constituents in black pepper oleoresin have higher affinities for HPBCD than piperine (major compound in black pepper oleoresin). Thermograms showed the disappearance of oxidation peaks of black pepper oleoresin, proving complex formation with HPBCD. Phase solubility results indicated 1:1 stoichiometric inclusion complex formation and an increase of black pepper oleoresin aqueous solubility with HPBCD concentration. Nano-encapsulation with HPBCD did not affect (P > 0.05) total phenolic content; however, it enhanced (P < 0.05) black pepper oleoresin antioxidant activity. Black pepper oleoresin and its inclusion complex were analyzed for their antimicrobial activity against Escherichia coli K12 and Salmonella enterica serovar Typhimurium LT2. Both free and encapsulated black pepper oleoresin effectively inhibited bacterial growth within the concentration range tested. Black pepper oleoresin encapsulated in HPBCD was able to inhibit Salmonella at lower (P < 0.05) concentrations than its corresponding free extract. Therefore, black pepper oleoresin-HPBCD nanocapsules could have important applications in the food industry as antimicrobial and antioxidant system. © 2013 Institute of Food Technologists®

Enantioselective comprehensive two-dimensional gas chromatography of lavender essential oil.

PubMed

Krupčík, Ján; Gorovenko, Roman; Špánik, Ivan; Armstrong, Daniel W; Sandra, Pat

2016-12-01

The enantiomeric composition of several chiral markers in lavender essential oil was studied by flow modulated comprehensive two-dimensional gas chromatography operated in the reverse flow mode and hyphenated to flame ionization and quadrupole mass spectrometric detection. Two capillary column series were used in this study, 2,3-di-O-ethyl-6-O-tert-butyldimethylsilyl-β-cyclodextrin or 2,3,6-tri-O-methyl-β-cyclodextrin, as the chiral column in the first dimension and α polyethylene glycol column in the second dimension. Combining the chromatographic data obtained on these column series, the enantiomeric and excess ratios for α-pinene, β-pinene, camphor, lavandulol, borneol, and terpinen-4-ol were determined. This maybe a possible route to assess the authenticity of lavender essential oil. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Combined use of chiral ionic liquid and cyclodextrin for MEKC: Part I. Simultaneous enantioseparation of anionic profens

PubMed Central

Wang, Bin; He, Jun; Bianchi, Victoria; Shamsi, Shahab A.

2009-01-01

The enantiomers of five profen (PROF) drugs were simultaneously separated by MEKC with the combined use of 2, 3, 6-tri-O-methyl-β-cyclodextrin (TM-β-CD) and chiral cationic ionic liquid (IL), N-undecenoxy-carbonyl-L-leucinol bromide (L-UCLB), which formed micelles in aqueous buffers. Enantioseparations of these PROF drugs were optimized by varying the chain length and concentration of the IL surfactant using a standard recipe containing 35 mM TM-β-CD, 5 mM sodium acetate at pH 5.0. The batch-to-batch reproducibility of L-UCLB was tested and found to have no significant impact in terms of enantiomeric resolution, efficiency and migration time. Finally, this method was successfully applied for the quantitative determination of ibuprofen in pharmaceutical tablets. PMID:19650046

A new C-methylated flavonoid glycoside from Pinus densiflora.

PubMed

Jung, M J; Choi, J H; Chung, H Y; Jung, J H; Choi, J S

2001-12-01

A new C-methyl flavonol glycoside, 5,7,8,4'-tetrahydroxy-3-methoxy-6-methylflavone 8-O-beta-D-glucopyranoside (1), has been isolated from the needles of Pinus densiflora, together with kaempferol 3-O-beta-(6"-acetyl)-galactopyranoside.

Thermodynamic investigation of the interaction between cyclodextrins and preservatives - Application and verification in a mathematical model to determine the needed preservative surplus in aqueous cyclodextrin formulations.

PubMed

Holm, René; Olesen, Niels Erik; Alexandersen, Signe Dalgaard; Dahlgaard, Birgitte N; Westh, Peter; Mu, Huiling

2016-05-25

Preservatives are inactivated when added to conserve aqueous cyclodextrin (CD) formulations due to complex formation between CDs and the preservative. To maintain the desired conservation effect the preservative needs to be added in apparent surplus to account for this inactivation. The purpose of the present work was to establish a mathematical model, which defines this surplus based upon knowledge of stability constants and the minimal concentration of preservation to inhibit bacterial growth. The stability constants of benzoic acid, methyl- and propyl-paraben with different frequently used βCDs were determined by isothermal titration calorimetry. Based upon this knowledge mathematical models were constructed to account for the equilibrium systems and to calculate the required concentration of the preservations, which was evaluated experimentally based upon the USP/Ph. Eur./JP monograph. The mathematical calculations were able to predict the needed concentration of preservation in the presence of CDs; it clearly demonstrated the usefulness of including all underlying chemical equilibria in a mathematical model, such that the formulation design can be based on quantitative arguments. Copyright © 2015 Elsevier B.V. All rights reserved.

Mycelium growth stimulation of the desert truffle Terfezia claveryi chatin by β-cyclodextrin.

PubMed

López-Nicolás, José Manuel; Pérez-Gilabert, Manuela; García-Carmona, Francisco; Lozano-Carrillo, María Cecilia; Morte, Asunción

2013-01-01

The commercial value of Terfezia claveryi, an edible desert truffle with important gastronomic, nutritional, and antioxidant properties, has led to growing interest in its cultivation. The erratic and slow growth of T. claveryi mycelium in vitro represents an impairment to obtain mycorrhizal plants, and it makes necessary to find a new culture medium able to overcome these drawbacks. In this work, we analyze the effect of cyclodextrins (CDs) on the growth of T. claveryi mycelium. Different parameters, including colony diameter, growth rate, and colony fresh weight, were evaluated, both in the presence and absence of these encapsulant agents. The results obtained confirm the ability of CDs to stimulate the growth of T. claveryi mycelium when present in the culture medium. A similar effect was observed when CDs were added to the culture medium of Tuber melanosporum. Three natural (α-, β-, and γ) and two modified (hydroxypropil-β and methyl-β) CDs were assayed. The best results were obtained with β-cyclodextrin, but no improvement was observed with its chemically modified derivatives. CDs complex the different compounds present in the culture medium which impair mycelial growth. © 2013 American Institute of Chemical Engineers.

Comparison of Positively and Negatively Charged Achiral Co-Monomers Added to Cyclodextrin Monolith: Improved Chiral Separations in Capillary Electrochromatography

PubMed Central

Lu, Yang; Shamsi, Shahab A.

2014-01-01

Cyclodextrins (CDs) and their derivatives have been one of the most popular and successful chiral additives used in electrokinetic chromatography because of the presence of multiple chiral centers, which leads to multiple chiral interactions. However, there has been relatively less published work on the use of CDs as monolithic media for capillary electrochromatography (CEC). The goal of this study was to show how the addition of achiral co-monomer to a polymerizable CD such as glycidyl methacrylate β-cyclodextrin (GMA/β-CD) can affect the enantioselective separations in monolithic CEC. To achieve this goal, polymeric monoliths columns were prepared by co-polymerizing GMA/β-CD with cationic or anionic achiral co-monomers [(2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS) and vinyl benzyltrimethyl-ammonium (VBTA)] in the presence of conventional crosslinker (ethylene dimethacrylate) and ternary porogen system including butanediol, propanol and water. A total of 34 negatively charged compounds, 30 positively charged compounds and 33 neutral compounds were screened to compare the enantioresolution capability on the GMA/β-CD, GMA/β-CD-VBTA and GMA/β-CD-AMPS monolithic columns. PMID:24108813

Design of Safer Flame Retardant Textiles through Inclusion Complex Formation with Cyclodextrins: A Combined Experimental and Modeling Study

NASA Astrophysics Data System (ADS)

Zhang, Nanshan

Triphenyl phosphate (TPP) is widely used as a phosphorus flame retardant. It is also one component of a commercial flame retardant mixture known as Firemaster 550. TPP is likely to be released into the environment due to its high volatility and has been detected at a concentration as high as 47,000 ng/m3 in air. Recent studies have also indicated that FRs like TPP could contribute to obesity and osteoporosis in humans. Cyclodextrins (CDs) are enzymatic degradation products of starch and consist of several (alpha-1,4)-linked alpha-Dglucopyranose units. CDs own a hydrophilic outside and a hydrophobic inner cavity, which enables the formation of non-covalently bonded cyclodextrin inclusion complexes (CD-ICs) with a vast array of molecules. We hypothesize that the formation of inclusion complexes between TPP and cyclodextrins will reduce its exposure yet also retain flame retarding properties of TPP, since the formation of FR-CD-ICs is expected to eliminate unnecessary loss of FRs, especially volatile FR compounds like TPP, and release them only during a fire when they are actually needed. After creating the TPP-beta-CD-IC, we applied it to polyethylene terephthalate (PET) films by a hot press technique. Flame tests indicated TPP-beta-CD-IC exhibited flame resistant performance matching that of neat TPP, even though much less TPP was contained in its beta-CD-IC. Incorporation of FRs and other chemical additives into textile substrates in the form of their crystalline CD-ICs is a promising way to reduce the exposure of hazardous chemicals to humans and to our environment while not impacting their efficacy. Two other parent CDs (alpha-CD and gamma-CD) were applied and their abilities to form ICs with guest TPP were studied. Results from a series of characterization methods, including FTIR, DSC, TGA, XRD and NMR indicated the successful synthesis of TPP-gamma-CD-IC via two routes. However, alpha-CD appears unable to form an IC with TPP, which is likely attributable to a size mismatch between them. A novel analytical chemistry technique - tandem mass spectrometry (ESI-Q-TOF) was used to study the inclusion complexes of TPP and CDs. Successful formation of TPP-beta-/gamma-CD-IC was further proved by ESI mass spec in the positive mode. Experimental results demonstrated that 1:1 inclusion complex ions of the guest FR and the host CDs were detected. Experimentally alpha-CD cannot form an IC with TPP and this was further confirmed by tandem mass spec. Mass spectrometry provides a fast and accurate method to investigate cyclodextrin inclusion complexes and verify the formation of ICs. Computational methods were applied to help understand the energetically favorable geometry of TPP and beta-/gamma-CD in their IC form. Semi-empirical theoretical methods (PM3 and PM6) were used to find the global minima of TPP-CD geometry and density functional theory calculations at a B3LYP/6-31G(d) level were employed for elaborate geometry optimization. Solvent effect was also considered using the polarized continuum model (IEF-PCM). Analysis of the results indicated that after optimization, IC geometries provided by PM6 had stronger interactions and were more energetically favorable than the ones calculated by PM3. DFT calculations are more accurate than PM3/PM6 and enabled more interactions between the host and the guest than two semi-empirical approaches. DFT calculations also proved that initial structures prepared by PM6 were more favorable in H-bonding profiles and key energy parameters. For TPP-beta-CD system in vacuum and water, Model A owned a lower total and complexation energy while a stronger interaction between them was present in Model B. In TPP-gamma-CD system, Model B was preferred than Model A in both vacuum and water. This was potentially attributed to more H-bonds formed between TPP and gamma-CD in Model B and its ability to retain most of the internal linkages among primary hydroxyl groups.

Similarity of different beta-strands flanked in loops by glycines and prolines from distinct (alpha/beta)8-barrel enzymes: chance or a homology?

PubMed Central

Janecek, S.

1995-01-01

Many (alpha/beta)8-barrel enzymes contain their conserved sequence regions at or around the beta-strand segments that are often preceded and succeeded by glycines and prolines, respectively. alpha-Amylase is one of these enzymes. Its sequences exhibit a very low degree of similarity, but strong conservation is seen around its beta-strands. These conserved regions were used in the search for similarities with beta-strands of other (alpha/beta)8-barrel enzymes. The analysis revealed an interesting similarity between the segment around the beta 2-strand of alpha-amylase and the one around the beta 4-strand of glycolate oxidase that are flanked in loops by glycines and prolines. The similarity can be further extended on other members of the alpha-amylase and glycolate oxidase subfamilies, i.e., cyclodextrin glycosyltransferase and oligo-1,6-glucosidase, and flavocytochrome b2, respectively. Moreover, the alpha-subunit of tryptophan synthase, the (alpha/beta)8-barrel enzyme belonging to the other subfamily of (alpha/beta)8-barrels, has both investigated strands, beta 2 and beta 4, similar to beta 2 of alpha-amylase and beta 4 of glycolate oxidase. The possibilities of whether this similarity exists only by chance or is a consequence of some processes during the evolution of (alpha/beta)8-barrel proteins are briefly discussed. PMID:7549888

Similarity of different beta-strands flanked in loops by glycines and prolines from distinct (alpha/beta)8-barrel enzymes: chance or a homology?

PubMed

Janecek, S

1995-06-01

Many (alpha/beta)8-barrel enzymes contain their conserved sequence regions at or around the beta-strand segments that are often preceded and succeeded by glycines and prolines, respectively. alpha-Amylase is one of these enzymes. Its sequences exhibit a very low degree of similarity, but strong conservation is seen around its beta-strands. These conserved regions were used in the search for similarities with beta-strands of other (alpha/beta)8-barrel enzymes. The analysis revealed an interesting similarity between the segment around the beta 2-strand of alpha-amylase and the one around the beta 4-strand of glycolate oxidase that are flanked in loops by glycines and prolines. The similarity can be further extended on other members of the alpha-amylase and glycolate oxidase subfamilies, i.e., cyclodextrin glycosyltransferase and oligo-1,6-glucosidase, and flavocytochrome b2, respectively. Moreover, the alpha-subunit of tryptophan synthase, the (alpha/beta)8-barrel enzyme belonging to the other subfamily of (alpha/beta)8-barrels, has both investigated strands, beta 2 and beta 4, similar to beta 2 of alpha-amylase and beta 4 of glycolate oxidase. The possibilities of whether this similarity exists only by chance or is a consequence of some processes during the evolution of (alpha/beta)8-barrel proteins are briefly discussed.

Biopharmaceutical characterization of praziquantel cocrystals and cyclodextrin complexes prepared by grinding.

PubMed

Cugovčan, Martina; Jablan, Jasna; Lovrić, Jasmina; Cinčić, Dominik; Galić, Nives; Jug, Mario

2017-04-15

Mechanochemical activation using several different co-grinding additives was applied as a green chemistry approach to improve physiochemical and biopharmaceutical properties of praziquantel (PZQ). Liquid assisted grinding with an equimolar amount of citric acid (CA), malic acid (MA), salicylic acid (SA) and tartaric acid (TA) gained in cocrystal formation, which all showed pH-dependent solubility and dissolution rate. However, the most soluble cocrystal of PZQ with MA was chemically unstable, as seen during the stability testing. Equimolar cyclodextrin complexes prepared by neat grinding with amorphous hydroxypropyl-β-cyclodextrin (HPβCD) and randomly methylated β-cyclodextrin (MEβCD) showed the highest improvement in drug solubility and the dissolution rate, but only PZQ/HPβCD product presented an acceptable chemical and photostability profile. A combined approach, by co-grinding the drug with both MA and HPβCD in equimolar ratio, also gave highly soluble amorphous product which again was chemical instable and therefore not suitable for the pharmaceutical use. Studies on Caco-2 monolayer confirmed the biocompatibility of PZQ/HPβCD complex and showed that complexation did not adversely affect the intrinsically high PZQ permeability (P app (PZQ)=(3.72±0.33)×10 -5 cms -1 and P app (PZQ/HPβCD)=(3.65±0.21)×10 -5 cms -1 ; p>0.05). All this confirmed that the co-grinding with the proper additive is as a promising strategy to improve biopharmaceutical properties of the drug. Copyright © 2017 Elsevier B.V. All rights reserved.

beta-Methyl-15-p-iodophenylpentadecanoic acid metabolism and kinetics in the isolated rat heart.

PubMed

DeGrado, T R; Holden, J E; Ng, C K; Raffel, D M; Gatley, S J

1989-01-01

The use of 15-p-iodophenyl-beta-methyl-pentadecanoic acid (beta Me-IPPA) as an indicator of long chain fatty acid (LCFA) utilization in nuclear medicine studies was evaluated in the isolated, perfused, working rat heart. Time courses of radioactivity (residue curves) were obtained following bolus injections of both beta Me-IPPA and its straight chain counterpart 15-p-iodophenyl-pentadecanoic acid (IPPA). IPPA kinetics clearly indicated flow independent impairment of fatty acid oxidation caused by the carnitine palmitoyltransferase I inhibitor 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA). In contrast, beta Me-IPPA kinetics were insensitive to changes in fatty acid oxidation rate and net utilization of long chain fatty acid. Analysis of radiolabeled species in coronary effluent and heart homogenates showed the methylated fatty acid to be readily incorporated into complex lipids but a poor substrate for oxidation. POCA did not significantly alter metabolism of the tracer, suggesting that the tracer is poorly metabolized beyond beta Me-IPPA-CoA in the oxidative pathway.

Organic/inorganic hybrid filters based on dendritic and cyclodextrin "nanosponges" for the removal of organic pollutants from water.

PubMed

Arkas, Michael; Allabashi, Roza; Tsiourvas, Dimitris; Mattausch, Eva-Maria; Perfler, Reinhard

2006-04-15

Long-alkyl chain functionalized poly(propylene imine) dendrimer, poly(ethylene imine) hyperbranched polymer, and beta-cyclodextrin derivatives, which are completely insoluble in water, have the property of encapsulating organic pollutants from water. Ceramic porous filters can be impregnated with these compounds resulting in hybrid organic/ inorganic filter modules. These hybrid filter modules were tested for the effective purification of water, by continuous filtration experiments, employing a variety of water pollutants. It has been established that polycyclic aromatic hydrocarbons (PAHs) can be removed very efficiently (more than 95%), and final concentrations of several ppb (microg/ L) are easily obtained. Representatives of the pollutant group of trihalogen methanes (THMs), monoaromatic hydrocarbons (BTX), and pesticides (simazine) can also be removed (>80%), although the filters are saturated considerably faster in these cases.

Fe-Ni Nanoparticles supported on carbon nanotube-co-cyclodextrin polyurethanes for the removal of trichloroethylene in water

NASA Astrophysics Data System (ADS)

Krause, Rui W. M.; Mamba, Bhekie B.; Dlamini, Langelihle N.; Durbach, Shane H.

2010-02-01

Nanoscale bimetallic particles of nickel on iron were supported on carbon nanotubes and then co-polymerized with β-cyclodextrin (CNTs/CD) and the resulting polymers applied to the degradation of pollutants in water. The bimetallic nanoparticles (BMNPs) were first embedded on functionalized carbon nanotubes (f-CNTs) before being copolymerized with beta cyclodextrin (β-CD) and hexamethylene diisocyanate (HMDI) forming a water-insoluble polyurethane. The particle size and distribution of BMNPs were determined by Transmission Electron Microscopy (TEM), and the surface area was determined by using the Brunauer-Emmett-Teller (BET) method. Energy dispersive X-ray spectroscopy (EDXS) was used to confirm the formation of the BMNPs. Degradation of trichloroethylene (TCE) as a model pollutant was studied and more than 98% reduction in TCE was achieved by the polymers. Polymers with the BMNPs maintained their efficiency in degrading TCE after several cycles compared to metal-free polymers. The degradation was monitored by using gas chromatography-mass spectrometry (GC-MS), while the production of chlorides was verified by using ion chromatography (IC). Atomic absorption spectroscopy (AAS) was employed to determine the possible leaching of the BMNPs from the polymer, and confirmed to be extremely low.

Beta-cyclodextrin enhanced gastroprotective effect of (-)-linalool, a monoterpene present in rosewood essential oil, in gastric lesion models.

PubMed

da Silva, Francilene Vieira; de Barros Fernandes, Hélio; Oliveira, Irisdalva Sousa; Viana, Ana Flávia Seraine Custódio; da Costa, Douglas Soares; Lopes, Miriam Teresa Paz; de Lira, Kamila Lopes; Quintans-Júnior, Lucindo José; de Sousa, Adriano Antunes; de Cássia Meneses Oliveira, Rita

2016-11-01

(-)-Linalool is a monoterpene constituent of many essential oils. This particular monoterpene has both anti-inflammatory and antimicrobial activity. Moreover, this compound has been shown to be antinociceptive. However, the poor chemical stability and short half-life prevents the clinical application of (-)-linalool and many other essential oils. Important to the topic of this study, β-cyclodextrin (β-CD) has been used to increase the solubility, stability, and pharmacological effects of numerous lipophilic compounds in vivo. In this study, the gastroprotective activities of (-)-linalool (LIN) and linalool incorporated into inclusion complex containing β-cyclodextrin (LIN-βCD) were evaluated using models of acute and chronic gastric ulcers in rodents. LIN and LIN-βCD showed strong gastroprotective activity (p < 0.001). The LIN-βCD complex revealed that the gastroprotective effect was significantly improved compared with LIN uncomplexed, suggesting that this improvement is related to increased solubility and stability. Taking together the potentiation of the antioxidant profile of this monoterpene, our results suggest that β-CD may represent an important tool for improved gastroprotective activity of (-)-linalool and other water-insoluble compounds.

Cholesterol regulates multiple forms of vesicle endocytosis at a mammalian central synapse.

PubMed

Yue, Hai-Yuan; Xu, Jianhua

2015-07-01

Endocytosis in synapses sustains neurotransmission by recycling vesicle membrane and maintaining the homeostasis of synaptic membrane. A role of membrane cholesterol in synaptic endocytosis remains controversial because of conflicting observations, technical limitations in previous studies, and potential interference from non-specific effects after cholesterol manipulation. Furthermore, it remains unclear whether cholesterol participates in distinct forms of endocytosis that function under different activity levels. In this study, applying the whole-cell membrane capacitance measurement to monitor endocytosis in real time at the rat calyx of Held terminals, we found that disrupting cholesterol with dialysis of cholesterol oxidase or methyl-β-cyclodextrin impaired three different forms of endocytosis, including slow endocytosis, rapid endocytosis, and endocytosis of the retrievable membrane that exists at the surface before stimulation. The effects were observed when disruption of cholesterol was mild enough not to change Ca(2+) channel current or vesicle exocytosis, indicative of stringent cholesterol requirement in synaptic endocytosis. Extracting cholesterol with high concentrations of methyl-β-cyclodextrin reduced exocytosis, mainly by decreasing the readily releasable pool and the vesicle replenishment after readily releasable pool depletion. Our study suggests that cholesterol is an important, universal regulator in multiple forms of vesicle endocytosis at mammalian central synapses. © 2015 International Society for Neurochemistry.

Synthetic mucin fragments: synthesis of O-sulfo and O-methyl derivatives of allyl O-(beta-D-galactopyranosyl)-(1-->3)-2-acetamido-2-deoxy-alpha-D- galactopyranoside as potential compounds for sulfotransferases.

PubMed

Jain, R K; Piskorz, C F; Matta, K L

1995-10-02

Allyl 2-acetamido-4,6-O-(4-methoxybenzylidene)-2-deoxy-alpha-D-galact opy ranoside (1) was condensed with either 2,3,4,6-tetra-O-acetyl-alpha-D-galactopyranosyl bromide (2) or 2,3,4-tri-O-benzoyl-6-O-bromoacetyl-alpha-D-galactopyranosyl bromide (14) in the presence of mercuric cyanide. Selective substitution with methyl, sulfo or both at desired positions, followed by the removal of protecting groups, afforded allyl O-(beta-D-galactopyranosyl)-(1-->3)-2-acetamido-2-deoxy-6-O-methyl-alpha -D- galactopyranoside (5), allyl O-(6-O-sulfo-beta-D-galactopyranosyl sodium salt)-(1-->3)-2-acetamido-2-deoxy-6- O-methyl-alpha-D-galactopyranoside (10), allyl O-(beta-D-galactopyranosyl)-(1-->3)-2-acetamido-2-deoxy-6-O-sulfo-alpha- D- galactopyranoside sodium salt (13), allyl O-(6-O-sulfo-beta-D-galactopyranosyl sodium salt)-(1-->3)-2-acetamido-2-deoxy- alpha-D-galactopyranoside (17) and allyl O-(3-O-sulfo-beta-D-galactopyranosyl sodium salt)-(1-->3)-2-acetamido-2-deoxy- alpha-D-galactopyranoside (22). The structures of compounds 5, 10, 13, 17 and 22 were established by 13C NMR and FAB mass spectroscopy.

Peripheral substitution of pheophorbides and bacteriopheophorbides to promote inclusion into inert carrier systems for PDT

NASA Astrophysics Data System (ADS)

Roehrs, Susanne; Ruebner-Heuermann, Anja; Hartwich, G.; Scheer, H.; Moser, Joerg G.

1996-01-01

Pheophorbide a ethyl ester, pyropheophorbide a ethyl ester, and bacteriopheophorbide ethyl ester were substituted in 31-position with tert.butyl phenoxy or tert.butyl benzoic acid ester groups resp. in order to enhance affinity to (beta) -cyclodextrin dimers which form inclusion complexes with these photosensitizing drugs. This is a first step to construct inert transport complexes in order to photosensitize specifically cancer cells.

Stochastic detection of enantiomers.

PubMed

Kang, Xiao-Feng; Cheley, Stephen; Guan, Xiyun; Bayley, Hagan

2006-08-23

The rapid quantification of the enantiomers of small chiral molecules is very important, notably in pharmacology. Here, we show that the enantiomers of drug molecules can be distinguished by stochastic sensing, a single-molecule detection technique. The sensing element is an engineered alpha-hemolysin protein pore, fitted with a beta-cyclodextrin adapter. By using the approach, the enantiomeric composition of samples of ibuprofen and thalidomide can be determined in less than 1 s.

Enhancement of the release of azelaic acid through the synthetic membranes by inclusion complex formation with hydroxypropyl-beta-cyclodextrin.

PubMed

Manosroi, Jiradej; Apriyani, Maria Goretti; Foe, Kuncoro; Manosroi, Aranya

2005-04-11

The aim of this study was to investigate the release rates of azelaic acid and azelaic acid-hydroxypropyl-beta-cyclodextrin (HPbetaCD) inclusion complex through three types of synthetic membranes, namely cellophane, silicone and elastomer membranes. Solid inclusion complexes of azelaic acid-HPbetaCD at the molar ratio of 1:1 were prepared by coevaporation and freeze-drying methods, subsequently characterized by differential scanning calorimetry, X-ray diffractometry and dissolution studies. Solid inclusion complex obtained by coevaporation method which exhibited the inclusion of azelaic acid in the HPbetaCD cavity and gave the highest dissolution rate of azelaic acid was selected for the release study. Release studies of azelaic acid and this complex through the synthetic membranes were conducted using vertical Franz diffusion cells at 30 degrees C for 6 days. The release rates of azelaic acid through the synthetic membranes were enhanced by the formation of inclusion complex with HPbetaCD at the molar ratio of 1:1, with the increasing fluxes of about 41, 81 and 28 times of the uncomplexed system in cellophane, silicone and elastomer membranes, respectively. The result from this study can be applied for the development of azelaic acid for topical use.

Complexation induced fluorescence and acid-base properties of dapoxyl dye with γ-cyclodextrin: a drug-binding application using displacement assays.

PubMed

Pal, Kaushik; Mallick, Suman; Koner, Apurba L

2015-06-28

Host-guest complexation of dapoxyl sodium sulphonate (DSS), an intramolecular charge transfer dye with water-soluble and non-toxic macrocycle γ-cyclodextrin (γ-CD), has been investigated in a wide pH range. Steady-state absorption, fluorescence and time-resolved fluorescence measurements confirm the positioning of DSS into the hydrophobic cavity of γ-CD. A large fluorescence enhancement ca. 30 times, due to 1 : 2 complex formation and host-assisted guest-protonation have been utilised for developing a method for the utilisation of CD based drug-delivery applications. A simple fluorescence-displacement based approach is implemented at physiological pH for the assessment of binding strength of pharmaceutically useful small drug molecules (ibuprofen, paracetamol, methyl salicylate, salicylic acid, aspirin, and piroxicam) and six important antibiotic drugs (resazurin, thiamphenicol, chloramphenicol, ampicillin, kanamycin, and sorbic acid) with γ-CD.

Quality by design in the chiral separation strategy for the determination of enantiomeric impurities: development of a capillary electrophoresis method based on dual cyclodextrin systems for the analysis of levosulpiride.

PubMed

Orlandini, S; Pasquini, B; Del Bubba, M; Pinzauti, S; Furlanetto, S

2015-02-06

Quality by design (QbD) concepts, in accordance with International Conference on Harmonisation Pharmaceutical Development guideline Q8(R2), represent an innovative strategy for the development of analytical methods. In this paper QbD principles have been comprehensively applied in the set-up of a capillary electrophoresis method aimed to quantify enantiomeric impurities. The test compound was the chiral drug substance levosulpiride (S-SUL) and the developed method was intended to be used for routine analysis of the pharmaceutical product. The target of analytical QbD approach is to establish a design space (DS) of critical process parameters (CPPs) where the critical quality attributes (CQAs) of the method have been assured to fulfil the desired requirements with a selected probability. QbD can improve the understanding of the enantioseparation process, including both the electrophoretic behavior of enantiomers and their separation, therefore enabling its control. The CQAs were represented by enantioresolution and analysis time. The scouting phase made it possible to select a separation system made by sulfated-β-cyclodextrin and a neutral cyclodextrin, operating in reverse polarity mode. The type of neutral cyclodextrin was included among other CPPs, both instrumental and related to background electrolyte composition, which were evaluated in a screening phase by an asymmetric screening matrix. Response surface methodology was carried out by a Doehlert design and allowed the contour plots to be drawn, highlighting significant interactions between some of the CPPs. DS was defined by applying Monte-Carlo simulations, and corresponded to the following intervals: sulfated-β-cyclodextrin concentration, 9-12 mM; methyl-β-cyclodextrin concentration, 29-38 mM; Britton-Robinson buffer pH, 3.24-3.50; voltage, 12-14 kV. Robustness of the method was examined by a Plackett-Burman matrix and the obtained results, together with system repeatability data, led to define a method control strategy. The method was validated and was finally applied to determine the enantiomeric purity of S-SUL in pharmaceutical dosage forms. Copyright © 2015 Elsevier B.V. All rights reserved.

Basolateral cholesterol depletion alters Aquaporin-2 post-translational modifications and disrupts apical plasma membrane targeting.

PubMed

Moeller, Hanne B; Fuglsang, Cecilia Hvitfeldt; Pedersen, Cecilie Nøhr; Fenton, Robert A

2018-01-01

Apical plasma membrane accumulation of the water channel Aquaporin-2 (AQP2) in kidney collecting duct principal cells is critical for body water homeostasis. Posttranslational modification (PTM) of AQP2 is important for regulating AQP2 trafficking. The aim of this study was to determine the role of cholesterol in regulation of AQP2 PTM and in apical plasma membrane targeting of AQP2. Cholesterol depletion from the basolateral plasma membrane of a collecting duct cell line (mpkCCD14) using methyl-beta-cyclodextrin (MBCD) increased AQP2 ubiquitylation. Forskolin, cAMP or dDAVP-mediated AQP2 phosphorylation at Ser269 (pS269-AQP2) was prevented by cholesterol depletion from the basolateral membrane. None of these effects on pS269-AQP2 were observed when cholesterol was depleted from the apical side of cells, or when MBCD was applied subsequent to dDAVP stimulation. Basolateral, but not apical, MBCD application prevented cAMP-induced apical plasma membrane accumulation of AQP2. These studies indicate that manipulation of the cholesterol content of the basolateral plasma membrane interferes with AQP2 PTM and subsequently regulated apical plasma membrane targeting of AQP2. Copyright © 2017 Elsevier Inc. All rights reserved.

Enantioseparation of thalidomide and its hydroxylated metabolites using capillary electrophoresis with various cyclodextrins and their combinations as chiral buffer additives.

PubMed

Meyring, M; Chankvetadze, B; Blaschke, G

1999-09-01

The separation of thalidomide (TD) and its hydroxylated metabolites including their simultaneous enantioseparation was studied in capillary electrophoresis (CE) using four different randomly substituted charged cyclodextrin (CD) derivatives, the combinations of some of them with each other, and beta-CD. TD, as well as two metabolites recently found in incubations of human liver microsomes and human blood, 5-hydroxythalidomide (5-OH-TD) and one of the diastereomeric 5'-hydroxythalidomides (5'-OH-TD), are neutral compounds. Therefore, they were resolved using charged chiral selectors in CE. Two different separation modes (normal polarity and carrier mode) and two different capillaries (fused-silica and polyacrylamide-coated) were tested. Based on the behavior of the individual CDs, their designed combinations were selected in order to improve the separation selectivity and enantioselectivity. Under optimized conditions all three chiral compounds and their enantiomers were resolved simultaneously.

Effect of cholesterol-loaded-cyclodextrin on sperm viability and acrosome reaction in boar semen cryopreservation.

PubMed

Lee, Yong-Seung; Lee, Seunghyung; Lee, Sang-Hee; Yang, Boo-Keun; Park, Choon-Keun

2015-08-01

This study was undertaken to examine the effect of cholesterol-loaded-cyclodextrin (CLC) on boar sperm viability and spermatozoa cryosurvival during boar semen cryopreservation, and methyl-β-cyclodextrin (MBCD) was treated for comparing with CLC. Boar semen treated with CLC and MBCD before freezing process to monitor the effect on survival and capacitation status by flow cytometry with appropriate fluorescent probes. Sperm viability was higher in 1.5mg CLC-treated sperm (76.9±1.01%, P<0.05) than un-treated and MBCD-treated sperm before cryopreservation (58.7±1.31% and 60.3±0.31%, respectively). For CTC patterns, F-pattern was higher in CLC treated sperm than MBCD-treated sperm, for B-pattern was higher in CLC-treated sperm than fresh sperm (P<0.05). For AR pattern (an acrosome-reacted sperm) was lower in CLC-treated sperm than MBCD-treated sperm (P<0.05). Moreover, we examined in vitro development of porcine oocytes after in vitro fertilization using CLC-treated frozen-thawed semen, in which CLC treatment prior to freezing and thawing increased the development of oocytes to blastocyst stage in vitro. In conclusion, CLC could protect the viability of spermatozoa from cryodamage prior to cryopreservation in boar semen. Copyright © 2015 Elsevier B.V. All rights reserved.

[Studies on formulations of Panax notoginsenosides for intranasal administration].

PubMed

Xu, Qing-fang; Fang, Xiao-ling; Chen, Dao-feng; Li, Jun-chan

2003-11-01

To develop high bioavailability preparations without irritation for Panax notoginsenosides. The effects of some additives such as microcrystalline cellulose, beta-cyclodextrin and hydroxypropyl cellulose on drug in the preparations were examined. Saponins of Panax notoginseng (PNS) was absorbed in rabbits more when administered intranasally than through other routines, and the formulations including MCC both gave high bioavailability and low irritation. Bioavailability of Panax notoginsenosides can be increased through changing routine of administration and formulations.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Warner-Schmid, D.; Hoshi, Suwaru; Armstrong, D.W.

Aqueous solutions of nonionic surfactants are known to undergo phase separations at elevated temperatures. This phenomenon is known as clouding,' and the temperature at which it occurs is refereed to as the cloud point. Permethylhydroxypropyl-[beta]-cyclodextrin (PMHP-[beta]-CD) was synthesized and aqueous solutions containing it were found to undergo similar cloud-point behavior. Factors that affect the phase separation of PMHP-[beta]-CD were investigated. Subsequently, the cloud-point extractions of several aromatic compounds (i.e., acetanilide, aniline, 2,2[prime]-dihydroxybiphenyl, N-methylaniline, 2-naphthol, o-nitroaniline, m-nitroaniline, p-nitroaniline, nitrobenzene, o-nitrophenol, m-nitrophenol, p-nitrophenol, 4-phenazophenol, 3-phenylphenol, and 2-phenylbenzimidazole) from dilute aqueous solution were evaluated. Although the extraction efficiency of the compounds varied, mostmore » can be quantitatively extracted if sufficient PMHP-[beta]-CD is used. For those few compounds that are not extracted (e.g., o-nitroacetanilide), the cloud-point procedure may be an effective one-step isolation or purification method. 18 refs., 2 figs., 3 tabs.« less

Analyses of polycyclic aromatic hydrocarbon (PAH) and chiral-PAH analogues-methyl-β-cyclodextrin guest-host inclusion complexes by fluorescence spectrophotometry and multivariate regression analysis.

PubMed

Greene, LaVana; Elzey, Brianda; Franklin, Mariah; Fakayode, Sayo O

2017-03-05

The negative health impact of polycyclic aromatic hydrocarbons (PAHs) and differences in pharmacological activity of enantiomers of chiral molecules in humans highlights the need for analysis of PAHs and their chiral analogue molecules in humans. Herein, the first use of cyclodextrin guest-host inclusion complexation, fluorescence spectrophotometry, and chemometric approach to PAH (anthracene) and chiral-PAH analogue derivatives (1-(9-anthryl)-2,2,2-triflouroethanol (TFE)) analyses are reported. The binding constants (K b ), stoichiometry (n), and thermodynamic properties (Gibbs free energy (ΔG), enthalpy (ΔH), and entropy (ΔS)) of anthracene and enantiomers of TFE-methyl-β-cyclodextrin (Me-β-CD) guest-host complexes were also determined. Chemometric partial-least-square (PLS) regression analysis of emission spectra data of Me-β-CD-guest-host inclusion complexes was used for the determination of anthracene and TFE enantiomer concentrations in Me-β-CD-guest-host inclusion complex samples. The values of calculated K b and negative ΔG suggest the thermodynamic favorability of anthracene-Me-β-CD and enantiomeric of TFE-Me-β-CD inclusion complexation reactions. However, anthracene-Me-β-CD and enantiomer TFE-Me-β-CD inclusion complexations showed notable differences in the binding affinity behaviors and thermodynamic properties. The PLS regression analysis resulted in square-correlation-coefficients of 0.997530 or better and a low LOD of 3.81×10 -7 M for anthracene and 3.48×10 -8 M for TFE enantiomers at physiological conditions. Most importantly, PLS regression accurately determined the anthracene and TFE enantiomer concentrations with an average low error of 2.31% for anthracene, 4.44% for R-TFE and 3.60% for S-TFE. The results of the study are highly significant because of its high sensitivity and accuracy for analysis of PAH and chiral PAH analogue derivatives without the need of an expensive chiral column, enantiomeric resolution, or use of a polarized light. Published by Elsevier B.V.

Supramolecular Ferric Porphyrins as Cyanide Receptors in Aqueous Solution

PubMed Central

2011-01-01

All fundamental data about binding of the cyanide to a supramolecular complex composed of a per-O-methylated β-cyclodextrin dimer having an imidazole linker (Im3CD) and an anionic ferric porphyrin (Fe(III)TPPS) indicate that the Fe(III)TPPS/Im3CD complex is much better as an cyanide receptor in vivo than hydroxocobalamin, whose cyanide binding ability is lowered by its strong binding to serum proteins in the blood. PMID:24900285

Development of liposomal and microemulsion formulations for transdermal delivery of clonazepam: effect of randomly methylated β-cyclodextrin.

PubMed

Mura, Paola; Bragagni, Marco; Mennini, Natascia; Cirri, Marzia; Maestrelli, Francesca

2014-11-20

Transdermal administration of clonazepam, a poorly water-soluble benzodiazepine, is an interesting strategy for overcoming the drawbacks of its oral administration. With this aim, two nano-carrier formulations, based on ultra-deformable liposomes and microemulsions, have been developed to favour clonazepam transdermal delivery. Considering the solubilizing power of methyl-βcyclodextrin (Me-βCD) toward clonazepam and its potential positive influence on transdermal drug delivery, the effect of its addition to these formulations was investigated. Artificial lipophilic membranes simulating the skin allowed a rapid evaluation of the drug permeation properties from the systems, compared with those from an aqueous drug suspension, with or without Me-βCD. The best formulations were further characterized by permeation through excised rabbit ear skin. All the formulations increased drug permeability, ranging from 2-fold (liposomes without Me-βCD), up to over 4-fold (microemulsions containing Me-βCD). The different formulations allowed for pointing out different possible permeation enhancing mechanisms of Me-βCD: increase in drug solubility and thermodynamic activity in the vehicle, when added to the drug aqueous suspension; interactions with the vesicle bilayer, in case of liposomal formulations; interactions with the skin membrane lipids, as evidenced in experiments with excised rabbit ear for microemulsions containing Me-βCD, that were then selected for further in vivo studies. Copyright © 2014. Published by Elsevier B.V.

Physicochemical and thermodynamic characterization of the encapsulation of methyl jasmonate by natural and modified cyclodextrins using reversed-phase high-pressure liquid chromatography.

PubMed

López-Nicolás, José Manuel; Escorial Camps, Marta; Pérez-Sánchez, Horacio; García-Carmona, Francisco

2013-11-27

Although the combinations of methyl jasmonate (MeJA) and cyclodextrins (CDs) have been used by different authors to stimulate the production of several metabolites, no study has been published about the possible formation of MeJA-CD complexes when these two molecules are added together to the reaction medium as elicitors. For this reason and because knowledge of the possible complexation process of MeJA with CD under different physicochemical conditions is essential if these two molecules are to be used in cell cultures, this paper looks at the complexation of MeJA with natural and modified CDs using a reversed-phase high-pressure liquid chromatography (RP-HPLC) system. The interaction of MeJA with β-CD was more efficient than with α- and γ-CDs. However, a modified CD, HP-β-CD, was the most effective of all of the CDs tested. Moreover, MeJA formed complexes with CD with a 1:1 stoichiometry, and the formation constants of these complexes were strongly dependent upon the temperature of the mobile phase used but not the pH. To obtain information about the mechanism of the affinity of MeJA for CD, the thermodynamic parameters ΔG°, ΔH°, and ΔS° were calculated. Finally, molecular modeling studies were carried out to propose which molecular interactions are established in the complexation process.

Cholesterol depletion by methyl-β-cyclodextrin enhances cell proliferation and increases the number of desmin-positive cells in myoblast cultures.

PubMed

Portilho, Débora M; Soares, Carolina P; Morrot, Alexandre; Thiago, Leandro S; Butler-Browne, Gillian; Savino, Wilson; Costa, Manoel L; Mermelstein, Cláudia

2012-11-05

Skeletal myogenesis comprises myoblast replication and differentiation into striated multinucleated myotubes. Agents that interfere with myoblast replication are important tools for the understanding of myogenesis. Recently, we showed that cholesterol depletion by methyl-β-cyclodextrin (MCD) enhances the differentiation step in chick-cultured myogenic cells, involving the activation of the Wnt/β-catenin signaling pathway. However, the effects of cholesterol depletion on myoblast replication have not been carefully studied. Here we show that MCD treatment increases cell proliferation in primary chick myogenic cell cultures. Treatment of myogenic cells with the anti-mitotic reagent cytosine arabinoside, immediately following cholesterol depletion, blocks the MCD-induced effects on proliferation. Cholesterol depletion induced an increase in the number of desmin-positive mononucleated cells, and an increase in desmin expression. MCD induces an increase in the expression of the cell cycle regulator p53 and the master switch gene MyoD1. Treatment with BIO, a specific inhibitor of GSK3β, induced effects similar to MCD on cell proliferation; while treatment with Dkk1, a specific inhibitor of the Wnt/β-catenin pathway, neutralized the effects of MCD. These findings indicate that rapid changes in the cholesterol content in cell membranes of myoblasts can induce cell proliferation, possibly by the activation of the Wnt/β-catenin signaling pathway. Copyright © 2012 Elsevier B.V. All rights reserved.

Beta-methyl substitution of cyclohexylalanine in Dmt-Tic-Cha-Phe peptides results in highly potent delta opioid antagonists.

PubMed

Tóth, Géza; Ioja, Eniko; Tömböly, Csaba; Ballet, Steven; Tourwé, Dirk; Péter, Antal; Martinek, Tamás; Chung, Nga N; Schiller, Peter W; Benyhe, Sándor; Borsodi, Anna

2007-01-25

The opioid peptide TIPP (H-Tyr-Tic-Phe-Phe-OH, Tic:1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) was substituted with Dmt (2',6'-dimethyltyrosine) and a new unnatural amino acid, beta-MeCha (beta-methyl-cyclohexylalanine). This double substitution led to a new series of opioid peptides displaying subnanomolar delta antagonist activity and mu agonist or antagonist properties depending on the configuration of the beta-MeCha residue. The most promising analog, H-Dmt-Tic-(2S,3S)-beta-MeCha-Phe-OH was a very selective delta antagonist both in the mouse vas deferens (MVD) assay (Ke = 0.241 +/- 0.05 nM) and in radioligand binding assay (K i delta = 0.48 +/- 0.05 nM, K i mu/K i delta = 2800). The epimeric peptide H-Dmt-Tic-(2S,3R)-beta-MeCha-Phe-OH and the corresponding peptide amide turned out to be mixed partial mu agonist/delta antagonists in the guinea pig ileum and MVD assays. Our results constitute further examples of the influence of Dmt and beta-methyl substitution as well as C-terminal amidation on the potency, selectivity, and signal transduction properties of TIPP related peptides. Some of these compounds represent valuable pharmacological tools for opioid research.

Anticonvulsant properties of alpha, gamma, and alpha, gamma-substituted gamma-butyrolactones.

PubMed

Klunk, W E; Covey, D F; Ferrendelli, J A

1982-09-01

Derivatives of gamma-butyrolactone (GBL) substituted on the alpha- and/or gamma-positions were synthesized and tested for their effects on behavior in mice, on the electroencephalographs and blood pressure of paralyzed-ventilated guinea pigs, and on electrical activity of incubated hippocampal slices. Several compounds, including alpha-ethyl-alpha-methyl GBL (alpha-EMGBL), alpha, alpha-dimethyl GBL, alpha, gamma-diethyl-alpha, gamma-dimethyl GBL, and gamma-ethyl-gamma-methyl GBL, prevented seizures induced by pentylenetetrazol, beta-ethyl-beta-methyl-gamma-butyrolactone (beta-EMGBL), picrotoxin, or all three compounds in mice and guinea pigs but had no effect on seizures induced by maximal electroshock or bicuculline. Neither gamma-hydroxybutyrate (GHB) nor alpha-isopropylidine GBL had any anticonvulsant activity. The anticonvulsant alpha-substituted compounds had a potent hypotensive effect and antagonized the hypertensive effect of beta-EMGBL, alpha-EMGBL was tested in incubated hippocampal slices and was found to depress basal activity and antagonize excitation induced by beta-EMGBL. These results demonstrate that alpha-alkyl-substituted GBL and, to a lesser extent, gamma-substituted derivatives are anticonvulsant agents and that their effects are strikingly different from those of GHB or beta-alkyl-substituted GBLs, which are epileptogenic. Possibly beta- and alpha-substituted GBLs act at the same site as agonists and antagonists, respectively.

Elucidation of solution state complexation in wet-granulated oven-dried ibuprofen and beta-cyclodextrin: FT-IR and 1H-NMR studies.

PubMed

Ghorab, M K; Adeyeye, M C

2001-08-01

The effect of oven-dried wet granulation on the complexation of beta-cyclodextrin with ibuprofen (IBU) in solution was investigated using Fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance (1H NMR), and molecular modeling. Granulation was carried out using 5 mL of three different granulating solvents; water, ethanol (95% v/v), and isopropanol and the granules were oven-dried at 60 degrees C for 2 h. The granules were compared to oven-dried physical mixture and conventionally prepared complex. Phase solubility study was performed to investigate the stability of the granulation-formed complexes in solution. FT-IR was used to examine the complexation in the granules while 1H NMR, and molecular modeling studies were carried out to determine the mechanism of complexation in the water-prepared granules. The solubility studies suggested a 1:1 complex between IBU and betaCD. It also showed that the stability of the complex in solution was in the following order with respect to the granulating solvents: ethanol > water > isopropanol. The FT-IR study revealed a shift in the carboxylic acid stretching band and decrease in the intensities of the C-H bending bands of the isopropyl group and the out-of-plane aromatic ring, of IBU, in granules compared to the oven-dried physical mixture. This indicated that granules might have some extent of solid state complexation that could further enhance dissolution and the IBU-betaCD solution state complexation. 1H NMR showed that water prepared oven-dried granules had a different 1H NMR spectrum compared to similarly made oven-dried physical mixture, indicative of complexation in the former. The 1H NMR and the molecular modeling studies together revealed that solution state complexation from the granules occurred by inclusion of the isopropyl group together with part of the aromatic ring of IBU into the betaCD cavity probably through its wider side. These results indicate that granulation process induced faster complexation in solution which enhances the solubility and the dissolution rate of poorly soluble drugs. The extent of complexation in the granules was dependent on the type of solvent used.

Chlorhexidine: beta-cyclodextrin inhibits yeast growth by extraction of ergosterol.

PubMed

Teixeira, K I R; Araújo, P V; Sinisterra, R D; Cortés, M E

2012-04-01

Chlorhexidine (Cx) augmented with beta-cyclodextrin (β-cd) inclusion compounds, termed Cx:β-cd complexes, have been developed for use as antiseptic agents. The aim of this study was to examine the interactions of Cx:β-cd complexes, prepared at different molecular ratios, with sterol and yeast membranes. The Minimal Inhibitory Concentration (MIC) against the yeast Candida albicans (C.a.) was determined for each complex; the MICs were found to range from 0.5 to 2 μg/mL. To confirm the MIC data, quantitative analysis of viable cells was performed using trypan blue staining. Mechanistic characterization of the interactions that the Cx:β-cd complexes have with the yeast membrane and assessment of membrane morphology following exposure to Cx:β-cd complexes were performed using Sterol Quantification Method analysis (SQM) and scanning electron microscopy (SEM). SQM revealed that sterol extraction increased with increasing β-cd concentrations (1.71 ×10(3); 1.4 ×10(3); 3.45 ×10(3), and 3.74 ×10(3) CFU for 1:1, 1:2, 1:3, and 1:4, respectively), likely as a consequence of membrane ergosterol solubilization. SEM images demonstrated that cell membrane damage is a visible and significant mechanism that contributes to the antimicrobial effects of Cx:β-cd complexes. Cell disorganization increased significantly as the proportion of β-cyclodextrin present in the complex increased. Morphology of cells exposed to complexes with 1:3 and 1:4 molar ratios of Cx:β-cd were observed to have large aggregates mixed with yeast remains, representing more membrane disruption than that observed in cells treated with Cx alone. In conclusion, nanoaggregates of Cx:β-cd complexes block yeast growth via ergosterol extraction, permeabilizing the membrane by creating cluster-like structures within the cell membrane, possibly due to high amounts of hydrogen bonding.

Stereospecific 1,4-addition to an alpha,beta-unsaturated steroidal epoxide: syntheses of new 15-oxygenated sterols.

PubMed

Parish, E J; Tsuda, M; Schroepfer, G J

1988-11-01

3 beta-Benzoyloxy-14 alpha,15 alpha-epoxy-5 alpha-cholest-7-ene (1) is a key intermediate in the synthesis of C-7 and C-15 oxygenated sterols. Treatment of 1 with benzoyl chloride resulted in the formation of 3 beta,15 alpha-bis-benzoyloxy-7 alpha-chloro-5 alpha-cholest-8(14)-ene (2). Reaction of 2 with LiAlH4 or LiAlD4 resulted in the formation of 5 alpha-cholest-7-ene-3 beta,15 alpha-diol (3a) or [14 alpha-2H]5 alpha-cholest-7-ene-3 beta,15 alpha-diol (3b). Diol 3b was selectively oxidized by Ag2CO3/celite to [14 alpha-2H]5 alpha-cholest-7-en-15 alpha-ol-3-one (4). Treatment of 1 with MeMgI/CuI gave 7 alpha-methyl-5 alpha-cholest-8(14)-ene-3 beta,15 alpha-diol (5). Selective oxidation of 5 with pyridinium chlorochromate (PCC)/pyridine or oxidation with PCC resulted in the formation of 7 alpha-methyl-5 alpha-cholest-8(14)-en-3 beta-ol-15-one (6) and 7 alpha-methyl-5 alpha-cholest-8(14)-ene-3,15-dione, respectively. Reduction of 6 with LiAlH4 yielded 5 and 7 alpha-methyl-5 alpha-cholest-8(14)-ene-3 beta,15 beta-diol (6). Reaction of 1 with benzoic acid/pyridine gave 3 beta,7 alpha-bis-benzoyloxy-5 alpha-cholest-8(14)-en-15 alpha-ol (9). Treatment of 9 with LiAlH4 or ethanolic KOH resulted in the formation of 5 alpha-cholest-8(14)-ene-3 beta,7 alpha,15 alpha-triol (10). Dibenzoate 9, upon brief treatment with mineral acid, gave 3 beta-benzoyloxy-5 alpha-cholest-8(14)-ene-15-one (11). Oxidation of 9 with PCC yielded 3 beta,7 alpha-bis-benzoyloxy-5 alpha-cholest-8(14)-ene-15-one (12). Ketone 12 was also prepared by the selective hydride reduction of 5 alpha-cholest-8(14)-en-7 alpha-ol-3,15-dione (13) to give 5 alpha-cholest-8(14)-ene-3 beta,7 alpha-diol-15-one (14), which was then treated with benzoyl chloride to produce 12.

Novel ethinyl estradiol-beta-cyclodextrin clathrate formulation does not influence the relative bioavailability of ethinyl estradiol or coadministered drospirenone.

PubMed

Blode, Hartmut; Schürmann, Rolf; Benda, Norbert

2008-03-01

A new combined oral contraceptive formulation has been developed consisting of a beta-cyclodextrin (betadex) clathrate formulation of ethinyl estradiol in combination with drospirenone (EE-betadex clathrate/drsp). In this novel EE-betadex clathrate/drsp preparation, betadex serves as an inert complexing agent to enhance stability and shelf-life. The study was conducted to investigate the relative bioavailability and pharmacokinetic parameters of EE and drsp after oral administration of EE-betadex clathrate/drsp. This was an open-label, randomized, single-dose, three-period, three-treatment, crossover study conducted in 18 healthy postmenopausal women aged 45-75 years. The women received single oral doses of 40 mcg EE/6 mg drsp formulated as EE-betadex clathrate/drsp or EE/drsp (EE as a free steroid) tablets, or as a microcrystalline suspension on three separate occasions. Serum samples were collected for pharmacokinetic analyses. The relative bioavailability of EE and drsp after EE-betadex clathrate/drsp tablet administration was comparable with that achieved with the EE/drsp tablet (107% and 101%, respectively). In addition, the inclusion of EE in a betadex clathrate does not affect the pharmacokinetics of either EE or drsp. There were no safety concerns with any of the medications. The betadex clathrate formulation of EE, when combined with DRSP, does not affect the pharmacokinetics and relative bioavailability of either EE or drsp.

Visible Light-Cured Glycol Chitosan Hydrogel Containing a Beta-Cyclodextrin-Curcumin Inclusion Complex Improves Wound Healing In Vivo.

PubMed

Yoon, Sun-Jung; Hyun, Hoon; Lee, Deok-Won; Yang, Dae Hyeok

2017-09-10

Scarless wound healing is ideal for patients suffering from soft tissue defects. In this study, we prepared a novel wet dressing (β-CD-ic-CUR/GC) based on the visible light-cured glycol chitosan (GC) hydrogel and inclusion complex between beta-cyclodextrin (β-CD) and curcumin (CUR). We also evaluated its efficacy in the acceleration of wound healing as compared to that of CUR-loaded GC (CUR/GC). The conjugation of glycidyl methacrylate (GM) to GC for photo-curing was confirmed by ¹H-NMR measurement, and the photo-cured GC hydrogel was characterized by the analyses of rheology, swelling ratio, SEM and degradation rate. After visible light irradiation, the surface/cross-sectional morphologies and storage (G')/loss (G'') moduli revealed the formation of hydrogel with interconnected porosity. The dressing β-CD-ic-CUR/GC exhibited a controlled release of 90% CUR in a sustained manner for 30 days. On the other hand, CUR/GC showed CUR release of 16%. β-CD acted as an excipient in improving the water-solubility of CUR and affected the release behavior of CUR. The in vivo animal tests including measurement of the remaining unhealed wound area and histological analyses showed that β-CD-ic-CUR/GC may have potential as a wet dressing agent to enhance soft tissue recovery in open fractures.

Monitoring dediazoniation product formation by high-performance liquid chromatography after derivatization.

PubMed

Bravo-Díaz, Carlos; González-Romero, Elisa

2003-03-14

A derivatization protocol that exploits the rapid reaction between arenediazonium ions and a suitable coupling agent followed by high-performance liquid chromatography analyses of the reaction mixture was employed to determine the product distribution, the rate constants for product formation and the association constant of 4-nitrobenzenediazonium, PNBD, ion with beta-cyclodextrin, beta-CD. The derivatization of PNBD with the coupling agent leads to the formation of a stable azo dye that prevents by-side reactions of PNBD with the solvents of the mobile phase, including water, or the metallic parts of the chromatographic system that would eventually lead to erroneous identification and quantification of dediazoniation products. The results show that in the presence of beta-CD, nitrobenzene is formed at the expense of 4-nitrophenol, which is the major product in its absence. The observed rate constants for the interaction between PNBD and beta-CD increase upon increasing [beta-CD] showing a saturation profile indicative of the formation of an inclusion complex between PNBD and beta-CD. By fitting the experimental data to a simplified Lineaweaver-Burk equation, the corresponding association constant and the maximum acceleration rate of beta-CD towards PNBD were estimated. The protocol is applicable under a variety of experimental conditions provided that the rate of the coupling reaction is much faster than that of dediazoniation.

Determination of morphine and codeine in urine using poly(dimethylsiloxane) microchip electrophoresis with electrochemical detection.

PubMed

Zhang, Qian-Li; Xu, Jing-Juan; Li, Xiang-Yun; Lian, Hong-Zhen; Chen, Hong-Yuan

2007-01-04

In this paper, a poly(dimethylsiloxane) (PDMS) microchip with electrochemical (EC) detection was developed for rapid separation and detection of morphine and codeine. It was found that morphine and codeine were well separated within 140 s in phosphate buffer solution (PBS) (pH 6.6, 40 mM)-beta-cyclodextrin (beta-CD) (20 mM)-acetonitrile (30%, v/v). The detection limit was 0.2 microM for morphine and 1 microM for codeine. The protocol was successfully applied to monitoring the amount of morphine and codeine in human urine. Compared with the conventional methods, the presented method had many advantages such as lower instrument cost, less reagent consumption and shorter analysis time.

Non-fibrillar amyloid-{beta} peptide reduces NMDA-induced neurotoxicity, but not AMPA-induced neurotoxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Niidome, Tetsuhiro, E-mail: tniidome@pharm.kyoto-u.ac.jp; Goto, Yasuaki; Kato, Masaru

2009-09-04

Amyloid-{beta} peptide (A{beta}) is thought to be linked to the pathogenesis of Alzheimer's disease. Recent studies suggest that A{beta} has important physiological roles in addition to its pathological roles. We recently demonstrated that A{beta}42 protects hippocampal neurons from glutamate-induced neurotoxicity, but the relationship between A{beta}42 assemblies and their neuroprotective effects remains largely unknown. In this study, we prepared non-fibrillar and fibrillar A{beta}42 based on the results of the thioflavin T assay, Western blot analysis, and atomic force microscopy, and examined the effects of non-fibrillar and fibrillar A{beta}42 on glutamate-induced neurotoxicity. Non-fibrillar A{beta}42, but not fibrillar A{beta}42, protected hippocampal neurons frommore » glutamate-induced neurotoxicity. Furthermore, non-fibrillar A{beta}42 decreased both neurotoxicity and increases in the intracellular Ca{sup 2+} concentration induced by N-methyl-D-aspartate (NMDA), but not by {alpha}-amino-3-hydrozy-5-methyl-4-isoxazole propionic acid (AMPA). Our results suggest that non-fibrillar A{beta}42 protects hippocampal neurons from glutamate-induced neurotoxicity through regulation of the NMDA receptor.« less

Stereoselective synthesis of nicotinamide beta-riboside and nucleoside analogs.

PubMed

Franchetti, Palmarisa; Pasqualini, Michela; Petrelli, Riccardo; Ricciutelli, Massimo; Vita, Patrizia; Cappellacci, Loredana

2004-09-20

The beta-anomers of N-ribofuranosylnicotine-3-carboxamide (beta-NAR) and its nicotinic acid analog (beta-NaR) were obtained by stereoselective synthesis via glycosylation of the presilylated bases under Vorbruggen's protocol. A NAR analog, methylated in position 3 of the ribosylic moiety, is also reported.

Quasielastic small-angle neutron scattering from heavy water solutions of cyclodextrins

NASA Astrophysics Data System (ADS)

Kusmin, André; Lechner, Ruep E.; Saenger, Wolfram

2011-01-01

We present a model for quasielastic neutron scattering (QENS) by an aqueous solution of compact and inflexible molecules. This model accounts for time-dependent spatial pair correlations between the atoms of the same as well as of distinct molecules and includes all coherent and incoherent neutron scattering contributions. The extension of the static theory of the excluded volume effect [A. K. Soper, J. Phys.: Condens. Matter 9, 2399 (1997)] to the time-dependent (dynamic) case allows us to obtain simplified model expressions for QENS spectra in the low Q region in the uniform fluid approximation. The resulting expressions describe the quasielastic small-angle neutron scattering (QESANS) spectra of D _2O solutions of native and methylated cyclodextrins well, yielding in particular translational and rotational diffusion coefficients of these compounds in aqueous solution. Finally, we discuss the full potential of the QESANS analysis (that is, beyond the uniform fluid approximation), in particular, the information on solute-solvent interactions (e.g., hydration shell properties) that such an analysis can provide, in principle.

Variation in susceptibility of laboratory and field strains of three stored-grain insect species to beta-cyfluthrin and chlorpyrifos-methyl plus deltamethrin applied to concrete surfaces

USDA-ARS?s Scientific Manuscript database

The efficacy of beta-cyfluthrin and chlorpyrifos-methyl plus deltamethrin applied to clean, concrete floors of empty bins prior to grain storage against field strains of stored-grain insects is unknown. We exposed adults of 16 strains of the red flour beetle, Tribolium castaneum (Herbst); 8 strains ...

Combined use of chiral ionic liquid surfactants and neutral cyclodextrins: evaluation of ionic liquid head groups for enantioseparation of neutral compounds in capillary electrophoresis.

PubMed

Liu, Yijin; Shamsi, Shahab A

2014-09-19

Cyclodextrins (CDs) are most commonly used chiral selectors in capillary electrophoresis (CE). Although the use of neutral CDs and its derivatives have shown to resolve plethora of charged enantiomers, they cannot resolve neutral enantiomers. The use of ionic liquids (ILs) surfactants forming successful complex with CDs present itself an opportunity to resolve neutral enantiomers. In this work, the effect of IL head groups and their complexation ability with heptakis (2,3,6-tri-O-methyl)-β-cyclodextrin (TM-β-CD) was studied for the separation of neutral enantiomers by CE. First, cationic IL type surfactants with different chiral head groups were synthesized. Physicochemical properties such as critical micelle concentration were determined by surface tension, whereas aggregation and polarity were determined by fluorescence spectroscopy. The complexation ability of ILs with TM-β-CD was characterized in the gas phase by CE-mass spectrometry. The influence of the type of ILs head group and its concentration on chiral resolution, resolution per unit time and selectivity were investigated for four structurally diverse neutral compounds. The binding constants of the neutral analytes to the IL-CD complex were estimated by y-reciprocal method. The hydrophobicity of the side chain of the IL head group displayed significant effect on the binding constants and enantioseparations. Copyright © 2014 Elsevier B.V. All rights reserved.

Separation of enilconazole enantiomers in capillary electrophoresis with cyclodextrin-type chiral selectors and investigation of structure of selector-selectand complexes by using nuclear magnetic resonance spectroscopy.

PubMed

Gogolashvili, Ann; Tatunashvili, Elene; Chankvetadze, Lali; Sohajda, Tamas; Szeman, Julianna; Salgado, Antonio; Chankvetadze, Bezhan

2017-08-01

In the present study, the enantiomer migration order (EMO) of enilconazole in the presence of various cyclodextrins (CDs) was investigated by capillary electrophoresis (CE). Opposite EMO of enilconazole were observed when β-CD or the sulfated heptakis(2-O-methyl-3,6-di-O-sulfo)-β-CD (HMDS-β-CD) was used as the chiral selectors. Nuclear magnetic resonance (NMR) spectroscopy was used to study the mechanism of chiral recognition between enilconazole enantiomers and those two cyclodextrins. On the basis of rotating frame nuclear Overhauser (ROESY) experiments, the structure of an inclusion complex between enilconazole and β-CD was derived, in which (+)-enilconazole seemed to form a tighter complex than the (-)-enantiomer. This correlates well with the migration order of enilconazole enantiomers observed in CE. No evidence of complexation between enilconazole and HMDS-β-CD could be gathered due to lack of intermolecular nuclear Overhauser effect (NOE). Most likely the interaction between enilconazole and HMDS-β-CD leads to formation of a shallow external complex that is sufficient for separation of enantiomers in CE but cannot be evidenced based on ROESY experiment. Thus, in this particular case CE documents the presence of intermolecular interactions which are at least very difficult to be evidenced by other instrumental techniques. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Oxygen radical absorbance capacity (ORAC) of cyclodextrin-solubilized flavonoids, resveratrol and astaxanthin as measured with the ORAC-EPR method

PubMed Central

Sueishi, Yoshimi; Ishikawa, Misa; Yoshioka, Daisuke; Endoh, Nobuyuki; Oowada, Shigeru; Shimmei, Masashi; Fujii, Hirotada; Kotake, Yashige

2012-01-01

Recently, we proposed an oxygen radical absorbance capacity method that directly quantifies the antioxidant’s scavenging capacity against free radicals and evaluated the radical scavenging abilities for water soluble antioxidant compounds. In this study, we determined the radical scavenging abilities of lipophilic antioxidants which were solubilized by cyclodextrin in water. Commonly employed fluorescence-based method measures the antioxidant’s protection capability for the fluorescent probe, while we directly quantify free-radical level using electron paramagnetic resonance spin trapping technique. In addition, the spin trapping-based method adopted controlled UV-photolysis of azo-initiator for free radical generation, but in fluorescence-based method, thermal decomposition of azo-initiator was utilized. We determined the radical scavenging abilities of seven well-known lipophilic antioxidants (five flavonoids, resveratrol and astaxanthin), using methylated β-cyclodextrin as a solubilizer. The results indicated that the agreement between spin trapping-based and fluorescence-based values was only fair partly because of a large variation in the previous fluorescence-based data. Typical radical scavenging abilities in trolox equivalent unit are: catechin 0.96; epicatechin 0.94; epigallocatechin gallate 1.3; kaempferol 0.37; myricetin 3.2; resveratrol 0.64; and astaxanthin 0.28, indicating that myricetin possesses the highest antioxidant capacity among the compounds tested. We sorted out the possible causes of the deviation between the two methods. PMID:22448093

Oxygen radical absorbance capacity (ORAC) of cyclodextrin-solubilized flavonoids, resveratrol and astaxanthin as measured with the ORAC-EPR method.

PubMed

Sueishi, Yoshimi; Ishikawa, Misa; Yoshioka, Daisuke; Endoh, Nobuyuki; Oowada, Shigeru; Shimmei, Masashi; Fujii, Hirotada; Kotake, Yashige

2012-03-01

Recently, we proposed an oxygen radical absorbance capacity method that directly quantifies the antioxidant's scavenging capacity against free radicals and evaluated the radical scavenging abilities for water soluble antioxidant compounds. In this study, we determined the radical scavenging abilities of lipophilic antioxidants which were solubilized by cyclodextrin in water. Commonly employed fluorescence-based method measures the antioxidant's protection capability for the fluorescent probe, while we directly quantify free-radical level using electron paramagnetic resonance spin trapping technique. In addition, the spin trapping-based method adopted controlled UV-photolysis of azo-initiator for free radical generation, but in fluorescence-based method, thermal decomposition of azo-initiator was utilized. We determined the radical scavenging abilities of seven well-known lipophilic antioxidants (five flavonoids, resveratrol and astaxanthin), using methylated β-cyclodextrin as a solubilizer. The results indicated that the agreement between spin trapping-based and fluorescence-based values was only fair partly because of a large variation in the previous fluorescence-based data. Typical radical scavenging abilities in trolox equivalent unit are: catechin 0.96; epicatechin 0.94; epigallocatechin gallate 1.3; kaempferol 0.37; myricetin 3.2; resveratrol 0.64; and astaxanthin 0.28, indicating that myricetin possesses the highest antioxidant capacity among the compounds tested. We sorted out the possible causes of the deviation between the two methods.

Enzymic aromatization of 6-alkyl-substituted androgens, potent competitive and mechanism-based inhibitors of aromatase.

PubMed Central

Numazawa, M; Yoshimura, A; Oshibe, M

1998-01-01

To gain insight into the relationships between the aromatase inhibitory activity of 6-alkyl-substituted androgens, potent competitive inhibitors, and their ability to serve as a substrate of aromatase, we studied the aromatization of a series of 6alpha- and 6beta-alkyl (methyl, ethyl, n-propyl, n-pentyl and n-heptyl)-substituted androst-4-ene-3,17-diones (ADs) and their androsta-1,4-diene-3,17-dione (ADD) derivatives with human placental aromatase, by gas chromatography-mass spectrometry. Among the inhibitors examined, ADD and its 6alpha-alkyl derivatives with alkyl functions less than three carbons long, together with 6beta-methyl ADD, are suicide substrates of aromatase. All of the steroids, except for 6beta-n-pentyl ADD and its n-heptyl analogue as well as 6beta-n-heptyl AD, were found to be converted into the corresponding 6-alkyl oestrogens. The 6-methyl steroids were aromatized most efficiently in each series, and the aromatization rate essentially decreased in proportion to the length of the 6-alkyl chains in each series, where the 6alpha-alkyl androgens were more efficient substrates than the corresponding 6beta isomers. The Vmax of 6alpha-methyl ADD was approx. 2.5-fold that of the natural substrate AD and approx. 3-fold that of the parent ADD. On the basis of this, along with the facts that the rates of a mechanism-based inactivation of aromatase by ADD and its 6alpha-methyl derivative are similar, it is implied that alignment of 6alpha-methyl ADD in the active site could favour the pathway leading to oestrogen over the inactivation pathway, compared with that of ADD. The relative apparent Km values for the androgens obtained in this study are different from the relative Ki values obtained previously, indicating that there is a difference between the ability to serve as an inhibitor and the ability to serve as a substrate in the 6-alkyl androgen series. PMID:9405288

Development of a new delivery system consisting in 'drug-in cyclodextrin-in PLGA nanoparticles'.

PubMed

Mura, Paola; Maestrelli, Francesca; Cecchi, Matteo; Bragagni, Marco; Almeida, Antonio

2010-01-01

A combined approach based on drug cyclodextrin (CD) complexation and loading into PLGA nanoparticles (NP) has been developed to improve oxaprozin therapeutic efficiency. This strategy exploits the solubilizing and stabilizing properties of CDs and the prolonged-release and targeting properties of PLGA NPs. Drug-loaded NPs, prepared by double-emulsion, were examined for dimensions, zeta-potential and entrapment efficiency. Solid-state studies demonstrated the absence of drug-polymer interactions and assessed the amorphous state of the drug-CD complex loaded into NPs. Drug release rate from NPs was strongly influenced by the presence and kind of CD used. The percentage released at 24 h varied from 16% (plain drug-loaded NPs) to 50% (drug-betaCD-loaded NPs) up to 100% (drug-methylbetaCD-loaded NPs). This result suggests the possibility of using CD complexation not only to promote, but also to regulate drug release rate from NPs, by selecting the proper type of CD or CD combination.

Displacement chromatography on cyclodextrin silicas. IV. Separation of the enantiomers of ibuprofen.

PubMed

Farkas, G; Irgens, L H; Quintero, G; Beeson, M D; al-Saeed, A; Vigh, G

1993-08-13

A displacement chromatographic method has been developed for the preparative separation of the enantiomers of ibuprofen using a beta-cyclodextrin silica stationary phase. The retention behavior of ibuprofen was studied in detail: the log k' vs. polar organic modifier concentration, the log k' vs. pH, the log k' vs. buffer concentration and the log k' vs. 1/T relationships; also, the alpha vs. polar organic modifier concentration, the alpha vs. pH, the alpha vs. buffer concentration and the log alpha vs. 1/T relationships have been determined in order to find the carrier solution composition which results in maximum chiral selectivity and sufficient, but not excessive solute retention (1 < k' < 30). 4-tert.-Butylcyclohexanol, a structurally similar but more retained compound than ibuprofen, was selected as displacer for the separation. Even with an alpha value as small as 1.08, good preparative chiral separations were observed both in the displacement mode and in the overloaded elution mode, up to a sample load of 0.5 mg.

Enantioseparation of dopa and related compounds by cyclodextrin-modified microemulsion electrokinetic chromatography.

PubMed

Borst, Claudia; Holzgrabe, Ulrike

2008-09-19

A chiral microemulsion electrokinetic chromatography method has been developed for the enantiomeric separation of 3,4-dihydroxyphenylalanine (dopa), its precursors phenylalanine and tyrosine, and the structurally related substance methyldopa. The separations were achieved using an oil-in-water microemulsion, which consisted of the oil-compound ethyl acetate, the surfactant sodium dodecylsulfate (SDS), the co-surfactant 1-butanol, the organic modifier propan-2-ol and 20mM phosphate buffer pH 2.5 or 2.0 as aqueous phase. For enantioseparation sulfated beta-cyclodextrin was added. The resolution of each racemate was optimized by varying the concentration of the buffer and all components of the microemulsion. Enantioseparation could be achieved for dl-dopa, dl-phenylalanine and dl-tyrosine within 13 min with a resolution of 4.3, 3.1 and 3.3, respectively, and for methyldopa in 17 min (Rs: 1.4). The established methods allowed the detection of dopa, phenylalanine, tyrosine and methyldopa with a limit at 0.5, 1.0, 0.2 and 2.0 microg/ml.

Cyclodextrin-insulin complex encapsulated polymethacrylic acid based nanoparticles for oral insulin delivery.

PubMed

Sajeesh, S; Sharma, Chandra P

2006-11-15

Present investigation was aimed at developing an oral insulin delivery system based on hydroxypropyl beta cyclodextrin-insulin (HPbetaCD-I) complex encapsulated polymethacrylic acid-chitosan-polyether (polyethylene glycol-polypropylene glycol copolymer) (PMCP) nanoparticles. Nanoparticles were prepared by the free radical polymerization of methacrylic acid in presence of chitosan and polyether in a solvent/surfactant free medium. Dynamic light scattering (DLS) experiment was conducted with particles dispersed in phosphate buffer (pH 7.4) and size distribution curve was observed in the range of 500-800 nm. HPbetaCD was used to prepare non-covalent inclusion complex with insulin and complex was analyzed by Fourier transform infrared (FTIR) and fluorescence spectroscopic studies. HPbetaCD complexed insulin was encapsulated into PMCP nanoparticles by diffusion filling method and their in vitro release profile was evaluated at acidic/alkaline pH. PMCP nanoparticles displayed good insulin encapsulation efficiency and release profile was largely dependent on the pH of the medium. Enzyme linked immunosorbent assay (ELISA) study demonstrated that insulin encapsulated inside the particles was biologically active. Trypsin inhibitory effect of PMCP nanoparticles was evaluated using N-alpha-benzoyl-L-arginine ethyl ester (BAEE) and casein as substrates. Mucoadhesive studies of PMCP nanoparticles were conducted using freshly excised rat intestinal mucosa and the particles were found fairly adhesive. From the preliminary studies, cyclodextrin complexed insulin encapsulated mucoadhesive nanoparticles appear to be a good candidate for oral insulin delivery.

Spray-Freeze Drying: a Suitable Method for Aerosol Delivery of Antibodies in the Presence of Trehalose and Cyclodextrins.

PubMed

Pouya, Maryam Amini; Daneshmand, Behnaz; Aghababaie, Shabnam; Faghihi, Homa; Vatanara, Alireza

2018-05-08

We aimed to prepare spray-freeze-dried powder of IgG considering physicochemical stability and aerodynamic aspects. Spray-freeze drying (SFD) exposes proteins to various stresses which should be compensated by suitable stabilizers. The competence of cyclodextrins (CDs), namely beta-cyclodextrin (βCD) and hydroxypropyl βCD (HPβCD), at very low concentrations, was investigated in the presence of separate mannitol- and trehalose-based formulations. Spray-freeze-dried preparations were quantified in terms of monomer recovery and conformation by size exclusion chromatography (SEC-HPLC) and Fourier transform infrared (FTIR) spectroscopy, respectively. Differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) were employed to identify the thermal characteristics of powders. Particle morphology was visualized by scanning electron microscopy (SEM). Aerodynamic behavior of powders was checked through an Anderson cascade impactor (ACI). Although all formulations protected antibody from aggregation during the SFD process (aggregation < 1%), mannitol-containing ones failed upon the storage (19.54% in the worst case). Trehalose-HPβCD incomparably preserved the formulation with fine particle fraction (FPF) of 51.29%. Crystallization of mannitol resulted in IgG destabilization upon storage. Although employed concentration of CDs is too low (less than 50:1 molar ratio to protein), they successfully served as stabilizing agents in SFD with perfect improvement in aerosol functionality. Graphical Abstract ᅟ.

Variation in the DNA methylation pattern of expressed and nonexpressed genes in chicken.

PubMed

Cooper, D N; Errington, L H; Clayton, R M

1983-01-01

Using methyl-sensitive and -insensitive restriction enzymes, Hpa II and Msp I, the methylation status of various chicken genes was examined in different tissues and developmental stages. Tissue-specific differences in methylation were found for the delta-crystallin, beta-tubulin, G3PDH, rDNA, and actin genes but not for the histone genes. Developmental decreases in methylation were noted for the delta-crystallin and actin genes in chicken kidney between embryo and adult. Since most of the sequences examined were housekeeping genes, transcriptional differences are apparently not a necessary accompaniment to changes in DNA methylation at the CpG sites examined. The only exception is sperm DNA where the delta-crystallin, beta-tubulin, and actin genes are highly methylated and almost certainly not transcribed. However the G3PDH genes are no more highly methylated in sperm than in other somatic tissues. Many sequences homologous to the rDNA and histone probes used are unmethylated in all tissues examined including sperm, but a methylated rDNA subfraction is more heavily methylated in sperm than in other tissues. We speculate as to the significance of these differences in sperm DNA methylation in the light of possible requirements for early gene activation and the probable deleterious mutagenic effects of heavy methylation within coding sequences.

Requirement of cholesterol in the viral envelope for dengue virus infection.

PubMed

Carro, Ana C; Damonte, Elsa B

2013-06-01

The role of cholesterol in the virus envelope or in the cellular membranes for dengue virus (DENV) infection was examined by depletion with methyl-beta-cyclodextrin (MCD) or nystatin. Pretreatment of virions with MCD or nystatin significantly reduced virus infectivity in a dose-dependent manner. By contrast, pre-treatment of diverse human cell lines with MCD or nystatin did not affect DENV infection. The four DENV serotypes were similarly inactivated by cholesterol-extracting drugs and infectivity was partially rescued when virion suspensions were treated with MCD in the presence of bovine serum. The addition of serum or exogenous water-soluble cholesterol after MCD treatment did not produce a reversion of MCD inactivating effect. Furthermore, virion treatment with extra cholesterol exerted also a virucidal effect. Binding and uptake of cholesterol-deficient DENV into the host cell were not impaired, whereas the next step of fusion between virion envelope and endosome membrane leading to virion uncoating and release of nucleocapsids to the cytoplasm appeared to be prevented, as determined by the retention of capsid protein in cells infected with MCD inactivated-DENV virions. Thereafter, the infection was almost completely inhibited, given the failure of viral RNA synthesis and viral protein expression in cells infected with MCD-treated virions. These data suggest that envelope cholesterol is a critical factor in the fusion process for DENV entry. Copyright © 2013 Elsevier B.V. All rights reserved.

Cholesterol effectively blocks entry of flavivirus.

PubMed

Lee, Chyan-Jang; Lin, Hui-Ru; Liao, Ching-Len; Lin, Yi-Ling

2008-07-01

Japanese encephalitis virus (JEV) and dengue virus serotype 2 (DEN-2) are enveloped flaviviruses that enter cells through receptor-mediated endocytosis and low pH-triggered membrane fusion and then replicate in intracellular membrane structures. Lipid rafts, cholesterol-enriched lipid-ordered membrane domains, are platforms for a variety of cellular functions. In this study, we found that disruption of lipid raft formation by cholesterol depletion with methyl-beta-cyclodextrin or cholesterol chelation with filipin III reduces JEV and DEN-2 infection, mainly at the intracellular replication steps and, to a lesser extent, at viral entry. Using a membrane flotation assay, we found that several flaviviral nonstructural proteins are associated with detergent-resistant membrane structures, indicating that the replication complex of JEV and DEN-2 localizes to the membranes that possess the lipid raft property. Interestingly, we also found that addition of cholesterol readily blocks flaviviral infection, a result that contrasts with previous reports of other viruses, such as Sindbis virus, whose infectivity is enhanced by cholesterol. Cholesterol mainly affected the early step of the flavivirus life cycle, because the presence of cholesterol during viral adsorption greatly blocked JEV and DEN-2 infectivity. Flavirial entry, probably at fusion and RNA uncoating steps, was hindered by cholesterol. Our results thus suggest a stringent requirement for membrane components, especially with respect to the amount of cholesterol, in various steps of the flavivirus life cycle.

Insertion of targeting domains into the envelope glycoprotein of Moloney murine leukemia virus (MoMLV)-based vectors modulates the route of mCAT-1-mediated viral entry.

PubMed

Viejo-Borbolla, A; Pizzato, M; Blair, E D; Schulz, T F

2005-03-01

Several groups have inserted targeting domains into the envelope glycoprotein (Env) of Moloney murine leukemia virus (MoMLV) in an attempt to produce targeted retroviral vectors for human gene therapy. While binding of these modified Envs to the target molecule expressed on the surface of human cells was observed, specific high-titer infection of human cells expressing the target molecule was not achieved. Here we investigate the initial steps in the entry process of targeted MoMLV vectors both in murine and human cells expressing the MoMLV receptor, the mouse cationic amino acid transporter-1 (mCAT-1). We show that insertion of a small ligand targeted to E-selectin and of a single chain antibody (scFv) targeted to folate-binding protein (FBP) into the N-terminus of MoMLV Env results in the reduction of the infectivity and the kinetics of entry of the MoMLV vectors. The use of soluble receptor-binding domain (sRBD), bafilomycin A1 (BafA1) and methyl-beta-cyclodextrin (MbetaC) increase the infectivity of the MoMLV vectors targeted to FBP (MoMLV-FBP) suggesting that the scFv targeted to FBP increases the threshold for fusion and might re-route entry of the targeted MoMLV-FBP vector towards an endocytic, non-productive pathway.

Purification and biochemical characterization of a thermostable extracellular glucoamylase produced by the thermotolerant fungus Paecilomyces variotii.

PubMed

Michelin, Michele; Ruller, Roberto; Ward, Richard J; Moraes, Luiz Alberto B; Jorge, João A; Terenzi, Héctor F; Polizeli, Maria de Lourdes T M

2008-01-01

An extracellular glucoamylase produced by Paecilomyces variotii was purified using DEAE-cellulose ion exchange chromatography and Sephadex G-100 gel filtration. The purified protein migrated as a single band in 7% PAGE and 8% SDS-PAGE. The estimated molecular mass was 86.5 kDa (SDS-PAGE). Optima of temperature and pH were 55 degrees C and 5.0, respectively. In the absence of substrate the purified glucoamylase was stable for 1 h at 50 and 55 degrees C, with a t (50) of 45 min at 60 degrees C. The substrate contributed to protect the enzyme against thermal denaturation. The enzyme was mainly activated by manganese metal ions. The glucoamylase produced by P. variotii preferentially hydrolyzed amylopectin, glycogen and starch, and to a lesser extent malto-oligossacarides and amylose. Sucrose, p-nitrophenyl alpha-D-maltoside, methyl-alpha-D-glucopyranoside, pullulan, alpha- and beta-cyclodextrin, and trehalose were not hydrolyzed. After 24 h, the products of starch hydrolysis, analyzed by thin layer chromatography, showed only glucose. The circular dichroism spectrum showed a protein rich in alpha-helix. The sequence of amino acids of the purified enzyme VVTDSFR appears similar to glucoamylases purified from Talaromyces emersonii and with the precursor of the glucoamylase from Aspergillus oryzae. These results suggested the character of the enzyme studied as a glucoamylase (1,4-alpha-D-glucan glucohydrolase).

Recombinant VSV G proteins reveal a novel raft-dependent endocytic pathway in resorbing osteoclasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mulari, Mika T.K.; Centre for Military Medicine, Research Department, Lahti; Nars, Martin

2008-05-01

Transcytotic membrane flow delivers degraded bone fragments from the ruffled border to the functional secretory domain, FSD, in bone resorbing osteoclasts. Here we show that there is also a FSD-to-ruffled border trafficking pathway that compensates for the membrane loss during the matrix uptake process and that rafts are essential for this ruffled border-targeted endosomal pathway. Replacing the cytoplasmic tail of the vesicular stomatitis virus G protein with that of CD4 resulted in partial insolubility in Triton X-100 and retargeting from the peripheral non-bone facing plasma membrane to the FSD. Recombinant G proteins were subsequently endosytosed and delivered from the FSDmore » to the peripheral fusion zone of the ruffled border, which were both rich in lipid rafts as suggested by viral protein transport analysis and visualizing the rafts with fluorescent recombinant cholera toxin. Cholesterol depletion by methyl-{beta}-cyclodextrin impaired the ruffled border-targeted vesicle trafficking pathway and inhibited bone resorption dose-dependently as quantified by measuring the CTX and TRACP 5b secreted to the culture medium and by measuring the resorbed area visualized with a bi-phasic labeling method using sulpho-NHS-biotin and WGA-lectin. Thus, rafts are vital for membrane recycling from the FSD to the late endosomal/lysosomal ruffled border and bone resorption.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Petrov, Alexey M., E-mail: fysio@rambler.ru; Zakyrjanova, Guzalija F., E-mail: guzik121192@mail.ru; Yakovleva, Anastasia A., E-mail: nastya1234qwer@mail.ru

Highlights: • We examine the involvement of PKC in MCD induced synaptic vesicle exocytosis. • PKC inhibitor does not decrease the effect MCD on MEPP frequency. • PKC inhibitor prevents MCD induced FM1-43 unloading. • PKC activation may switch MCD induced exocytosis from kiss-and-run to a full mode. • Inhibition of phospholipase C does not lead to similar change in exocytosis. - Abstract: Previous studies demonstrated that depletion of membrane cholesterol by 10 mM methyl-beta-cyclodextrin (MCD) results in increased spontaneous exocytosis at both peripheral and central synapses. Here, we investigated the role of protein kinase C in the enhancement ofmore » spontaneous exocytosis at frog motor nerve terminals after cholesterol depletion using electrophysiological and optical methods. Inhibition of the protein kinase C by myristoylated peptide and chelerythrine chloride prevented MCD-induced increases in FM1-43 unloading, whereas the frequency of spontaneous postsynaptic events remained enhanced. The increase in FM1-43 unloading still could be observed if sulforhodamine 101 (the water soluble FM1-43 quencher that can pass through the fusion pore) was added to the extracellular solution. This suggests a possibility that exocytosis of synaptic vesicles under these conditions could occur through the kiss-and-run mechanism with the formation of a transient fusion pore. Inhibition of phospholipase C did not lead to similar change in MCD-induced exocytosis.« less

Strategy to enhance efficacy of doxorubicin in solid tumor cells by methyl-β-cyclodextrin: Involvement of p53 and Fas receptor ligand complex

PubMed Central

Mohammad, Naoshad; Vikram Singh, Shivendra; Malvi, Parmanand; Chaube, Balkrishna; Athavale, Dipti; Vanuopadath, Muralidharan; Nair, Sudarslal Sadasivan; Nair, Bipin; Bhat, Manoj Kumar

2015-01-01

Doxorubicin (DOX) is one of the preferred drugs for treating breast and liver cancers. However, its clinical application is limited due to severe side effects and the accompanying drug resistance. In this context, we investigated the effect on therapeutic efficacy of DOX by cholesterol depleting agent methyl-β-cyclodextrin (MCD), and explored the involvement of p53. MCD sensitizes MCF-7 and Hepa1–6 cells to DOX, Combination of MCD and marginal dose of DOX reduces the cell viability, and promoted apoptosis through induction of pro-apoptotic protein, Bax, activation of caspase-8 and caspase-7, down regulation of anti-apoptotic protein Bcl-2 and finally promoting PARP cleavage. Mechanistically, sensitization to DOX by MCD was due to the induction of FasR/FasL pathway through p53 activation. Furthermore, inhibition of p53 by pharmacological inhibitor pifithrin-α (PFT-α) or its specific siRNA attenuated p53 function and down-regulated FasR/FasL, thereby preventing cell death. Animal experiments were performed using C57BL/6J mouse isografted with Hepa1–6 cells. Tumor growth was retarded and survival increased in mice administered MCD together with DOX to as compared to either agent alone. Collectively, these results suggest that MCD enhances the sensitivity to DOX for which wild type p53 is an important determinant. PMID:26149967

Capacitation in the presence of methyl-β-cyclodextrin results in enhanced zona pellucida-binding ability of stallion spermatozoa.

PubMed

Bromfield, Elizabeth G; Aitken, R John; Gibb, Zamira; Lambourne, Sarah R; Nixon, Brett

2014-02-01

While IVF has been widely successful in many domesticated species, the development of a robust IVF system for the horse remains an elusive and highly valued goal. A major impediment to the development of equine IVF is the fact that optimised conditions for the capacitation of equine spermatozoa are yet to be developed. Conversely, it is known that stallion spermatozoa are particularly susceptible to damage arising as a consequence of capacitation-like changes induced prematurely in response to semen handling and transport conditions. To address these limitations, this study sought to develop an effective system to both suppress and promote the in vitro capacitation of stallion spermatozoa. Our data indicated that the latter could be achieved in a bicarbonate-rich medium supplemented with a phosphodiesterase inhibitor, a cyclic AMP analogue, and methyl-β-cyclodextrin, an efficient cholesterol-withdrawing agent. The populations of spermatozoa generated under these conditions displayed a number of hallmarks of capacitation, including elevated levels of tyrosine phosphorylation, a reorganisation of the plasma membrane leading to lipid raft coalescence in the peri-acrosomal region of the sperm head, and a dramatic increase in their ability to interact with heterologous bovine zona pellucida (ZP) and undergo agonist-induced acrosomal exocytosis. Furthermore, this functional transformation was effectively suppressed in media devoid of bicarbonate. Collectively, these results highlight the importance of efficient cholesterol removal in priming stallion spermatozoa for ZP binding in vitro.

Effect of O-methyl-β-cyclodextrin-modified magnetic nanoparticles on the uptake and extracellular level of l-glutamate in brain nerve terminals.

PubMed

Horák, Daniel; Beneš, Milan; Procházková, Zuzana; Trchová, Miroslava; Borysov, Arsenii; Pastukhov, Artem; Paliienko, Konstantin; Borisova, Tatiana

2017-01-01

Changes in cholesterol concentration in the plasma membrane of presynaptic nerve terminals nonspecifically modulate glutamate transport and homeostasis in the central nervous system. Reduction of the cholesterol content in isolated rat brain nerve terminals (synaptosomes) using cholesterol-depleting agents decreases the glutamate uptake and increases the extracellular level of glutamate in nerve terminals. Extraction of cholesterol from the plasma membrane and its further removal from the synaptosomes by external magnetic field can be achieved by means of magnetic nanoparticles with immobilized cholesterol-depleting agent such as O-methyl-β-cyclodextrin (MCD). A simple approach is developed for preparation of maghemite (γ-Fe 2 O 3 ) nanoparticles containing chemically bonded MCD. The method is based on preparation of a silanization agent containing MCD. It is synthesized by the reaction of triethoxy(3-isocyanatopropyl)silane with MCD. Base-catalyzed silanization of superparamagnetic γ-Fe 2 O 3 provides a relatively stable colloid product containing 48μmol of MCDg -1 . MCD-modified γ-Fe 2 O 3 nanoparticles decrease the initial rate of the uptake and accumulation of l-[ 14 C]glutamate and increase the extracellular l-[ 14 C]glutamate level in the preparation of nerve terminals. The effect of MCD-immobilized nanoparticles is the same as that of MCD solution; moreover, magnetic manipulation of the nanoparticles enables removal of bonded cholesterol. Copyright © 2016 Elsevier B.V. All rights reserved.

Enantioseparation of cetirizine by chromatographic methods and discrimination by 1H-NMR.

PubMed

Taha, Elham A; Salama, Nahla N; Wang, Shudong

2009-03-01

Cetirizine is an antihistaminic drug used to prevent and treat allergic conditions. It is currently marketed as a racemate. The H1-antagonist activity of cetirizine is primarily due to (R)-levocetirizine. This has led to the introduction of (R)-levocetirizine into clinical practice, and the chiral switching is expected to be more selective and safer. The present work represents three methods for the analysis and chiral discrimination of cetirizine. The first method was based on the enantioseparation of cetirizine on silica gel TLC plates using different chiral selectors as mobile phase additives. The mobile phase enabling successful resolution was acetonitrile-water 17: 3, (v/v) containing 1 mM of chiral selector, namely hydroxypropyl-beta-cyclodextrin, chondroitin sulphate or vancomycin hydrochloride. The second method was a validated high performance liquid chromatography (HPLC), based on stereoselective separation of cetirizine and quantitative determination of its eutomer (R)-levocetirizine on a monolithic C18 column using hydroxypropyl-beta-cyclodextrin as a chiral mobile phase additive. The resolved peaks of (R)-levocetirizine and (S)-dextrocetirizine were confirmed by further mass spectrometry. The third method used a (1)H-NMR technique to characterize cetirizine and (R)-levocetirizine. These methods are selective and accurate, and can be easily applied for chiral discrimination and determination of cetirizine in drug substance and drug product in quality control laboratory. Moreover, chiral purity testing of (R)-levocetirizine can also be monitored by the chromatographic methods. Copyright 2009 John Wiley & Sons, Ltd.

The effect of freeze-dried antibody concentrations on its stability in the presence of trehalose and hydroxypropyl-β-cyclodextrin: a Box-Behnken statistical design.

PubMed

Faghihi, Homa; Khalili, Fatemeh; Amini, Mohsen; Vatanara, Alireza

2017-09-01

The present study aimed at preparation and optimization of stable freeze-dried immunoglobulin G (IgG) applying proper amount of antibody with efficient combination of trehalose and hydroxypropyl-β-cyclodextrin (HPβCD). Response surface methodology was employed through a three-factor, three-level Box-Behnken design. Amounts of IgG (X 1 ), trehalose (X 2 ) and HPβCD (X 3 ) were independent variables. Aggregation following process (Y 1 ), after one month at 45 °C (Y 2 ), upon two month at 45 °C (Y 3 ) and beta-sheet content of IgG (Y 4 ) were determined as dependent variables. Results were fitted to quadratic models (except for beta-sheet content), describing the inherent relationship between main factors. Optimized formulation composed of 55.85 mg IgG, 52.51 mg trehalose and 16.01 mg HPβCD was prepared. The calculated responses of the optimized formulation were as follows: Y 1  = 0.19%, Y 2  = 0.78%, Y 3  = 1.88% and Y 4  = 68.60%, respectively. The thermal analysis confirmed the amorphous nature of optimum formulation and the integrity of IgG was shown to be favorably preserved. Validation of the optimization study demonstrated high degree of prognostic ability. The DOE study successfully predicted the optimum values of antibody as well as stabilizers for desirable process and storage stabilization of freeze-dried IgG.

Enantioselective separation of all-E-astaxanthin and its determination in microbial sources.

PubMed

Grewe, Claudia; Menge, Sieglinde; Griehl, Carola

2007-09-28

A method for the enantioselective separation of all-E-astaxanthin (3,3'-dihydroxy-beta,beta-carotene-4,4'-dione), an important colorant in the feed industry, was developed. Different chiral stationary phases (CSPs) such as Pirkle phases (R,R Ulmo and l-leucine), modified polysaccharides and a beta-cyclodextrin have been investigated on their separation performance of astaxanthin enantiomers. Direct resolution was only achieved employing the Chiralcel OD-RH (cellulose-tris-3,5-dimethylphenyl-carbamate) under reversed phase conditions. The chiral separation of the enantiomeric forms of astaxanthin produced in microalgae and yeasts was reported. The yeast Xanthophyllomyces sp. produces astaxanthin predominantly in the R,R configuration, whereas in the green microalgae Scenedesmus sp. astaxanthin is built primarily in the S,S form. The separation method for the identification of astaxanthin enantiomers is of great interest since astaxanthin is used as functional food additive in human nutrition. Moreover the method may be used as a food chain indicator in farmed salmon.

Simple and sensitive HPLC method with fluorescence detection for the measurement of ibuprofen in rat plasma: application to a long-lasting dosage form.

PubMed

Hassan, Ahmed Sheikh; Sapin, Anne; Ubrich, Nathalie; Maincent, Philippe; Bolzan, Claire; Leroy, Pierre

2008-10-01

A simple and sensitive high-performance liquid chromatography (HPLC) assay applied to the measurement of ibuprofen in rat plasma has been developed. Two parameters have been investigated to improve ibuprofen detectability using fluorescence detection: variation of mobile phase pH and the use of beta-cyclodextrin (beta-CD). Increasing the pH value from 2.5 to 6.5 and adding 5 mM beta-CD enhanced the fluorescence signal (lambda(exc) = 224 nm; lambda(em) = 290 nm) by 2.5 and 1.3-fold, respectively, when using standards. In the case of plasma samples, only pH variation significantly lowered detection and quantification limits, down to 10 and 35 ng/mL, respectively. Full selectivity was obtained with a single step for plasma treatment, that is, protein precipitation with acidified acetonitrile. The validated method was applied to a pharmacokinetic study of ibuprofen encapsulated in microspheres and subcutaneously administered to rats.

[Studies on chemical constituents from rhizome of Anemone flaccida].

PubMed

Zhang, Lan-tian; Takaishi, Yoshihisa; Zhang, Yan-wen; Duan, Hong-quan

2008-07-01

To study the chemical constituents from Anemone flaccida. Chemical constituents were isolated by repeated column chromatography (silica gel, Toyopearl HW-40C and preparative HPLC). The structures were elucidated on the basis of spectral data analysis. Twelve triterpenes were isolated and their structures were identified as follow: oleanolic acid (1), oleanolic acid 3-O-beta-D-glccopyranosyl-(1-->2)-beta-D-xylopyranoside (2), eleutheroside K (3), oleanolic acid 3-O-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-xylopyranoside (4), oleanolic acid 3-O-beta-D-glccopyranosyl-(1-->2)-alpha-L-arabinofurnoside (5), oleanolic acid 3-O-beta-D-glccuronopyranose (6), oleanolic acid 3-O-beta-D-glccuronopyranose methyl ester (7), oleanolic acid 28-O-alpha-L-rhamnopyranosyl(1-->4)-beta-D-glccopyranosyl (1-->6)-beta-D-glccopyranosyl (8), oleanolic acid 3-O-beta-D-glccuronopyranose 28-O-alpha-L-rhamnopyranosyl (1-->4)-beta-D-glccopyranosyl (1-->6)-beta-D-glccopyranoside (9), oleanolic acid 3-O-beta-D-glccopyranosyl methyl ester 28-O-alpha-L-rhamnopyranosyl (1-->4)-beta-D-glccopyranosyl (1-->6)-beta-D-glccopyranoside (10), oleanolic acid 3-O-beta-D-glccopyranosyl-(1-->2)-beta-D-xylopyranosyl-28-O-alpha-L-rhamnopyranosyl (1-->4)-beta-D-glccopyranosyl (1-->6)-beta-D-glccopyranoside (11), oleanolic acid 3-O-alpha-L-rh-amnopyranosyl-(1-->2)-alpha-L-arabinopyrnosyl-28-O-alpha-L-rhamnopyranosyl (1-->4)-beta-D-glccopyranosyl (1-->6)-beta-D-glccopyranoside (12). compounds 5-8, 10, 12 were isolated from this plant for the first time. Compounds 2, 5 and 11 showed positive anti-tumor activities.

The specificity of induction of alpha-galactosidase from Saccharomyces carlsbergensis.

PubMed

Flórez, I G; Lazo, P S; Ochoa, A G; Gascón, S

1981-04-17

A number of sugars and derivatives have been tested for their ability to induce the synthesis of alpha-galactosidase from Saccharomyces carlsbergensis. Besides galactose and the substrates of the enzyme melibiose, raffinose and stachyose, D-galacturonic acid, L-arabinose, D-tagatose, methyl-alpha-D-galactoside, lactose and isopropyl-beta-D-thiogalactoside were able to act as inducers. Of these, methyl-alpha-D-galactoside, lactose, isopropyl-beta-D-thiogalactoside and L-arabinose have been shown to be gratuitous inducers with which kinetic studies of induction have been carried out. Lactose was the most efficient inducer, giving a maximal differential rate of synthesis of the enzyme of 110 mU/10(7) cells at a concentration of 180 mM, followed by L-arabinose (60 mU/10(7) cells at 40 mM), isopropyl-beta-D-thiogalactoside (43 mU/10(7) cells at 60 mM) and methyl-alpha-D-galactoside (25 mU/10(7) cells at 150 mM). The concentration of inducer required to obtain half-maximal induction was similar for lactose, L-arabinose and isopropyl-beta-D-thiogalactoside and about 5-fold higher for methyl-alpha-D-galactoside. The property of the compounds to act as inducers was compared to their ability to interact with the enzyme and the results discussed in terms of the molecular structures which are recognized by the enzyme and by the induction machinery.

Cyclodextrin-based star polymers as a versatile platform for nanochemotherapeutics: Enhanced entrapment and uptake of idarubicin.

PubMed

Nafee, N; Hirosue, M; Loretz, B; Wenz, G; Lehr, C-M

2015-05-01

A series of cyclodextrin-based star polymers were synthesized using β-cyclodextrin (CD) as hydrophilic core, methyl methacrylate (MMA) and tert-butyl acrylate (tBA) as hydrophobic arms. Star polymers, either homopolymers or random/block copolymers, showed narrow molecular weight distributions. Grafting hydrophobic arms created CD-based nanoparticles (CD-NPs) in the size range (130-200nm) with narrow PdI <0.15 and slightly negative ζ-potential. Particle surface could be modified with chitosan to impart a positive surface charge. Colloidal stability of CD-NPs was a function of pH as revealed by the pH-titration curves. CD-NPs were used as carrier for the chemotherapeutic drug idarubicin (encapsulation efficiency, EE ∼40%) ensuring prolonged release profile (∼80% after 48h). For cell-based studies, coumarin-6 was encapsulated as a fluorescent marker (EE ∼75%). Uptake studies carried out on A549 and Caco-2 cell lines proved the uptake of coumarin-loaded NPs as a function of time and preferential localization in the cytoplasm. Uptake kinetics revealed no saturation or plateau over 6h. Chitosan-modified NPs showed significantly improved, concentration-dependent cellular uptake. Meanwhile, CD-NPs were non-cytotoxic on both cell lines over the concentration range (0.25-3mg/ml) as studied by MTT and LDH assays. In conclusion, CD star polymers can be considered a versatile platform for a new class of biocompatible nanochemotherapy. Copyright © 2015 Elsevier B.V. All rights reserved.

Resveratrol-cyclodextrin complex affects the expression of genes associated with lipid metabolism in bovine in vitro produced embryos.

PubMed

Torres, V; Hamdi, M; Millán de la Blanca, M G; Urrego, R; Echeverri, J; López-Herrera, A; Rizos, D; Gutiérrez-Adán, A; Sánchez-Calabuig, M J

2018-03-26

Antioxidants have been widely used during in vitro production to decrease the negative effect of reactive oxygen species. It was reported that the complex resveratrol-methyl β-cyclodextrin (RV-CD) improves resveratrol's stability and bioavailability and increases its antioxidant activity. This study evaluates the effect of RV-CD during in vitro oocyte maturation (IVM) or in vitro embryo culture (IVC) on developmental competence and quantitative changes in gene expression of developmental important genes. In experiment 1, RV-CD was added to IVM media and maturation level, embryo development and oocytes, cumulus cells, and blastocysts gene expression by RT-qPCR were examined. In experiment 2, presumptive zygotes were cultured in SOF supplemented with RV-CD and embryo development and blastocysts gene expression by RT-qPCR were studied. A group without RV-CD (control - ) and a group with cyclodextrin (control + ) were included. No differences were found in cleavage rate or blastocyst yield between groups. However, the expression of LIPE was higher in blastocysts derived from oocytes treated with resveratrol compared with control groups (p < .05). Blastocysts produced by IVC with resveratrol showed that RV-CD could modify the expression of genes related to lipid metabolism (CYP51A1, PNPLA2 and MTORC1) compared with control groups (p < .05). RV-CD in the IVM and IVC media could reduce accumulated fat by increasing lipolysis and suppressing lipogenesis of blastocysts. © 2018 Blackwell Verlag GmbH.

Mutational analysis of the myxovirescin biosynthetic gene cluster reveals novel insights into the functional elaboration of polyketide backbones.

PubMed

Simunovic, Vesna; Müller, Rolf

2007-07-23

It has been proposed that two acyl carrier proteins (ACPs)-TaB and TaE--and two 3-hydroxy-3-methylglutaryl synthases (HMGSs)--TaC and TaF--could constitute two functional ACP-HMGS pairs (TaB/TaC and TaE/TaF) responsible for the incorporation of acetate and propionate units into the myxovirescin A scaffold, leading to the formation of beta-methyl and beta-ethyl groups, respectively. It has been suggested that three more proteins--TaX and TaY, which are members of the superfamily of enoyl-CoA hydratases (ECHs), and a variant ketosynthase (KS) TaK--are shared between two ACP-HMGS pairs, to give the complete set of enzymes required to perform the beta-alkylations. The beta-methyl branch is presumably further hydroxylated (by TaH) and methylated to produce the methoxymethyl group observed in myxovirescin A. To substantiate this hypothesis, a series of gene-deletion mutants were created, and the effects of these mutations on myxovirescin production were examined. As predicted, DeltataB and DeltataE ACP mutants revealed similar phenotypes to their associated HMGS mutants DeltataC and DeltataF, respectively, thus providing direct evidence for the role of TaE/TaF in the formation of the beta-ethyl branch and implying a role for TaB/TaC in the formation of the beta-methyl group. Production of myxovirescin A was dramatically reduced in a DeltataK mutant and abolished in both the DeltataX and the DeltataY mutant backgrounds. Analysis of a DeltataH mutant confirmed the role of the cytochrome P450 TaH in hydroxylation of the beta-methyl group. Taken together, these experiments support a model in which the discrete ACPs TaB and TaE are compatible only with their associated HMGSs TaC and TaF, respectively, and function in a substrate-specific manner. Both TaB and TaC are essential for myxovirescin production, and the TaB/TaC pair can rescue antibiotic production in the absence of either TaE or TaF. Finally, the reduced level of myxovirescin production in the DeltataE mutant, relative to the DeltataF strain, suggests an additional function of the TaE ACP.

Metabolism of designer drugs of abuse: an updated review.

PubMed

Meyer, Markus R; Maurer, Hans H

2010-06-01

This paper reviews the metabolism of new designer drugs of abuse that have emerged on the black market during the last years and is an update of a review published in 2005. The presented review contains data concerning the so-called 2C compounds (phenethylamine type) such as 4-bromo-2,5-dimethoxy-beta-phenethylamine (2C-B), 4-iodo-2,5-dimethoxy-beta-phenethylamine (2C-I), 2,5-dimethoxy-4-methyl-beta-phenethylamine (2C-D), 4-ethyl-2,5-dimethoxy-beta-phenethylamine (2C-E), 4-ethylthio-2,5-dimethoxy-beta-phenethylamine (2C-T-2), and 2,5-dimethoxy-4-propylthio-beta-phenethylamine (2C-T-7), beta-keto designer drugs such as 2-methylamino-1-(3,4-methylenedioxyphenyl)butan-1-one (butylone, bk-MBDB), 2-ethylamino-1-(3,4-methylenedioxyphenyl)propan-1-one (ethylone, bk-MDEA), 2-methylamino-1-(3,4-methylene notdioxy notphenyl)propan-1-one (methylone, bk-MDMA), and 2-methylamino-1-p-tolylpropane-1-one (mephedrone, 4-methyl-methcathinone), pyrrolidino notphenones such as 4-methyl-pyrrolidinobutyrophenone (MPBP) and alpha-pyrrolidinovalerophenone (PVP), phencyclidine-derived drugs such as N (1 phenylcyclohexyl) propanamine (PCPr), N-(1-phenylcyclohexyl)-2-ethoxyethanamine (PCEEA), N-(1-phenylcyclohexyl)-3-methoxypropanamine (PCMPA), and N-(1-phenylcyclohexyl)-2-methoxyethanamine (PCMEA), tryptamines such as 5-methoxy-N,N-diisopropyl nottryptamine (5-MeO-DIPT), and finally alpha-methylfentanyl (alpha-MF) and 3-methylfentanyl (3-MF). Papers have been considered and reviewed on the identification of in vivo or in vitro human or animal metabolites and the cytochrome P450 or monoamineoxidase isoenzyme-dependent metabolism.

Biodiesel fuel production from waste cooking oil by the inclusion complex of heteropoly acid with bridged bis-cyclodextrin.

PubMed

Zou, Changjun; Zhao, Pinwen; Shi, Lihong; Huang, Shaobing; Luo, Pingya

2013-10-01

The inclusion complex of Cs2.5H0.5PW12O40 with bridged bis-cyclodextrin (CsPW/B) is prepared as a highly efficient catalyst for the direct production of biodiesel via the transesterification of waste cooking oil. CsPW/B is characterized by X-ray diffraction, and the biodiesel is analyzed by Gas Chromatography-Mass Spectrometer. The conversion rate of waste cooking oil is up to 94.2% under the optimum experimental conditions that are methanol/oil molar ratio of 9:1, catalyst dosage of 3 wt%, temperature of 65 °C and reaction time of 180 min. The physical properties of biodiesel sample satisfy the requirement of ASTM D6751 standards. The novel CsPW/B catalyst used for the transesterification can lead to 96.9% fatty acid methyl esters and 86.5% of the biodiesel product can serve as the ideal substitute for diesel fuel, indicating its excellent potential application in biodiesel production. Copyright © 2013 Elsevier Ltd. All rights reserved.

Encapsulation of small ionic molecules within alpha-cyclodextrins.

PubMed

Rodriguez, Javier; Elola, M Dolores

2009-02-05

Results from molecular dynamics experiments pertaining to the encapsulation of ClO4- within the hydrophobic cavity of an aqueous alpha-cyclodextrin (alpha-CD) are presented. Using a biased sampling procedure, we constructed the Gibbs free energy profile associated with the complexation process. The profile presents a global minimum at the vicinity of the primary hydroxyl groups, where the ion remains tightly coordinated to four water molecules via hydrogen bonds. Our estimate for the global free energy of encapsulation yields DeltaGenc approximately -2.5 kBT. The decomposition of the average forces acting on the trapped ion reveals that the encapsulation is controlled by Coulomb interactions between the ion and OH groups in the CD, with a much smaller contribution from the solvent molecules. Changes in the previous results, arising from the partial methylation of the host CD and modifications in the charge distribution of the guest molecule are also discussed. The global picture that emerges from our results suggests that the stability of the ClO4- encapsulation involves not only the individual ion but also its first solvation shell.

Depletion with Cyclodextrin Reveals Two Populations of Cholesterol in Model Lipid Membranes

PubMed Central

Litz, Jonathan P.; Thakkar, Niket; Portet, Thomas; Keller, Sarah L.

2016-01-01

Recent results provide evidence that cholesterol is highly accessible for removal from both cell and model membranes above a threshold concentration that varies with membrane composition. Here we measured the rate at which methyl-β-cyclodextrin depletes cholesterol from a supported lipid bilayer as a function of cholesterol mole fraction. We formed supported bilayers from two-component mixtures of cholesterol and a PC (phosphatidylcholine) lipid, and we directly visualized the rate of decrease in area of the bilayers with fluorescence microscopy. Our technique yields the accessibility of cholesterol over a wide range of concentrations (30–66 mol %) for many individual bilayers, enabling fast acquisition of replicate data. We found that the bilayers contain two populations of cholesterol, one with low surface accessibility and the other with high accessibility. A larger fraction of the total membrane cholesterol appears in the more accessible population when the acyl chains of the PC-lipid tails are more unsaturated. Our findings are most consistent with the predictions of the condensed-complex and cholesterol bilayer domain models of cholesterol-phospholipid interactions in lipid membranes. PMID:26840728

Formulation, characterization and evaluation of cyclodextrin-complexed bendamustine-encapsulated PLGA nanospheres for sustained delivery in cancer treatment.

PubMed

Gidwani, Bina; Vyas, Amber

2016-03-01

PLGA nanospheres are considered to be promising drug carrier in the treatment of cancer. Inclusion complex of bendamustine (BM) with epichlorohydrin beta cyclodextrin polymer was prepared by freeze-drying method. Phase solubility study revealed formation of AL type complex with stability constant (Ks = 645 M(-1)). This inclusion complex was encapsulated into PLGA nanospheres using solid-in-oil-in-water (S/O/W) technique. The particle size and zeta potential of PLGA nanospheres loaded with cyclodextrin-complexed BM were about 151.4 ± 2.53 nm and - 31.9 ± (-3.08) mV. In-vitro release study represented biphasic release pattern with 20% burst effect and sustained slow release. DSC studies indicated that inclusion complex incorporated in PLGA nanospheres was not in a crystalline state but existed in an amorphous or molecular state. The cytotoxicity experiment was studied in Z-138 cells and IC50 value was found to be 4.3 ± 0.11 µM. Cell viability studies revealed that the PLGA nanospheres loaded with complex exerts a more pronounced effect on the cancer cells as compared to the free drug. In conclusion, PLGA nanospheres loaded with inclusion complex of BM led to sustained drug delivery. The nanospheres were stable after 3 months of storage conditions with slight change in their particle size, zeta potential and entrapment efficiency.

Phytochemical Study of the Ecuadorian Species Lepechinia mutica (Benth.) Epling and High Antifungal Activity of Carnosol against Pyricularia oryzae.

PubMed

Ramírez, Jorge; Gilardoni, Gianluca; Ramón, Erika; Tosi, Solveig; Picco, Anna Maria; Bicchi, Carlo; Vidari, Giovanni

2018-04-19

The plant Lepechinia mutica (Benth.) Epling (family Lamiaceae) is endemic to Ecuador. In the present study, we report some major non-volatile secondary metabolites from the leaves and the chemistry of the essential oil distilled from the flowers. The main identified compounds were carnosol, viridiflorol, ursolic acid, oleanolic acid, chrysothol, and 5-hydroxy-4′,7-dimethoxy flavone. Their structures were determined by X-ray diffraction and NMR and MS techniques. The essential oil showed a chemical composition similar to that distilled from the leaves, but with some qualitative and quantitative differences regarding several minor compounds. The main constituents (>4%) were: δ-3-carene (24.23%), eudesm-7(11)-en-4-ol (13.02%), thujopsan-2-α-ol (11.90%), β-pinene (7.96%), valerianol (5.19%), and co-eluting limonene and β-phellandrene (4.47%). The volatile fraction was also submitted to enantioselective analysis on a β-cyclodextrin column, obtaining the separation and identification of the enantiomers for α-thujene, β-pinene, sabinene, α-phellandrene, limonene and β-phellandrene. Furthermore, the anti-fungal activity of non-volatile secondary metabolites was tested in vitro, with carnosol resulting in being very active against the “blast disease” caused by the fungus Pyricularia oryzae .

Suppression of glutamate-induced excitotoxicity by 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride in rat glial cultures.

PubMed

Kim, Eun-A; Hahn, Hoh-Gyu; Kim, Key-Sun; Kim, Tae Ue; Choi, Soo Young; Cho, Sung-Woo

2010-07-01

We have screened new drugs with a view to developing effective drugs against glutamate-induced excitotoxicity. In the present work, we show effects of a new drug, 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride against glutamate-induced excitotoxicity in primary rat glial cultures. Pretreatment of glial cells with 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride for 2 h significantly protected glial cells against glutamate-induced excitotoxicity in a time- and dose-dependent manner with an optimum concentration of 100 microM. The drug significantly reduced production of proinflammatory cytokines, tumor necrosis factor-alpha, and interlukin-1beta in glutamate-induced excitotoxicity. The drug also prevented glutamate-induced intracellular Ca2+ influx and reduced the subsequent overproduction of nitric oxide and reactive oxygen species. Furthermore, the drug preserved the mitochondrial potential and inhibited the overproduction of cytochrome c. In addition, the drug effectively attenuated the protein level changes of beta-catenin and glycogen synthase kinase-3beta. These results suggest that 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride effectively protected primary cultures of rat glial cells against glutamate-induced excitotoxicity.

New pregnane and steroidal glycosides from Tribulus terrestris L.

PubMed

Liu, Tao; Chen, Gang; Yi, Guo-Qing; Xu, Jian-Kun; Zhang, Tian-Long; Hua, Hui-Ming; Pei, Yue-Hu

2010-03-01

Three new steroidal saponins were isolated from the fruits of Tribulus terrestris L. Their structures were elucidated by spectroscopic and chemical analysis as 16beta-(4'-methyl-5'-O-beta-D-glucopyranosyl-pentanoxy)-5alpha-pregn-3beta-ol-12,20-dione-3-O-beta-D-glucopyranosyl-(1 --> 2)-beta-D-glucopyranosyl-(1 --> 4)-beta-D-galactopyranoside (1), 2alpha,3beta-dihydroxy-5alpha-pregn-16-en-20-one 3-O-beta-D-glucopyranosyl-(1 --> 4)-beta-D-galactopyranoside (2) and 26-O-beta-D-glucopyranosyl-(25R)-5alpha-furostan-20(22)-en-2alpha,3beta,26-triol-3-O-beta-D-glucopyranosyl-(1 --> 4)-beta-D-galactopyranoside (3).

Engineering ..beta..-Oxidation in Yarrowia lipolytica for Methyl Ketone Production

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sanchez i Nogue, Violeta; Ramirez, Kelsey J; Singer, Christine

Medium- and long-chain methyl ketones are fatty acid-derived compounds that can be used as biofuel blending agents, flavors and fragrances. However, their large-scale production from sustainable feedstocks is currently limited due to the lack of robust microbial biocatalysts. The oleaginous yeast Yarrowia lipolytica is a promising biorefinery platform strain for the production of methyl ketones from renewable lignocellulosic biomass due to its natively high flux towards fatty acid biosynthesis. In this study, we report the metabolic engineering of Y. lipolytica to produce long- and very long-chain methyl ketones. Truncation of peroxisomal ..beta..-oxidation by chromosomal deletion of pot1 resulted in themore » biosynthesis of saturated, mono-, and diunsaturated methyl ketones in the C13-C23 range. Additional overexpression and peroxisomal targeting of a heterologous bacterial methyl ketone biosynthesis pathway yielded an initial titer of 151.5 mg/L of saturated methyl ketones. Dissolved oxygen concentrations in the cultures were found to substantially impact cell morphology and methyl ketone biosynthesis. Bioreactor cultivation under optimized conditions resulted in a titer of 314.8 mg/L of total methyl ketones, representing more than a 6000-fold increase over the parental strain. This work highlights the potential of Y. lipolytica to serve as chassis organism for the biosynthesis of acyl-thioester derived long- and very long-chain methyl ketones.« less

Metallothionein-3 modulates the amyloid β endocytosis of astrocytes through its effects on actin polymerization.

PubMed

Lee, Sook-Jeong; Seo, Bo-Ra; Koh, Jae-Young

2015-12-04

Astrocytes may play important roles in the pathogenesis of Alzheimer's disease (AD) by clearing extracellular amyloid beta (Aβ) through endocytosis and degradation. We recently showed that metallothionein 3 (Mt3), a zinc-binding metallothionein that is enriched in the central nervous system, contributes to actin polymerization in astrocytes. Because actin is likely involved in the endocytosis of Aβ, we investigated the possible role of Mt3 in Aβ endocytosis by cortical astrocytes in this study. To assess the route of Aβ uptake, we exposed cultured astrocytes to fluorescently labeled Aβ1-40 or Aβ1-42 together with chloropromazine (CP) or methyl-beta-cyclodextrin (MβCD), inhibitors of clathrin- and caveolin-dependent endocytosis, respectively. CP treatment almost completely blocked Aβ1-40 and Aβ1-42 endocytosis, whereas exposure to MβCD had no significant effect. Actin disruption with cytochalasin D (CytD) or latrunculin B also completely blocked Aβ1-40 and Aβ1-42 endocytosis. Because the absence of Mt3 also results in actin disruption, we examined Aβ1-40 and Aβ1-42 uptake and expression in Mt3 (-/-) astrocytes. Compared with wild-type (WT) cells, Mt3 (-/-) cells exhibited markedly reduced Aβ1-40 and Aβ1-42 endocytosis and expression of Aβ1-42 monomers and oligomers. A similar reduction was observed in CytD-treated WT cells. Finally, actin disruption and Mt3 knockout each increased the overall levels of clathrin and the associated protein phosphatidylinositol-binding clathrin assembly protein (PICALM) in astrocytes. Our results suggest that the absence of Mt3 reduces Aβ uptake in astrocytes through an abnormality in actin polymerization. In light of evidence that Mt3 is downregulated in AD, our findings indicate that this mechanism may contribute to the extracellular accumulation of Aβ in this disease.

The use of supersaturation for the vaginal application of microbicides: a case study with dapivirine.

PubMed

Grammen, Carolien; Plum, Jakob; Van Den Brande, Jeroen; Darville, Nicolas; Augustyns, Koen; Augustijns, Patrick; Brouwers, Joachim

2014-11-01

In this study, we investigated the potential of supersaturation for the formulation of the poorly water-soluble microbicide dapivirine (DPV) in an aqueous vaginal gel in order to enhance its vaginal tissue uptake. Different excipients such as hydroxypropylmethylcellulose, polyethylene glycol 1000, and cyclodextrins were evaluated for their ability to inhibit precipitation of supersaturated DPV in the formulation vehicle as such as well as in biorelevant media. In vitro permeation assessment across HEC-1A cell layers demonstrated an enhanced DPV flux from supersaturated gels compared with suspension gels. The best performing supersaturated gel containing 500 μM DPV (supersaturation degree of 4) in the presence of sulfobutyl ether-beta-cyclodextrin (2.5%) appeared to be stable for at least 3 months. In addition, the gel generated a significant increase in vaginal drug uptake in rabbits as compared with suspension gels. We conclude that supersaturation is a possible strategy to enhance the vaginal concentration of hydrophobic microbicides, thereby increasing permeation into the vaginal submucosa. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Iridoid glycosides from Gardeniae Fructus for treatment of ankle sprain.

PubMed

Chen, Quan Cheng; Zhang, Wei Yun; Youn, Uijoung; Kim, Hongjin; Lee, IkSoo; Jung, Hyun-Ju; Na, MinKyun; Min, Byung-Sun; Bae, KiHwan

2009-04-01

The iridoid glycosides, genipin 1-O-beta-D-isomaltoside (1) and genipin 1,10-di-O-beta-D-glucopyranoside (2), together with six known iridoid glycosides, genipin 1-O-beta-D-gentiobioside (3), geniposide (4), scandoside methyl ester (5), deacetylasperulosidic acid methyl ester (6), 6-O-methyldeacetylasperulosidic acid methyl ester (7), and gardenoside (8) were isolated from an EtOH extract of Gardeniae Fructus. The structures and relative stereochemistries of the metabolites were elucidated on the basis of 1D- and 2D-NMR spectroscopic techniques, high-resolution mass spectrometry, and chemical evidence. Geniposide (4), one of the main compounds of Gardeniae Fructus, was tested for treatment of ankle sprain using an ankle sprain model in rats. From the second to fifth day, the geniposide (4) (100mg/ml) treated group exhibited significant differences (p<0.01) with approximately 21-34% reduction in swelling ratio compared with those of the vehicle treated control group. This indicated the potential effect of geniposide (4) for the treatment of disorders such as ankle sprain.

Sesquiterpenoids from roots of Taraxacum laevigatum and Taraxacum disseminatum.

PubMed

Zielińiska, K; Kisiel, W

2000-08-01

Chromatographic separation of ethanolic root extracts of Taraxacum laevigatum and Taraxacum disseminatum afforded a total of eight germacrane- and eudesmane-type sesquiterpenoids. including new compounds, 1beta,3beta,6alpha-trihydroxy-4alpha( 15)-dihydrocostic acid methyl ester and its 1-O-beta-glucopyranoside. Their structures were established by spectroscopic analyses. In addition, the structure of 4alpha(15), 11beta(13)-tetrahydroridentin B-1-O-beta-glucopyranoside was elucidated by extensive NMR studies.

Membrane electrodes for the determination of pyridostigmine bromide.

PubMed

El-Kosasy, Amira M; Salem, Maissa Y; El-Bardicy, Mohamed G; Abd El-Rahman, Mohamed K

2009-01-01

Two pyridostigmine bromide (PB) selective electrodes were investigated with 2-nitrophenyl octyl ether as a plasticizer in a polymeric matrix of carboxylated polyvinyl chloride (PVC-COOH), based on the interaction between the drug solution and the dissociated COOH groups in the PVC-COOH. One of the sensors was fabricated by using PVC-COOH only as anionic site without incorporation of an ionophore (sensor 1). The second sensor was constructed by using 2-hydroxy propyl beta-cyclodextrin as an ionophore (sensor 2). Linear responses of PB within a concentration range of 10(-3)-10(-2) and 10(-5)-10(-2) M, with slopes of 51.9 +/- 0.31 and 56.7 +/- 0.40 mV/decade over pH range of 5-10 were obtained using sensors 2 and 1, respectively. The proposed method displayed useful analytical characteristics for determination of PB in tablets with average recoveries of 100.22 +/- 0.62, and 100.15 +/- 0.72, and in plasma with average recoveries of 99.14 +/- 1.19 and 99.79 +/- 0.72, for sensors 2 and 1, respectively. The utility of 2-hydroxy propyl beta-cyclodextrin as an ionophore has a significant influence on increasing both membrane sensitivity and selectivity of sensor 2 in comparison with sensor 1. The methods were also used to determine the intact drug in the presence of its degradate, and thus could be used as stability-indicating methods. The results obtained by the proposed procedures were statistically analyzed and compared with those obtained by the U.S. Pharmacopeia method. No significant difference for either accuracy or precision was observed.

DNA methylation of retrotransposons, DNA transposons and genes in sugar beet (Beta vulgaris L.).

PubMed

Zakrzewski, Falk; Schmidt, Martin; Van Lijsebettens, Mieke; Schmidt, Thomas

2017-06-01

The methylation of cytosines shapes the epigenetic landscape of plant genomes, coordinates transgenerational epigenetic inheritance, represses the activity of transposable elements (TEs), affects gene expression and, hence, can influence the phenotype. Sugar beet (Beta vulgaris ssp. vulgaris), an important crop that accounts for 30% of worldwide sugar needs, has a relatively small genome size (758 Mbp) consisting of approximately 485 Mbp repetitive DNA (64%), in particular satellite DNA, retrotransposons and DNA transposons. Genome-wide cytosine methylation in the sugar beet genome was studied in leaves and leaf-derived callus with a focus on repetitive sequences, including retrotransposons and DNA transposons, the major groups of repetitive DNA sequences, and compared with gene methylation. Genes showed a specific methylation pattern for CG, CHG (H = A, C, and T) and CHH sites, whereas the TE pattern differed, depending on the TE class (class 1, retrotransposons and class 2, DNA transposons). Along genes and TEs, CG and CHG methylation was higher than that of adjacent genomic regions. In contrast to the relatively low CHH methylation in retrotransposons and genes, the level of CHH methylation in DNA transposons was strongly increased, pointing to a functional role of asymmetric methylation in DNA transposon silencing. Comparison of genome-wide DNA methylation between sugar beet leaves and callus revealed a differential methylation upon tissue culture. Potential epialleles were hypomethylated (lower methylation) at CG and CHG sites in retrotransposons and genes and hypermethylated (higher methylation) at CHH sites in DNA transposons of callus when compared with leaves. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

Implications of lipid raft disintegration: enhanced anti-inflammatory macrophage phenotype.

PubMed

Cuschieri, Joseph

2004-08-01

Lipid rafts are membrane microdomains characterized by an enriched cholesterol environment and appear to serve as a platform for signaling. Their role within the macrophage during endotoxin exposure is unknown. THP-1 cells were subjected to lipopolysaccharide stimulation with or without methyl-beta-cyclodextrin (MbetaCD) pretreatment, a cholesterol depleting agent. Cell surface expression of toll-like receptor-4 (TLR4) and platelet-activating factor receptor (PAFr) was determined by flow cytometry. Membrane receptor components and activation of the mitogen-activated protein kinases (MAPK) was determined from lipid raft and cellular protein by immunoblot. Inflammatory mediator production was determined from harvested supernatants by enzyme-linked immunosorbent assay. Surface expression of TLR4 and PAFr was not affected by MbetaCD. Lipopolysaccharide stimulation led to TLR4 mobilization to lipid rafts, MAPK activation, and inflammatory mediator production. Pretreatment with MbetaCD did not affect TLR4 mobilization to lipid rafts, but did result in lost lipid raft expression of the PAFr coupled G-protein, Galpha1. MbetaCD treatment led to selective attenuation of MAPK activation through ERK 1/2. This dysregulated signaling was associated with attenuated production of tumor necrosis factor-alpha, but increased production of interleukin-10. Lipid raft disintegration results in lost expression of Galpha1, dysregulated MAPK signaling, and selective anti-inflammatory mediator production. Therefore, modulation of lipid raft cholesterol content may represent a potential mechanism for regulation of macrophage phenotypic differentiation. Copyright 2004 Elsevier Inc.

Attenuation of Leishmania infantum chagasi Metacyclic Promastigotes by Sterol Depletion

PubMed Central

Gaur Dixit, Upasna; Barker, Jason H.; Teesch, Lynn M.; Love-Homan, Laurie; Donelson, John E.; Wilson, Mary E.

2013-01-01

The infectious metacyclic promastigotes of Leishmania protozoa establish infection in a mammalian host after they are deposited into the dermis by a sand fly vector. Several Leishmania virulence factors promote infection, including the glycosylphosphatidylinositol membrane-anchored major surface protease (MSP). Metacyclic Leishmania infantum chagasi promastigotes were treated with methyl-beta-cyclodextrin (MβCD), a sterol-chelating reagent, causing a 3-fold reduction in total cellular sterols as well as enhancing MSP release without affecting parasite viability in vitro. MβCD-treated promastigotes were more susceptible to complement-mediated lysis than untreated controls and reduced the parasite load 3-fold when inoculated into BALB/c mice. Paradoxically, MβCD-treated promastigotes caused a higher initial in vitro infection rate in human or murine macrophages than untreated controls, although their intracellular multiplication was hindered upon infection establishment. There was a corresponding larger amount of covalently bound C3b than iC3b on the parasite surfaces of MβCD-treated promastigotes exposed to healthy human serum in vitro, as well as loss of MSP, a protease that enhances C3b cleavage to iC3b. Mass spectrometry showed that MβCD promotes the release of proteins into the extracellular medium, including both MSP and MSP-like protein (MLP), from virulent metacyclic promastigotes. These data support the hypothesis that plasma membrane sterols are important for the virulence of Leishmania protozoa at least in part through retention of membrane virulence proteins. PMID:23630964

A role for exosomes in the constitutive and stimulus-induced ectodomain cleavage of L1 and CD44.

PubMed

Stoeck, Alexander; Keller, Sascha; Riedle, Svenja; Sanderson, Michael P; Runz, Steffen; Le Naour, Francois; Gutwein, Paul; Ludwig, Andreas; Rubinstein, Eric; Altevogt, Peter

2006-02-01

Ectodomain shedding is a proteolytic mechanism by which transmembrane molecules are converted into a soluble form. Cleavage is mediated by metalloproteases and proceeds in a constitutive or inducible fashion. Although believed to be a cell-surface event, there is increasing evidence that cleavage can take place in intracellular compartments. However, it is unknown how cleaved soluble molecules get access to the extracellular space. By analysing L1 (CD171) and CD44 in ovarian carcinoma cells, we show in the present paper that the cleavage induced by ionomycin, APMA (4-aminophenylmercuric acetate) or MCD (methyl-beta-cyclodextrin) is initiated in an endosomal compartment that is subsequently released in the form of exosomes. Calcium influx augmented the release of exosomes containing functionally active forms of ADAM10 (a disintegrin and metalloprotease 10) and ADAM17 [TACE (tumour necrosis factor a-converting enzyme)] as well as CD44 and L1 cytoplasmic cleavage fragments. Cleavage could also proceed in released exosomes, but only depletion of ADAM10 by small interfering RNA blocked cleavage under constitutive and induced conditions. In contrast, cleavage of L1 in response to PMA occurred at the cell surface and was mediated by ADAM17. We conclude that different ADAMs are involved in distinct cellular compartments and that ADAM10 is responsible for shedding in vesicles. Our findings open up the possibility that exosomes serve as a platform for ectodomain shedding and as a vehicle for the cellular export of soluble molecules.

Complexation of tocotrienol with gamma-cyclodextrin enhances intestinal absorption of tocotrienol in rats.

PubMed

Ikeda, Saiko; Uchida, Tomono; Ichikawa, Tomio; Watanabe, Takashi; Uekaji, Yukiko; Nakata, Daisuke; Terao, Keiji; Yano, Tomohiro

2010-01-01

To determine the bioavailability of tocotrienol complex with gamma-cyclodextrin, the effects of tocotrienol/gamma-cyclodextrin complex on tocotrienol concentration in rat plasma and tissues were studied. Rats were administered by oral gavage an emulsion containing tocotrienol, tocotrienol with gamma-cyclodextrin, or tocotrienol/gamma-cyclodextrin complex. At 3 h after administration, the plasma gamma-tocotrienol concentration of the rats administered tocotrienol/gamma-cyclodextrin complex was higher than that of the rats administered tocotrienol and gamma-cyclodextrin. In order to determine the effect of complexation on tocotrienol absorption, rats were injected with Triton WR1339, which prevents the catabolism of triacylglycerol-rich lipoprotein by lipoprotein lipase, and then administered by oral gavage an emulsion containing tocotrienol, tocotrienol with gamma-cyclodextrin, or tocotrienol/gamma-cyclodextrin complex. The plasma gamma-tocotrienol concentration of the Triton-treated rats administered tocotrienol/gamma-cyclodextrin complex was higher than that of the other Triton-treated rats. These results suggest that complexation of tocotrienol with gamma-cyclodextrin elevates plasma and tissue tocotrienol concentrations by enhancing intestinal absorption.

The conformation of the monomethyl ethers of methyl beta-lactoside in D2O and Me2SO-d6 solutions.

PubMed

Fernández, P; Jiménez-Barbero, J

1993-10-04

The solution conformations of all the possible monomethyl ethers of methyl beta-lactoside have been analysed using molecular mechanics and dynamics calculations and nuclear magnetic resonance data (variable temperature and NOE experiments). The overall shape of all the compounds studied is fairly similar and may be described by conformers included in a low-energy region with phi = -100 +/- 40 degrees and psi = -135 +/- 35 degrees, which is ca. 5% of the total potential energy surface for the glycosidic linkages of the disaccharides.

Hybridation of different chiral separation techniques with ICP-MS detection for the separation and determination of selenomethionine enantiomers: chiral speciation of selenized yeast.

PubMed

Méndez, S P; González, E B; Sanz-Medel, A

2001-05-01

Enantioseparation and determination of selenomethionine enantiomers in selenized yeast was investigated using chiral separation techniques based on different principles, coupled on-line to inductively coupled plasma mass spectrometry (ICP-MS) for selenium-specific detection. High performance liquid chromatography (HPLC) on a beta-cyclodestrin (beta-CD) column, cyclodextrin-modified micellar electrokinetic chromatography (CD-MEKC), gas chromatography (GC) on a Chirasil-L-Val column, and HPLC on a Chirobiotic T column have been investigated as the chiral separation techniques. For HPLC separation on the beta-CD column, and also for CD-MEKC, selenomethionine enantiomers were derivatized with NDA/CN(-). For chiral separation by GC, selenomethionine enantiomers were converted into their N-trifluoroacetyl (TFA)-O-alkyl esters. The developed hybridation methodologies are compared with respect to enantioselectivity, sensitivity and analysis time. The usefulness of the best-suited method [HPLC (Chirobiotic T)-ICP-MS] was demonstrated by its application to the successful chiral speciation of selenium and D-and L-selenomethionine content determination in selenized yeast. Copyright 2001 John Wiley & Sons, Ltd.

Amphiphilic Cyclodextrin Derivatives for Targeted Drug Delivery to Tumors.

PubMed

Erdogar, Nazlı; Varan, Gamze; Bilensoy, Erem

2017-01-01

Villiers has extensively studied cyclodextrins, a family of macrocyclic oligosaccharides linked by α-1,4 glycosidic bonds, in different fields since their discovery in 1891. The unique structure enabling inclusion complexation for natural cyclodextrins and cyclodextrin derivatives make them attractive for novel drug delivery systems. Cyclodextrins can be modified with long aliphatic chains to render an amphiphilic property and these different amphiphilic cyclodextrins are able to form nanoparticles without surfactants. In the literature, several different amphiphilic cyclodextrins are reported and applied to drug delivery and targeting especially to tumors. Specificly, folateconjugated amphiphilic cyclodextrin derivatives are used for active tumor targeting of poorly water soluble drugs and improve the efficacy and safety of therapeutic agents. On the other hand, effect of positive surface charge has also been under research in the recent years. Polycationic amphiphilic cyclodextrins have shown promise towards forming small complexes with negatively charged molecules such as drugs or plasmid DNA. Polycationic amphiphilic cyclodextrins enhance interaction with cell membrane due to their net positive surface charge. The scope of this review is to describe potential uses and pharmaceutical applications of tumor-targeted amphiphilic cyclodextrins, with focus on folate-conjugated cyclodextrin derivatives and polycationic cyclodextrin derivatives both studied by our group at Hacettepe University. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Microwave generated solid dispersions containing Ibuprofen.

PubMed

Moneghini, Mariarosa; Bellich, Barbara; Baxa, Pietro; Princivalle, Francesco

2008-09-01

The purpose of this study was to apply the attractive technique of the microwaves irradiation (MW) for the preparation of solvent-free solid dispersions (SD). In particular, the microwave technology has been considered in order to prepare an enhanced release dosage form for the poorly soluble drug Ibuprofen (IBU), employing PVP/VA 60/40 (PVP/VA 64) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) as hydrophilic carriers. Their physico-chemical characteristics and dissolution properties were compared to the corresponding physical mixtures and the drug alone. The results of physico-chemical characterization attested a correspondence of the solid state of the drug before and after irradiation treatment and that an amorphous form of the drug was obtained. This result, together with the presence of the hydrophilic polymers determined a remarkable enhancement of the in vitro dissolution rate of the drug suggesting that the microwave technique could be considered as a new and interesting method to prepare drug-polymer systems.

P110β Inhibition Reduces Histone H3K4 Di-Methylation in Prostate Cancer.

PubMed

Pang, Jun; Yang, Yue-Wu; Huang, Yiling; Yang, Jun; Zhang, Hao; Chen, Ruibao; Dong, Liang; Huang, Yan; Wang, Dongying; Liu, Jihong; Li, Benyi

2017-02-01

Epigenetic alteration plays a major role in the development and progression of human cancers, including prostate cancer. Histones are the key factors in modulating gene accessibility to transcription factors and post-translational modification of the histone N-terminal tail including methylation is associated with either transcriptional activation (H3K4me2) or repression (H3K9me3). Furthermore, phosphoinositide 3-kinase (PI3 K) signaling and the androgen receptor (AR) are the key determinants in prostate cancer development and progression. We recently showed that prostate-targeted nano-micelles loaded with PI3 K/p110beta specific inhibitor TGX221 blocked prostate cancer growth in vitro and in vivo. Our objective of this study was to determine the role of PI3 K signaling in histone methylation in prostate cancer, with emphasis on histone H3K4 methylation. PI3 K non-specific inhibitor LY294002 and p110beta-specific inhibitor TGX221 were used to block PI3 K/p110beta signaling. The global levels of H3K4 and H3K9 methylation in prostate cancer cells and tissue specimens were evaluated by Western blot assay and immunohistochemical staining. A synthetic androgen R1881 was used to stimulate AR activity in prostate cancer cells. A castration-resistant prostate cancer (CRPC) specific human tissue microarray (TMA) was used to assess the global levels of H3K4me2 methylation by immunostaining approach. Our data revealed that H3K4me2 levels were significantly elevated after androgen stimulation. With RNA silencing and pharmacology approaches, we further defined that inhibition of PI3 K/p110beta activity through gene-specific knocking down and small chemical inhibitor TGX221 abolished androgen-stimulated H3K4me2 methylation. Consistently, prostate cancer-targeted delivery of TGX221 in vivo dramatically reduced the global levels of H3K4me2 as assessed by immunohistochemical staining on tissue section of mouse xenografts from CRPC cell lines 22RV1 and C4-2. Finally, immunostaining data revealed a strong H3K4me2 immunosignal in CRPC tissues compared to primary tumors and benign prostate tissues. Taken together, our results suggest that PI3 K/p110beta-dependent signaling is involved in androgen-stimulated H3K4me2 methylation in prostate cancer, which might be used as a novel biomarker for disease prognosis and targeted therapy. Prostate 77:299-308, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Promoter methylation of E-cadherin, p16, and RAR-beta(2) genes in breast tumors and dietary intake of nutrients important in one-carbon metabolism

USDA-ARS?s Scientific Manuscript database

Aberrant DNA methylation plays a critical role in carcinogenesis, and the availability of dietary factors involved in 1-carbon metabolism may contribute to aberrant DNA methylation. We investigated the association of intake of folate, vitamins B(2), B(6), B(12), and methionine with promoter methylat...

Influence of cyclodextrin complexation on the in vivo photoprotective effects of oxybenzone.

PubMed

Felton, Linda A; Wiley, Cody J; Godwin, Donald A

2004-01-01

The objective of the current study was to investigate the influence of cyclodextrin complexation on the in vivo photoprotective effects of a model ultraviolet (UV) absorber, oxybenzone, and to compare these novel sunscreens to a commercial SPF 30 sunscreen product. Aqueous-based solutions and suspensions containing 2.7 mg/mL oxybenzone and up to 20% (w/w) hydroxypropyl-beta-cyclodextrin (HPCD) were prepared. The sunscreens were applied to the dorsal skin of SKH-1 hairless mice and the animals were exposed to up to two minimal erythemal doses (MEDs) of UV radiation. Control animals received no sunscreen treatment. Lipid damage, as quantified by decreases in the lipid melting temperature of the epidermis, was determined using differential scanning calorimetry immediately after UV exposure. The number of sunburn cells (SBCs) and the extent of edema were measured 24 hours postexposure. Results showed that all oxybenzone-containing formulations decreased the number of SBCs formed, diminished swelling, and reduced the physical damage to the skin structure, in comparison to control. Thus, complexation did not prevent oxybenzone from reacting with light. The 20% HPCD formulation exhibited more substantial photoprotection at UV exposures of one or two MEDs, as evidenced by the formation of fewer SBCs. The 5% HPCD formulation also provided substantial protection against epidermal lipid damage. These studies demonstrate that inclusion of HPCD in sunscreen formulations may enhance the in vivo photoprotective effects of the UV absorbers. No single HPCD-containing sunscreen, however, was found to be equivalent to a commercially available sunscreen product for all biomarkers investigated.

Enantioselective analysis of ibuprofen in human plasma by anionic cyclodextrin-modified electrokinetic chromatography.

PubMed

Jabor, Valquíria A P; Lanchote, Vera L; Bonato, Pierina S

2002-09-01

This paper reports the development of a rapid method for the enantioselective analysis of the nonsteroidal anti-inflammatory drug ibuprofen in human plasma by capillary electrophoresis employing the anionic cyclodextrin-modified electrokinetic chromatography mode. Sample cleanup was carried out by acidification with HCl followed by liquid-liquid extraction with hexane:isopropanol (99:1 v/v). The complete enantioselective analysis was performed within 10 min, using 100 mmol L(-1) phosphoric acid/triethanolamine buffer, pH 2.6, containing 2.0% w/v sulfated beta-cyclodextrin as chiral selector; fenoprofen, another nonsteroidal anti-inflammatory drug, was used as internal standard. The calibration curves were linear over the concentration range of 0.25-125.0 microg mL(-1) for each enantiomer of ibuprofen. The mean recoveries for ibuprofen enantiomers were up to 85%. The enantiomers studied could be quantified at three different concentrations (0.5, 5.0 and 50.0 microg mL(-1)) with a coefficient of variation and relative error not higher than 15%. The quantitation limit was 0.2 microg mL(-1) for (+)-(S)- and (-)-(R)-ibuprofen using 1 mL of human plasma. The plasma endogenous compounds and other drugs did not interfere with the present assay. The analysis of real plasma samples obtained from a healthy volunteer after administration of 600 mg of racemic ibuprofen showed a maximum plasma level of 29.6 and 39.9 microg mL(-1) of (-)-(R)- and (+)-(S)-ibuprofen, respectively, and the area under plasma concentration-time curve AUC(0-infinity) (+)-(S)/AUC(0-infinity) (-)-(R) ratio was 1.87.

Suitability of macrophage inflammatory protein-1beta production by THP-1 cells in differentiating skin sensitizers from irritant chemicals.

PubMed

Lim, Yeon-Mi; Moon, Seong-Joon; An, Su-Sun; Lee, Soo-Jin; Kim, Seo-Young; Chang, Ih-Seop; Park, Kui-Lea; Kim, Hyoung-Ah; Heo, Yong

2008-04-01

Worldwide restrictions in animal use for research have driven efforts to develop alternative methods. The study aimed to test the efficacy of the macrophage inflammatory protein-1beta (MIP-1beta) assay for testing chemicals' skin-sensitizing capacity. The assay was performed using 9 chemicals judged to be sensitizing and 7 non-sensitizing by the standard in vivo assays. THP-1 cells were cultured in the presence or absence of 4 doses, 0.01x, 0.1x, 0.5x, or 1x IC(50) (50% inhibitory concentration for THP-1 cell proliferation) of these chemicals for 24 hr, and the MIP-1beta level in the supernatants was determined. Skin sensitization by the test chemicals was determined by MIP-1beta production rates. The MIP-1beta production rate was expressed as the relative increase in MIP-1beta production in response to chemical treatment compared with vehicle treatment. When the threshold MIP-1beta production rate used was 100% or 105% of dimethyl sulfoxide, all the sensitizing chemicals tested (dinitrochlorobenzene, hexyl cinnamic aldehyde, eugenol, hydroquinone, dinitrofluorobenzene, benzocaine, nickel, chromium, and 5-chloro-2-methyl-4-isothiazolin-3-one) were positive, and all the non-sensitizing chemicals (methyl salicylate, benzalkonium chloride, lactic acid, isopropanol, and salicylic acid), with the exception of sodium lauryl sulfate, were negative for MIP-1beta production. These results indicate that MIP-1beta could be a biomarker for classification of chemicals as sensitizers or non-sensitizers.

Selectivity and stoichiometry boosting of beta-cyclodextrin in cationic/anionic surfactant systems: when host-guest equilibrium meets biased aggregation equilibrium.

PubMed

Jiang, Lingxiang; Yu, Caifang; Deng, Manli; Jin, Changwen; Wang, Yilin; Yan, Yun; Huang, Jianbin

2010-02-18

Cationic surfactant/anionic surfactant/beta-CD ternary aqueous systems provide a platform for the coexistence of the host-guest (beta-CD/surfactant) equilibrium and the biased aggregation (monomeric/aggregated surfactants) equilibrium. We report here that the interplay between the two equilibria dominates the systems as follows. (1) The biased aggregation equilibrium imposes an apparent selectivity on the host-guest equilibrium, namely, beta-CD has to always selectively bind the major surfactant (molar fraction > 0.5) even if binding constants of beta-CD to the pair of surfactants are quite similar. (2) In return, the host-guest equilibrium amplifies the bias of the aggregation equilibrium, that is, the selective binding partly removes the major surfactant from the aggregates and leaves the aggregate composition approaching the electroneutral mixing stoichiometry. (3) This composition variation enhances electrostatic attractions between oppositely charged surfactant head groups, thus resulting in less-curved aggregates. In particular, the present apparent host-guest selectivity is of remarkably high values, and the selectivity stems from the bias of the aggregation equilibrium rather than the difference in binding constants. Moreover, beta-CD is defined as a "stoichiometry booster" for the whole class of cationic/anionic surfactant systems, which provides an additional degree of freedom to directly adjust aggregate compositions of the systems. The stoichiometry boosting of the compositions can in turn affect or even determine microstructures and macroproperties of the systems.

The Chemical Potential of Plasma Membrane Cholesterol: Implications for Cell Biology.

PubMed

Ayuyan, Artem G; Cohen, Fredric S

2018-02-27

Cholesterol is abundant in plasma membranes and exhibits a variety of interactions throughout the membrane. Chemical potential accounts for thermodynamic consequences of molecular interactions, and quantifies the effective concentration (i.e., activity) of any substance participating in a process. We have developed, to our knowledge, the first method to measure cholesterol chemical potential in plasma membranes. This was accomplished by complexing methyl-β-cyclodextrin with cholesterol in an aqueous solution and equilibrating it with an organic solvent containing dissolved cholesterol. The chemical potential of cholesterol was thereby equalized in the two phases. Because cholesterol is dilute in the organic phase, here activity and concentration were equivalent. This equivalence allowed the amount of cholesterol bound to methyl-β-cyclodextrin to be converted to cholesterol chemical potential. Our method was used to determine the chemical potential of cholesterol in erythrocytes and in plasma membranes of nucleated cells in culture. For erythrocytes, the chemical potential did not vary when the concentration was below a critical value. Above this value, the chemical potential progressively increased with concentration. We used standard cancer lines to characterize cholesterol chemical potential in plasma membranes of nucleated cells. This chemical potential was significantly greater for highly metastatic breast cancer cells than for nonmetastatic breast cancer cells. Chemical potential depended on density of the cancer cells. A method to alter and fix the cholesterol chemical potential to any value (i.e., a cholesterol chemical potential clamp) was also developed. Cholesterol content did not change when cells were clamped for 24-48 h. It was found that the level of activation of the transcription factor STAT3 increased with increasing cholesterol chemical potential. The cholesterol chemical potential may regulate signaling pathways. Copyright © 2018. Published by Elsevier Inc.

Methyl-β-cyclodextrin quaternary ammonium chitosan conjugate: nanoparticles vs macromolecular soluble complex

PubMed Central

Piras, Anna Maria; Fabiano, Angela; Chiellini, Federica; Zambito, Ylenia

2018-01-01

Purpose The present study aimed to compare a novel cyclodextrin–polymer–drug complex in solution with a dispersed supramolecular nanosize system, made of the same complex, for ability to carry dexamethasone (DEX) across excised rat intestine. Results Methyl-β-cyclodextrin-quaternary ammonium chitosan conjugate (QA-Ch-MCD) was obtained by covalent grafting through a 10-atom spacer. The conjugate was characterized by 1H-NMR, resulting in 24.4% w/w of MCD content. Phase solubility profile analysis of the QA-Ch-MCD/DEX complex yielded an association constant of 14037 M−1, vs 4428 M−1 for the plain MCD/DEX complex. Nanoparticle (NP) dispersions resulted from ionotropic gelation of the QA-Ch-MCD/DEX complex by sodium tripolyphosphate, leading to 9.9%±1.4% drug loading efficiency. The mean diameter and zeta potential for NP were 299±32 nm (polydispersity index [PI] 0.049) and 11.5±1.1 mV, respectively. Those for QA-Ch-MCD/DEX were 2.7±0.4 nm (PI 0.048) and 6.7±0.6 mV. QA-Ch-MCD/DEX solutions and corresponding NP dispersions were compared in vitro for water-assisted transport through mucus, DEX permeation through excised rat intestine, and ex vivo mucoadhesivity. The complex showed higher mucoadhesion and lower transport rate through mucus; also, it provided faster drug permeation across excised rat intestine. Conclusion Carrier adhesion to mucus surface has played a most important role in favoring transepithelial permeation. Then, within the concerns of the present study, the use of NP seems not to provide any determinant advantage over using the simpler macromolecular complex. PMID:29731628

Analysis of physicochemical properties of ternary systems of oxaprozin with randomly methylated-ß-cyclodextrin and l-arginine aimed to improve the drug solubility.

PubMed

Mennini, Natascia; Maestrelli, Francesca; Cirri, Marzia; Mura, Paola

2016-09-10

The influence of l-arginine on the complexing and solubilizing power of randomly-methylated-β-cyclodextrin (RameβCD) towards oxaprozin, a very poorly soluble anti-inflammatory drug, was examined. The interactions between the components were investigated both in solution, by phase-solubility analysis, and in the solid state, by differential scanning calorimetry, FTIR and X-ray powder diffractometry. The morphology of the solid products was examined by Scanning Electron Microscopy. Results of phase-solubility studies indicated that addition of arginine enhanced the RameβCD complexing and solubilizing power of about 3.0 and 4.5 times, respectively, in comparison with the binary complex (both at pH≈6.8). The effect of arginine was not simply additive, but synergistic, being the ternary system solubility higher than the sum of those of the respective drug-CD and drug-arginine binary systems. Solid equimolar ternary systems were prepared by physical mixing, co-grinding, coevaporation and kneading techniques, to explore the effect of the preparation method on the physicochemical properties of the final products. The ternary co-ground product exhibited a dramatic increase in both drug dissolution efficiency and percent dissolved at 60min, whose values (83.6 and 97.1, respectively) were about 3 times higher than the sum of those given by the respective drug-CD and drug-aminoacid binary systems. Therefore, the ternary co-ground system with arginine and RameβCD appears as a very valuable product for the development of new more effective delivery systems of oxaprozin, with improved safety and bioavailability. Copyright © 2016 Elsevier B.V. All rights reserved.

Osh proteins regulate membrane sterol organization but are not required for sterol movement between the ER and PM

PubMed Central

Georgiev, Alexander; Sullivan, David P.; Kersting, Michael C.; Dittman, Jeremy S.; Beh, Christopher T.; Menon, Anant K.

2011-01-01

Sterol transport between the endoplasmic reticulum (ER) and plasma membrane (PM) occurs by an ATP-dependent, non-vesicular mechanism that is presumed to require sterol transport proteins (STPs). In Saccharomyces cerevisiae, homologues of the mammalian oxysterol-binding protein (Osh1–7) have been proposed to function as STPs. To evaluate this proposal we took two approaches. First we used dehydroergosterol (DHE) to visualize sterol movement in living cells by fluorescence microscopy. DHE was introduced into the PM under hypoxic conditions and observed to redistribute to lipid droplets on growing the cells aerobically. Redistribution required ATP and the sterol acyltransferase Are2, but did not require PM-derived transport vesicles. DHE redistribution occurred robustly in a conditional yeast mutant (oshΔ osh4-1ts) that lacks all functional Osh proteins at 37°C. In a second approach we used a pulse-chase protocol to analyze the movement of metabolically radiolabeled ergosterol from the ER to the PM. Arrival of radiolabeled ergosterol at the PM was assessed in isolated PM-enriched fractions as well by extracting sterols from intact cells with methyl-β-cyclodextrin. These experiments revealed that whereas ergosterol is transported effectively from the ER to the PM in Osh-deficient cells, the rate at which it moves within the PM to equilibrate with the methyl-β-cyclodextrin extractable sterol pool is slowed. We conclude (i) that the role of Osh proteins in nonvesicular sterol transport between the PM, ER and lipid droplets is either minimal, or subsumed by other mechanisms and (ii) that Osh proteins regulate the organization of sterols at the PM. PMID:21689253

Cholesterol-Independent Effects of Methyl-β-Cyclodextrin on Chemical Synapses

PubMed Central

Ormerod, Kiel G.; Coorssen, Jens R.; Mercier, A. Joffre

2012-01-01

The cholesterol chelating agent, methyl-β-cyclodextrin (MβCD), alters synaptic function in many systems. At crayfish neuromuscular junctions, MβCD is reported to reduce excitatory junctional potentials (EJPs) by impairing impulse propagation to synaptic terminals, and to have no postsynaptic effects. We examined the degree to which physiological effects of MβCD correlate with its ability to reduce cholesterol, and used thermal acclimatization as an alternative method to modify cholesterol levels. MβCD impaired impulse propagation and decreased EJP amplitude by 40% (P<0.05) in preparations from crayfish acclimatized to 14°C but not from those acclimatized to 21°C. The reduction in EJP amplitude in the cold-acclimatized group was associated with a 49% reduction in quantal content (P<0.05). MβCD had no effect on input resistance in muscle fibers but decreased sensitivity to the neurotransmitter L-glutamate in both warm- and cold-acclimatized groups. This effect was less pronounced and reversible in the warm-acclimatized group (90% reduction in cold, P<0.05; 50% reduction in warm, P<0.05). MβCD reduced cholesterol in isolated nerve and muscle from cold- and warm-acclimatized groups by comparable amounts (nerve: 29% cold, 25% warm; muscle: 20% cold, 18% warm; P<0.05). This effect was reversed by cholesterol loading, but only in the warm-acclimatized group. Thus, effects of MβCD on glutamate-sensitivity correlated with its ability to reduce cholesterol, but effects on impulse propagation and resulting EJP amplitude did not. Our results indicate that MβCD can affect both presynaptic and postsynaptic properties, and that some effects of MβCD are unrelated to cholesterol chelation. PMID:22590538

Heparin-mimicking multilayer coating on polymeric membrane via LbL assembly of cyclodextrin-based supramolecules.

PubMed

Deng, Jie; Liu, Xinyue; Ma, Lang; Cheng, Chong; Shi, Wenbin; Nie, Chuanxiong; Zhao, Changsheng

2014-12-10

In this study, multifunctional and heparin-mimicking star-shaped supramolecules-deposited 3D porous multilayer films with improved biocompatibility were fabricated via a layer-by-layer (LbL) self-assembly method on polymeric membrane substrates. Star-shaped heparin-mimicking polyanions (including poly(styrenesulfonate-co-sodium acrylate; Star-PSS-AANa) and poly(styrenesulfonate-co-poly(ethylene glycol)methyl ether methacrylate; Star-PSS-EGMA)) and polycations (poly(methyl chloride-quaternized 2-(dimethylamino)ethyl methacrylate; Star-PMeDMA) were first synthesized by atom transfer radical polymerization (ATRP) from β-cyclodextrin (β-CD) based cores. Then assembly of 3D porous multilayers onto polymeric membrane surfaces was carried out by alternating deposition of the polyanions and polycations via electrostatic interaction. The surface morphology and composition, water contact angle, blood activation, and thrombotic potential as well as cell viability for the coated heparin-mimicking films were systematically investigated. The results of surface ATR-FTIR spectra and XPS spectra verified successful deposition of the star-shaped supramolecules onto the biomedical membrane surfaces; scanning electron microscopy (SEM) and atomic force microscopy (AFM) observations revealed that the modified substrate had 3D porous surface morphology, which might have a great biological influence on the biointerface. Furthermore, systematic in vitro investigation of protein adsorption, platelet adhesion, human platelet factor 4 (PF4, indicates platelet activation), activate partial thromboplastin time (APTT), thrombin time (TT), coagulation activation (thrombin-antithrombin III complex (TAT, indicates blood coagulant)), and blood-related complement activation (C3a and C5a, indicates inflammation potential) confirmed that the heparin-mimicking multilayer coated membranes exhibited ultralow blood component activations and excellent hemocompatibility. Meanwhile, after surface coating, endothelial cell viability was also promoted, which indicated that the heparin-mimicking multilayer coating might extend the application fields of polymeric membranes in biomedical fields.

Conversion of Exogenous Cholesterol into Glycoalkaloids in Potato Shoots, Using Two Methods for Sterol Solubilisation

PubMed Central

Petersson, Erik V.; Nahar, Nurun; Dahlin, Paul; Broberg, Anders; Tröger, Rikard; Dutta, Paresh C.; Jonsson, Lisbeth; Sitbon, Folke

2013-01-01

Steroidal glycoalkaloids (SGA) are toxic secondary metabolites naturally occurring in the potato, as well as in certain other Solanaceous plant species, such as tomato, eggplant and pepper. To investigate the steroidal origin of SGA biosynthesis, cut potato shoots were fed cholesterol labelled with deuterium (D) in the sterol ring structure (D5- or D6-labelled), or side chain (D7-labelled), and analysed after three or five weeks. The labelled cholesterol and presence of D-labelled SGA were analysed by GC-MS and LC-MS/MS, respectively. When feeding D-labelled cholesterol solubilised in Tween-80, labelled cholesterol in free form became present in both leaves and stems, although the major part was recovered as steryl esters. Minor amounts of D-labelled SGA (α-solanine and α-chaconine) were identified in cholesterol-treated shoots, but not in blank controls, or in shoots fed D6-27-hydroxycholesterol. Solubilising the labelled cholesterol in methyl-β-cyclodextrin instead of Tween-80 increased the levels of labelled SGA up to 100-fold, and about 1 mole% of the labelled cholesterol was recovered as labelled SGA in potato leaves. Both side chain and ring structure D labels were retained in SGA, showing that the entire cholesterol molecule is converted to SGA. However, feeding side chain D7-labelled cholesterol resulted in D5-labelled SGA, indicating that two hydrogen atoms were released during formation of the SGA nitrogen-containing ring system. Feeding with D7-sitosterol did not produce any labelled SGA, indicating that cholesterol is a specific SGA precursor. In conclusion, we have demonstrated a superior performance of methyl-β-cyclodextrin for delivery of cholesterol in plant tissue feeding experiments, and given firm evidence for cholesterol as a specific sterol precursor of SGA in potato. PMID:24349406

Tenax TA extraction to understand the rate-limiting factors in methyl-β-cyclodextrin-enhanced bioremediation of PAH-contaminated soil.

PubMed

Sun, Mingming; Luo, Yongming; Teng, Ying; Christie, Peter; Jia, Zhongjun; Li, Zhengao

2013-06-01

The effectiveness of many bioremediation systems for PAH-contaminated soil may be constrained by low contaminant bioaccessibility due to limited aqueous solubility or large sorption capacity. Information on the extent to which PAHs can be readily biodegraded is of vital importance in the decision whether or not to remediate a contaminated soil. In the present study the rate-limiting factors in methyl-β-cyclodextrin (MCD)-enhanced bioremediation of PAH-contaminated soil were evaluated. MCD amendment at 10 % (w/w) combined with inoculation with the PAH-degrading bacterium Paracoccus sp. strain HPD-2 produced maximum removal of total PAHs of up to 35 %. The desorption of PAHs from contaminated soil was determined before and after 32 weeks of bioremediation. 10 % (w/w) MCD amendment (M2) increased the Tenax extraction of total PAHs from 12 to 30 % and promoted degradation by up to 26 % compared to 6 % in the control. However, the percentage of Tenax extraction for total PAHs was much larger than that of degradation. Thus, in the control and M2 treatment it is likely that during the initial phase the bioaccessibility of PAHs is high and biodegradation rates may be limited by microbial processes. On the other hand, when the soil was inoculated with the PAH-degrading bacterium (CKB and MB2), the slowly and very slowly desorbing fractions (F sl and F vl ) became larger and the rate constants of slow and very slow desorption (k sl and k vl ) became extremely small after bioremediation, suggesting that desorption is likely rate limiting during the second, slow phase of biotransformation. These results have practical implications for site risk assessment and cleanup strategies.

Introduction of a methyl group in alpha- or beta-position of 1-heteroarylethyl-4-phenylpiperazines affects their dopaminergic/serotonergic properties.

PubMed

Roglic, G; Andric, D; Kostic-Rajacic, S; Dukic, S; Soskic, V

2001-12-01

1-(2-Heteroarylalkyl)-4-phenylpiperazines containing methyl group in either the alpha- or the beta-position of the side alkyl chain were synthesized as racemic mixtures. They were evaluated for in vitro binding affinity at the D1 and D2 dopamine and 5-HT1A serotonin receptors using synaptosomal membranes of the bovine caudate nucleus and hippocampus, respectively, as a source of the corresponding receptors. Tritiated SCH 23390 (D1 receptor-selective), spiperone (D2 receptor-selective), and 8-OH-DPAT (5-HT1A receptor-selective) were employed as the radioligands. None of the new compounds expressed significant affinity for the D1 receptor. Introduction of the methyl group into the beta-position of the parent molecules increased the affinity for the D2 receptor (10b-13b), and decreased the affinity for the 5-HT1A receptor with the exception of imidazole (11b) which was a rather efficient displacer of 8-OH-DPAT. Most potent of the newly synthesized compounds in [3H]spiperone assay were compounds (+/-)6-[1-methyl-2- (4-phenylpiperazin-1-yl)-ethyl]-1,4-dihydroquinoxaline-2,3-dione (10b), Kd = 6.0 nM and (+/-)5-[1-methyl-2-(4-phenylpiperazin-1-yl)-ethyl]-1,3-dihydrobenzoimidazol- 2-thione (13b), Kd = 5.3 nM. However, compounds containing methyl group in alpha-position (10a-13a) of the parent molecules expressed a decreased affinity for the D2 receptor, while the affinity for the 5-HT1A receptor remained in the same range of concentrations as that of closely related achiral parent compounds (14-17) run in the same binding assays as references.

Invariant glycines and prolines flanking in loops the strand beta 2 of various (alpha/beta)8-barrel enzymes: a hidden homology?

PubMed Central

Janecek, S.

1996-01-01

The question of parallel (alpha/beta)8-barrel fold evolution remains unclear, owing mainly to the lack of sequence homology throughout the amino acid sequences of (alpha/beta)8-barrel enzymes. The "classical" approaches used in the search for homologies among (alpha/beta)8-barrels (e.g., production of structurally based alignments) have yielded alignments perfect from the structural point of view, but the approaches have been unable to reveal the homologies. These are proposed to be "hidden" in (alpha/beta)8-barrel enzymes. The term "hidden homology" means that the alignment of sequence stretches proposed to be homologous need not be structurally fully satisfactory. This is due to the very long evolutionary history of all (alpha/beta)8-barrels. This work identifies so-called hidden homology around the strand beta 2 that is flanked by loops containing invariant glycines and prolines in 17 different (alpha/beta)8-barrel enzymes, i.e., roughly in half of all currently known (alpha/beta)8-barrel proteins. The search was based on the idea that a conserved sequence region of an (alpha/beta)8-barrel enzyme should be more or less conserved also in the equivalent part of the structure of the other enzymes with this folding motif, given their mutual evolutionary relatedness. For this purpose, the sequence region around the well-conserved second beta-strand of alpha-amylase flanked by the invariant glycine and proline (56_GFTAIWITP, Aspergillus oryzae alpha-amylase numbering), was used as the sequence-structural template. The proposal that the second beta-strand of (alpha/beta)8-barrel fold is important from the evolutionary point of view is strongly supported by the increasing trend of the observed beta 2-strand structural similarity for the pairs of (alpha/beta)8-barrel enzymes: alpha-amylase and the alpha-subunit of tryptophan synthase, alpha-amylase and mandelate racemase, and alpha-amylase and cyclodextrin glycosyltransferase. This trend is also in agreement with the existing evolutionary division of the entire family of (alpha/beta)8-barrel proteins. PMID:8762144

Invariant glycines and prolines flanking in loops the strand beta 2 of various (alpha/beta)8-barrel enzymes: a hidden homology?

PubMed

Janecek, S

1996-06-01

The question of parallel (alpha/beta)8-barrel fold evolution remains unclear, owing mainly to the lack of sequence homology throughout the amino acid sequences of (alpha/beta)8-barrel enzymes. The "classical" approaches used in the search for homologies among (alpha/beta)8-barrels (e.g., production of structurally based alignments) have yielded alignments perfect from the structural point of view, but the approaches have been unable to reveal the homologies. These are proposed to be "hidden" in (alpha/beta)8-barrel enzymes. The term "hidden homology" means that the alignment of sequence stretches proposed to be homologous need not be structurally fully satisfactory. This is due to the very long evolutionary history of all (alpha/beta)8-barrels. This work identifies so-called hidden homology around the strand beta 2 that is flanked by loops containing invariant glycines and prolines in 17 different (alpha/beta)8-barrel enzymes, i.e., roughly in half of all currently known (alpha/beta)8-barrel proteins. The search was based on the idea that a conserved sequence region of an (alpha/beta)8-barrel enzyme should be more or less conserved also in the equivalent part of the structure of the other enzymes with this folding motif, given their mutual evolutionary relatedness. For this purpose, the sequence region around the well-conserved second beta-strand of alpha-amylase flanked by the invariant glycine and proline (56_GFTAIWITP, Aspergillus oryzae alpha-amylase numbering), was used as the sequence-structural template. The proposal that the second beta-strand of (alpha/beta)8-barrel fold is important from the evolutionary point of view is strongly supported by the increasing trend of the observed beta 2-strand structural similarity for the pairs of (alpha/beta)8-barrel enzymes: alpha-amylase and the alpha-subunit of tryptophan synthase, alpha-amylase and mandelate racemase, and alpha-amylase and cyclodextrin glycosyltransferase. This trend is also in agreement with the existing evolutionary division of the entire family of (alpha/beta)8-barrel proteins.

A comprehensive strategy in the development of a cyclodextrin-modified microemulsion electrokinetic chromatographic method for the assay of diclofenac and its impurities: Mixture-process variable experiments and quality by design.

PubMed

Orlandini, S; Pasquini, B; Caprini, C; Del Bubba, M; Squarcialupi, L; Colotta, V; Furlanetto, S

2016-09-30

A comprehensive strategy involving the use of mixture-process variable (MPV) approach and Quality by Design principles has been applied in the development of a capillary electrophoresis method for the simultaneous determination of the anti-inflammatory drug diclofenac and its five related substances. The selected operative mode consisted in microemulsion electrokinetic chromatography with the addition of methyl-β-cyclodextrin. The critical process parameters included both the mixture components (MCs) of the microemulsion and the process variables (PVs). The MPV approach allowed the simultaneous investigation of the effects of MCs and PVs on the critical resolution between diclofenac and its 2-deschloro-2-bromo analogue and on analysis time. MPV experiments were used both in the screening phase and in the Response Surface Methodology, making it possible to draw MCs and PVs contour plots and to find important interactions between MCs and PVs. Robustness testing was carried out by MPV experiments and validation was performed following International Conference on Harmonisation guidelines. The method was applied to a real sample of diclofenac gastro-resistant tablets. Copyright © 2016 Elsevier B.V. All rights reserved.

Cyclodextrin-containing hydrogels as an intraocular lens for sustained drug release

PubMed Central

Li, Xiao; Zhao, Yang; Wang, Kaijie; Yang, Xiaohui; Zhu, Siquan

2017-01-01

To improve the efficacy of anti-inflammatory factors in patients who undergo cataract surgery, poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) (p(HEMA-co-MMA)) hydrogels containing β-cyclodextrin (β-CD) (pHEMA/MMA/β-CD) were designed and prepared as intraocular lens (IOLs) biomaterials that could be loaded with and achieve the sustained release of dexamethasone. A series of pHEMA/MMA/β-CD copolymers containing different ratios of β-CD (range, 2.77 to 10.24 wt.%) were obtained using thermal polymerization. The polymers had high transmittance at visible wavelengths and good biocompatibility with mouse connective tissue fibroblasts. Drug loading and release studies demonstrated that introducing β-CD into hydrogels increased loading efficiency and achieved the sustained release of the drug. Administering β-CD via hydrogels increased the equilibrium swelling ratio, elastic modulus and tensile strength. In addition, β-CD increased the hydrophilicity of the hydrogels, resulting in a lower water contact angle and higher cellular adhesion to the hydrogels. In summary, pHEMA/MMA/β-CD hydrogels show great potential as IOL biomaterials that are capable of maintaining the sustained release of anti-inflammatory drugs after cataract surgery. PMID:29244868

Inclusion of Paracetamol into β-cyclodextrin nanocavities in solution and in the solid state

NASA Astrophysics Data System (ADS)

El-Kemary, Maged; Sobhy, Saffaa; El-Daly, Samy; Abdel-Shafi, Ayman

2011-09-01

We report on steady-state UV-visible absorption and emission characteristics of Paracetamol, drug used as antipyretic agent, in water and within cyclodextrins (CDs): β-CD, 2-hydroxypropyl- β-CD (HP- β-CD) and 2,6-dimethyl- β-CD (Me- β-CD). The results reveal that Paracetamol forms a 1:1 inclusion complex with CD. Upon encapsulation, the emission intensity enhances, indicating a confinement effect of the nanocages on the photophysical behavior of the drug. Due to its methyl groups, the Me- β-CD shows the largest effect for the drug. The observed binding constant showing the following trend: Me- β-CD > HP- β-CD > β-CD. The less complexing effectiveness of HP- β-CD is due to the steric effect of the hydroxypropyl-substituents, which can hamper the inclusion of the guest molecules. The solid state inclusion complex was prepared by co-precipitation method and its characterization was investigated by Fourier transform infrared spectroscopy, 1H NMR and X-ray diffractometry. These approaches indicated that Paracetamol was able to form an inclusion complex with CDs, and the inclusion compounds exhibited different spectroscopic features and properties from Paracetamol.

Gas chromatographic/mass spectrometric analysis of the essential oil of Houttuynia cordata Thunb by using on-column methylation with tetramethylammonium acetate.

PubMed

Ch, Muhammad Ishtiaq; Wen, Yang F; Cheng, YiYu

2007-01-01

This paper describes a simple and novel on-column derivatization procedure used with gas chromatography/mass spectrometry (GC/MS) for the analysis of essential oil of Houttuynia cordata Thunb (HCT), a traditional Chinese medicine. In the procedure, the essential oil was obtained by hydrodistillation, and the fatty acid components were derivatized with tetramethylammonium acetate (TMAA) at 250 degrees C and identified by GC/MS. Methylation improved the determination of both the fatty acids and the other components in the essential oil of HCT. To obtain optimum methylation conditions, several important factors were investigated with pentadecane as the internal standard and a GC inlet temperature of 250 degres C. Tetramethylammonium hydroxide (TMAH) and TMAA were compared as the derivatization agent, and a 2:1 ratio of TMAA to capric acid was evaluated. Fatty acid methyl esters produced good chromatographic peak shapes and did not interfere with the determination of dodecanal and caryophyllene. TMAA is a neutral methylation reagent, and it yielded no side reactions during derivatization. It was found that the fatty acid content of the essential oil was about 81%; among the methylated fatty acids found were capric acid, methyl (43.66%), methyl laurate (16.15%), methyl hexadecanoate (9.27%), undecanoic acid, methyl (5.62%), methyl oleate (1.98%), and methyl linoleate (1.40%). Other major constituents were (-)-beta-pinene (1.02%), beta-myrcene (1.62%), 1-terpinen-4-ol (1.59%), decanal (1.49%), and 2-undecanone (1.47%). The results obtained demonstrated good efficiency for the procedure. Pure chromatograms allowed quantitation, which was obtained by total volume integration. The on-column derivatization procedure was simple to perform, and it improved the sensitivity, the peak resolution, and the selectivity of the GC/MS determination.

Syntheses of all the possible monomethyl ethers and several deoxyhalo analogues of methyl beta-lactoside as ligands for the Ricinus communis lectins.

PubMed

Fernández, P; Jiménez-Barbero, J; Martín-Lomas, M

1994-02-17

The synthesis of all the possible monomethyl ethers of methyl beta-lactoside (1) has been performed from 1 in a straightforward way, making use of the different reactivity of the hydroxyl groups in alkylation and stannylation reactions. In addition, the deoxyfluoro derivatives of 1 at positions, 6,3',4',epi-4', and 6' have been prepared by reaction of the appropriate substrates with diethylaminosulfur trifluoride or tetrabutylammonium fluoride. Finally, the 6-deoxyiodo and 6'-bromodeoxy analogues of 1 have also been prepared.

Effects of methyl mercury exposure on pancreatic beta cell development and function.

PubMed

Schumacher, Lauren; Abbott, Louise C

2017-01-01

Methyl mercury is an environmental contaminant of worldwide concern. Since the discovery of methyl mercury exposure due to eating contaminated fish as the underlying cause of the Minamata disaster, the scientific community has known about the sensitivity of the developing central nervous system to mercury toxicity. Warnings are given to pregnant women and young children to limit consumption of foods containing methyl mercury to protect the embryonic, fetal and postnatally developing central nervous system. However, evidence also suggests that exposure to methyl mercury or various forms of inorganic mercury may also affect development and function of other organs. Numerous reports indicate a worldwide increase in diabetes, particularly type 2 diabetes. Quite recently, methyl mercury has been shown to have adverse effects on pancreatic beta (β) cell development and function, resulting in insulin resistance and hyperglycemia and may even lead to the development of diabetes. This review discusses possible mechanisms by which methyl mercury exposure may adversely affect pancreatic β cell development and function, and the role that methyl mercury exposure may have in the reported worldwide increase in diabetes, particularly type 2 diabetes. While additional information is needed regarding associations between mercury exposure and specific mechanisms of the pathogenesis of diabetes in the human population, methyl mercury's adverse effects on the body's natural sources of antioxidants suggest that one possible therapeutic strategy could involve supplementation with antioxidants. Thus, it is important that additional investigation be undertaken into the role of methyl mercury exposure and reduced pancreatic β cell function. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Bile salts stimulate mucin secretion by cultured dog gallbladder epithelial cells independent of their detergent effect.

PubMed

Klinkspoor, J H; Yoshida, T; Lee, S P

1998-05-15

1. Bile salts stimulate mucin secretion by the gallbladder epithelium. We have investigated whether this stimulatory effect is due to a detergent effect of bile salts. 2. The bile salts taurocholic acid (TC) and tauroursodeoxycholic acid (TUDC) and the detergents Triton X-100 (12.5-400 microM) and Tween-20 (0.1-3.2 mM) were applied to monolayers of cultured dog gallbladder epithelial cells. Mucin secretion was studied by measuring the secretion of [3H]N-acetyl-d-glucosamine-labelled glycoproteins. We also attempted to alter the fluidity of the apical membrane of the cells through extraction of cholesterol with beta-cyclodextrin (2.5-15 mM). The effect on TUDC-induced mucin secretion was studied. Cell viability was assessed by measuring lactate dehydrogenase (LDH) leakage or 51Cr release. 3. In contrast with the bile salts, the detergents were not able to cause an increase in mucin secretion without causing concomitant cell lysis. Concentrations of detergent that increased mucin release (>100 microM Triton X-100, >0.8 mM Tween-20), caused increased LDH release. Incubation with beta-cyclodextrin resulted in effective extraction of cholesterol without causing an increase in 51Cr release. However, no effect of the presumed altered membrane fluidity on TUDC (10 mM)-induced mucin secretion was observed. 4. The stimulatory effect of bile salts on mucin secretion by gallbladder epithelial cells is not affected by the fluidity of the apical membrane of the cells and also cannot be mimicked by other detergents. We conclude that the ability of bile salts to cause mucin secretion by the gallbladder epithelium is not determined by their detergent properties.

[Pharmaceutical application of cyclodextrins as multi-functional drug carriers].

PubMed

Uekama, Kaneto

2004-12-01

Owing to the increasingly globalized nature of the cyclodextrin (CyD)-related science and technology, development of the CyD-based pharmaceutical formulation is rapidly progressing. The pharmaceutically useful CyDs are classified into hydrophilic, hydrophobic, and ionic derivatives. Because of the multi-functional characteristics and bioadaptability, these CyDs are capable of alleviating the undesirable properties of drug molecules through the formation of inclusion complexes or the form of CyD/drug conjugates. This review outlines the current application of CyDs in drug delivery and pharmaceutical formulation, focusing on the following evidences. 1) The hydrophilic CyDs enhance the rate and extent of bioavailability of poorly water-soluble drugs. 2) The amorphous CyDs such as 2-hydroxypropyl-beta-CyD are useful for inhibition of polymorphic transition and crystallization rates of drugs during storage. 3) The delayed release formulation can be obtained by the use of enteric type CyDs such as O-carboxymethyl-O-ethyl-beta-CyD. 4) The hydrophobic CyDs are useful for modification of the release site and/or time profile of water-soluble drugs with prolonged therapeutic effects. 5) The branched CyDs are particularly effective in inhibiting the adsorption to hydrophobic surface of containers and aggregation of polypeptide and protein drugs. 6) The combined use of different CyDs and/or pharmaceutical additives can serve as more functional drug carriers, improving efficacy and reducing side effects. 7) The CyD/drug conjugates may provide a versatile means for the constructions of not only colonic delivery system but also site-specific drug release system, including gene delivery. On the basis of the above-mentioned knowledge, the advantages and limitations of CyDs in the design of advanced dosage forms will be discussed.

Solubility and stability of melatonin in propylene glycol and 2-hydroxypropyl-beta-cyclodextrin vehicles.

PubMed

Lee, B J; Choi, H G; Kim, C K; Parrott, K A; Ayres, J W; Sack, R L

1997-12-01

The physicochemical properties of melatonin (MT) in propylene glycol (PG) and 2-hydroxypropyl-beta-cyclodextrin (2-HPbetaCD) vehicles were characterized. MT was endothermally decomposed as determined by differential scanning calorimetry (DSC). Melting point and heat of fusion obtained were 116.9+/-0.24 degrees C and 7249+/-217 cal/mol, respectively. MT as received from a manufacture was very pure, at least 99.9%. The solubility of MT in PG solution increased slowly until reaching 40% PG and then steeply increased. Solubility of MT increased linearly as concentration of 2-HPbetaCD without PG increased (R(2)=0.993). MT solubility in the mixtures of PG and 2-HPbetaCD also increased linearly but was less than the sum of its solubility in 2-HPbetaCD and PG individually. The MT solubility was low in water, simulated gastric or intestinal fluid but the highest in the mixture of PG (40 v/v%) and 2-HPbetaCD (30 w/v%) although efficiency of MT solubilization in 2-HPbetaCD decreased as the concentration of PG increased. MT was degraded in a fashion of the first order kinetics (r(2)>0.90). MT was unstable in strong acidic solution (HCl-NaCl buffer, pH 1.4) but relatively stable in other pH values of 4 approximately 10 at 70 degrees C. In HCl-NaCl buffer, MT in 10% PG was more quickly degraded and then slowed down at a higher concentration. However, the degradation rate constant of MT in 2-HPbetaCD was not changed significantly when compared to the water. The current studies can be applied to the dosage formulations for the purpose of enhancing percutaneous absorption or bioavailability of MT.

Inclusion complexes of cypermethrin and permethrin with monochlorotriazinyl-beta-cyclodextrin: A combined spectroscopy, TG/DSC and DFT study

NASA Astrophysics Data System (ADS)

Yao, Qi; You, Bin; Zhou, Shuli; Chen, Meng; Wang, Yujiao; Li, Wei

2014-01-01

The suitable size hydrophobic cavity and monochlorotriazinyl group as a reactive anchor make MCT-β-CD to be widely used in fabric finishing. In this paper, the inclusion complexes of monochlorotriazinyl-beta-cyclodextrin (MCT-β-CD) with cypermethrin (CYPERM) and permethrin (PERM) are synthesized and analyzed by TG/DSC, FT-IR and Raman spectroscopy. TG/DSC reveals that the decomposed temperatures of inclusion complexes are lower by 25-30 °C than that of physical mixtures. DFT calculations in conjunction with FT-IR and Raman spectral analyses are used to study the structures of MCT-β-CD and their inclusion complexes. Four isomers of trisubstituted MCT-β-CD are designed and DFT calculations reveal that 1,3,5-trisubstituted MCT-β-CD has the lowest energy and can be considered as main component of MCT-β-CD. The ground-state geometries, vibrational wavenumbers, IR and Raman intensities of MCT-β-CD and their inclusion complexes were calculated at B3LYP/6-31G (d) level of theory. Upon examining the optimized geometry of inclusion complex, we find that the CYPERM and PERM are inserted into the toroid of MCT-β-CD from the larger opening. The band at 1646 cm-1 in IR and at 1668 cm-1 in Raman spectrum reveals that monochloroazinyl group of MCT-β-CD exists in ketone form but not in anion form. The noticeable IR and Raman shift of phenyl reveals that these two benzene rings of CYPERM and PERM stays inside the cavity of MCT-β-CD and has weak interaction with MCT-β-CD. This spectroscopy conclusion is consistent with theoretical predicted structure.

Direct investigation of the vectorization properties of amphiphilic cyclodextrins in phospholipid films.

PubMed

Javierre, Isabelle; Nedyalkov, Mickael; Petkova, Vera; Benattar, Jean Jacques; Weisse, Sandrine; Auzély-Velty, Rachel; Djedaïni-Pilard, Florence; Perly, Bruno

2002-10-01

Recently, new cyclodextrin derivatives were synthesized and shown to exhibit strong amphiphilic properties. In this paper, we study the action of these new amphiphilic cyclodextrins on phospholipids. Mixed phospholipid/cyclodextrin derivative films were prepared and studied using X-ray reflectivity for various phospholipid/cyclodextrin ratios. A molar ratio of 3 provides a highly stable film the molecular structure of which has been investigated in detail. The cholesterol tail of the cyclodextrin molecule was found to be anchored into the phospholipid film. The cyclodextrin moieties exposed to the aqueous medium are prone to the addition of the guest molecule Dosulepin, making them of high interest for drug delivery. For this purpose and as an example of a potential application, this cyclodextrin molecular carrier property is also addressed to this complex film architecture.

Enantiomeric separation of fluoxetine and norfluoxetine in plasma and serum samples with high detection sensitivity capillary electrophoresis.

PubMed

Desiderio, C; Rudaz, S; Raggi, M A; Fanali, S

1999-11-01

A capillary electrophoresis method was optimized for the stereoselective analysis of the antidepressant drug fluoxetine and its main demethylated metabolite norfluoxetine using a cyclodextrin-modified sodium phosphate buffer at pH 2.5. The combination of a neutral and a negatively charged cyclodextrin, dimethylated-beta- and phosphated-gamma-respectively, provided the baseline enantiomeric separation of the two compounds. The very low concentrations of chiral selectors employed together with the use of a high sensitivity detection cell of special design (zeta-shaped) in a diode array UV detector allowed us to reach a limit of detection of 0.005 and 0.01 microg/mL for fluoxetine and norfluoxetine, respectively. Analysis of fluoxetine and norfluoxetine standard mixtures showed a reproducibility of migration times and peak area and linearity in the concentration range of 0.1-2.0 microg/mL. The optimized method was applied to the analysis of clinical serum and plasma samples of patients under depression therapy. In all the analyzed samples the enantiomeric forms of fluoxetine and norfluoxetine were easily identified. The fluoxetine and metabolite enantiomeric ratio confirmed the stereoselectivity of the metabolic process of the fluoxetine drug in accordance with the literature data.

Using cyclodextrin complexation to enhance secondary photoprotection of topically applied ibuprofen.

PubMed

Godwin, Donald A; Wiley, Cody J; Felton, Linda A

2006-01-01

Each year millions of people are overexposed to the sun resulting in photodamage of the skin. Secondary photoprotection is the application of medicinal agents to the body after sun exposure to reduce this damage. The objective of this study was to determine the affects of hydroxypropyl-beta-cyclodextrin (HPCD) complexation on the secondary photoprotective properties of topically applied ibuprofen. Complexation of ibuprofen by HPCD was demonstrated by differential scanning calorimetry, while solubilities were determined using HPLC. A linear (r2>0.999) relationship was found between ibuprofen solubility and HPCD concentration. For subsequent experiments, the concentration of ibuprofen was held constant at the solubility in 10% HPCD (10.6 mg/ml), while the HPCD concentration varied from 0 to 20% (w/w). In vitro transdermal permeation experiments demonstrated a parabolic relationship between transdermal kinetic parameters and HPCD concentration, with maximum values for both flux and skin accumulation occurring with the 10% HPCD formulation. In vivo experiments were performed by exposing hairless mice to UV radiation and applying ibuprofen-HPCD formulations topically at various times following UV exposure. Edema and epidermal lipid damage data demonstrated that application of ibuprofen-HPCD formulations within 1h of UV exposure provided significant photoprotection.

The main chemical composition and in vitro antifungal activity of the essential oils of Ocimum basilicum Linn. var. pilosum (Willd.) Benth.

PubMed

Zhang, Ji-Wen; Li, Sheng-Kun; Wu, Wen-Jun

2009-01-08

The essential oils of the aerial parts of Ocimum basilicum Linn.var. pilosum (Willd.) Benth., an endemic medicinal plant growing in China, was obtained by hydrodistillation and analysed by GC-MS. Fifteen compounds, representing 74.19% of the total oil were identified. The main components were as follows: linalool (29.68%), (Z)-cinnamic acid methyl ester (21.49%), cyclohexene (4.41%), alpha- cadinol (3.99%), 2,4-diisopropenyl-1-methyl-1-vinylcyclohexane (2.27%), 3,5-pyridine-dicarboxylic acid, 2,6-dimethyl-diethyl ester (2.01%), beta-cubebene (1.97%), guaia-1(10),11-diene (1.58%), cadinene (1.41%) (E)-cinnamic acid methyl ester (1.36%) and beta-guaiene (1.30%). The essential oils showed significant antifungal activity against some plant pathogenic fungi.

The preparation, characterization, and pharmacokinetic studies of chitosan nanoparticles loaded with paclitaxel/dimethyl-β-cyclodextrin inclusion complexes

PubMed Central

Ye, Ya-Jing; Wang, Yun; Lou, Kai-Yan; Chen, Yan-Zuo; Chen, Rongjun; Gao, Feng

2015-01-01

A novel biocompatible and biodegradable drug-delivery nanoparticle (NP) has been developed to minimize the severe side effects of the poorly water-soluble anticancer drug paclitaxel (PTX) for clinical use. PTX was loaded into the hydrophobic cavity of a hydrophilic cyclodextrin derivative, heptakis (2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD), using an aqueous solution-stirring method followed by lyophilization. The resulting PTX/DM-β-CD inclusion complex dramatically enhanced the solubility of PTX in water and was directly incorporated into chitosan (CS) to form NPs (with a size of 323.9–407.8 nm in diameter) using an ionic gelation method. The formed NPs had a zeta potential of +15.9–23.3 mV and showed high colloidal stability. With the same weight ratio of PTX to CS of 0.7, the loading efficiency of the PTX/DM-β-CD inclusion complex-loaded CS NPs was 30.3-fold higher than that of the PTX-loaded CS NPs. Moreover, it is notable that PTX was released from the DM-β-CD/CS NPs in a sustained-release manner. The pharmacokinetic studies revealed that, compared with reference formulation (Taxol®), the PTX/DM-β-CD inclusion complex-loaded CS NPs exhibited a significant increase in AUC0→24h (the area under the plasma drug concentration–time curve over the period of 24 hours) and mean residence time by 2.7-fold and 1.4-fold, respectively. Therefore, the novel drug/DM-β-CD inclusion complex-loaded CS NPs have promising applications for the significantly improved delivery and controlled release of the poorly water-soluble drug PTX or its derivatives, thus possibly leading to enhanced therapeutic efficacy and less severe side effects. PMID:26170666

Abscisic acid related compounds and lignans in prunes (Prunus domestica L.) and their oxygen radical absorbance capacity (ORAC).

PubMed

Kikuzaki, Hiroe; Kayano, Shin-ichi; Fukutsuka, Naoko; Aoki, Asuka; Kasamatsu, Kumi; Yamasaki, Yuka; Mitani, Takahiko; Nakatani, Nobuji

2004-01-28

Four new abscisic acid related compounds (1-4), together with (+)-abscisic acid (5), (+)-beta-D-glucopyranosyl abscisate (6), (6S,9R)-roseoside (7), and two lignan glucosides ((+)-pinoresinol mono-beta-D-glucopyranoside (8) and 3-(beta-D-glucopyranosyloxymethyl)-2- (4-hydroxy-3-methoxyphenyl)-5-(3-hydroxypropyl)-7-methoxy-(2R,3S)-dihydrobenzofuran (9)) were isolated from the antioxidative ethanol extract of prunes (Prunus domestica L.). The structures of 1-4 were elucidated on the basis of NMR and MS spectrometric data to be rel-5-(3S,8S-dihydroxy-1R,5S-dimethyl-7-oxa-6-oxobicyclo[3,2,1]oct-8-yl)-3-methyl-2Z,4E-pentadienoic acid (1), rel-5-(3S,8S-dihydroxy-1R,5S-dimethyl-7-oxa-6-oxobicyclo[3,2,1]oct-8-yl)-3-methyl-2Z,4E-pentadienoic acid 3'-O-beta-d-glucopyranoside (2), rel-5-(1R,5S-dimethyl-3R,4R,8S-trihydroxy-7-oxa-6-oxobicyclo[3,2,1]oct-8-yl)-3-methyl-2Z,4E-pentadienoic acid (3), and rel-5-(1R,5S-dimethyl-3R,4R,8S-trihydroxy-7-oxabicyclo[3,2,1]- oct-8-yl)-3-methyl-2Z,4E-pentadienoic acid (4). The antioxidant activities of these isolated compounds were evaluated on the basis of oxygen radical absorbance capacity (ORAC). The ORAC values of abscisic acid related compounds (1-7) were very low. Two lignans (8 and 9) were more effective antioxidants whose ORAC values were 1.09 and 2.33 micromol of Trolox equiv/micromol, respectively.

Biochemical and kinetic analysis of the GH3 family beta-xylosidase from Aspergillus awamori X-100.

PubMed

Eneyskaya, Elena V; Ivanen, Dina R; Bobrov, Kirill S; Isaeva-Ivanova, Lyudmila S; Shabalin, Konstantin A; Savel'ev, Andrew N; Golubev, Alexander M; Kulminskaya, Anna A

2007-01-15

The beta-xylosidase from Aspergillus awamori X-100 belonging to the family 3 glycoside hydrolase revealed a distinctive transglycosylating ability to produce xylooligosaccharides with degree of polymerization more than 7. In order to explain this fact, the enzyme has been subjected to the detailed biochemical study. The enzymatic hydrolysis of p-nitrophenyl beta-D-xylopyranoside was found to occur with overall retention of substrate anomeric configuration suggesting cleavage of xylosidic bonds through a double-displacement mechanism. Kinetic study with aryl beta-xylopyranosides substrates, in which leaving group pK(a)s were in the range of 3.96-10.32, revealed monotonic function of log(k(cat)) and no correlation of log(k(cat)/Km) versus pKa values indicating deglycosylation as a rate-limiting step for the enzymatic hydrolysis. The classical bell-shaped pH dependence of k(cat)/Km indicated two ionizable groups in the beta-xylosidase active site with apparent pKa values of 2.2 and 6.4. The kinetic parameters of hydrolysis, Km and k(cat), of p-nitrophenyl beta-D-1,4-xylooligosaccharides were very close to those for hydrolysis of p-nitrophenyl-beta-D-xylopyranoside. Increase of p-nitrophenyl-beta-D-xylopyranoside concentration up to 80 mM led to increasing of the reaction velocity resulting in k(cat)(app)=81 s(-1). Addition of alpha-methyl D-xylopyranoside to the reaction mixture at high concentration of p-nitrophenyl-beta-D-xylopyranoside (50 mM) caused an acceleration of the beta-xylosidase-catalyzed reactions and appearance of a new transglycosylation product, alpha-methyl D-xylopyranosyl-1,4-beta-D-xylopyranoside, that was identified by 1H NMR spectroscopy. The kinetic model suggested for the enzymatic reaction was consistent with the results obtained.

Methylation of zebularine: a quantum mechanical study incorporating interactive 3D pdf graphs.

PubMed

Selvam, Lalitha; Vasilyev, Vladislav; Wang, Feng

2009-08-20

Methylation of a cytidine deaminase inhibitor, 1-(beta-D-ribofuranosyl)-2-pyrimidone (i.e., zebularine (zeb)), which produces 1-(beta-D-ribofuranosyl)-5-methyl-2-pyrimidinone (d5), has been investigated using density functional theory models. The optimized structures of zeb and d5 and the valence orbitals primarily responsible for the methylation in d5 are presented using state-of-the-art interactive (on a computer or online) three-dimensional (3D) graphics in a portable document format (pdf) file, 3D-PDF (http://www.web3d.org/x3d/vrml/ ). The facility to embed 3D molecular structures into pdf documents has been developed jointly at Swinburne University of Technology and the National Computational Infrastructure, the Australian National University. The methyl fragment in the base moiety shows little effect on the sugar puckering but apparently affects anisotropic properties, such as condensed Fukui functions. Binding energy spectra, both valence space and core space, are noticeably affected; in particular, in the outer-valence space (e.g., IP < 20 eV). The methyl fragment delocalizes and diffuses into almost all valence space, but orbitals 8 (57a, IP = 12.57 eV), 18 (47a, IP = 14.70 eV), and 37 (28a, IP = 22.15 eV) are identified as fingerprint for the methyl fragment. In the inner shell, however, the impact of the methyl can be localized and identified by chemical shift. A small, global, red shift is found for the O-K, N-K and sugar C-K spectra, whereas the base C-K spectrum exhibits apparent methyl-related changes.

[Studies on the chemical constituents of the roots of Anemone altaica].

PubMed

Zou, Zhong-jie; Yang, Jun-shan

2008-01-01

To investigate the chemical constituents of the roots of Anemone altaica Fisch. ex C. A. May. The constituents of n-BuOH-soluble portion were isolated and purified by means of chromatography. Compounds were identified by their physical characteristics and spectral features. Six compounds were isolated and identified as cimigenol-3-O-beta-D-xylopyranoside (1), cimigenol-3-O-beta-D-xylopyranol (1 -->3)-beta-D-xylopyranoside (2), isolariciresinol-9-O-beta-D-glucopyranoside (3), adenosine (4), uridine (5) and methyl-beta-D-glucopyranoside (6). All compounds are isolated from this genus for the first time.

Enteridinines A and B from slime mold Enteridium lycoperdon.

PubMed

Rezanka, Tomás; Dvoráková, Radmila; Hanus, Lumír O; Dembitsky, Valery M

2004-02-01

Two novel deoxysugar esters, named enteridinines A and B, were isolated from the slime mold Enteridium lycoperdon. Their structures, including the absolute configurations of the hydroxyl and methyl groups, were determined by means of extensive spectroscopic data such as UV, IR, MS, 1D and 2D NMR spectra. Enteridinines A and B have unique structures containing 1,7-dioxaspiro[5.5]undecanes with an O-beta-D-mycarosyl-(1-->4)-beta-D-olivosyl and an O-beta-L-olivomycosyl-(1-->4)-beta-D-amicetosyl-(1-->4)-beta-L-digitoxosyl unit, respectively, and showed growth inhibitory activities against Gram positive bacteria.

Synthesis of a thiol-β-cyclodextrin, a potential agent for controlling enzymatic browning in fruits and vegetables.

PubMed

Manta, Carmen; Peralta-Altier, Gabriela; Gioia, Larissa; Méndez, María F; Seoane, Gustavo; Ovsejevi, Karen

2013-11-27

A thiol-β-cyclodextrin was synthesized by a simple and environmentally friendly three-step method comprising epoxy activation of β-cyclodextrin, thiosulfate-mediated oxirane opening, and further reduction of the S-alkyl thiosulfate to a thiol group. The final step was optimized by using thiopropyl-agarose, a solid phase reducing agent with many advantages over soluble ones. β-Cyclodextrin thiolation was confirmed by titration with a thiol-reactive reagent, NMR studies, and MALDI-TOF/TOF. Thiolated cyclodextrin had an average value of one thiol group per molecule. Thiol-β-cyclodextrin proved to be an excellent agent for controlling polyphenol oxidase activity. This copper-containing enzyme is responsible for browning in fruits and vegetables. Under the same conditions, thiol-β-cyclodextrin generated a reductive microenvironment that increased the antibrowning effect on Red Delicious apples compared to unmodified β-cyclodextrin.

Viscosity reduction of isotonic solutions of the photosensitizer TPCS2a by cyclodextrin complexation.

PubMed

Tovsen, Marianne Lilletvedt; Tho, Ingunn; Tønnesen, Hanne Hjorth

2018-02-01

Meso-tetraphenyl chlorin disulphonate (TPCS 2a ) is a photosensitizer (PS) particularly developed and patented for use in the technology of photochemical internalization (PCI) against cancer. TPCS 2a is known to aggregate in aqueous media even at low concentrations (≥0.1 µM) and to form a high-viscosity network at clinically relevant concentrations (mM). The aim of this work was to evaluate the effect of two hydroxypropylated cyclodextrin derivatives of beta and gamma type, respectively i.e. HPβCD and HPγCD, on the aggregation and solubilization of TPCS 2a in isotonic solutions. Samples containing micromolar concentrations of TPCS 2a were studied spectrophotometrically, while samples containing a clinical relevant concentration (10 mM = 9 mg/ml) of TPCS 2a were evaluated by dynamic viscosity measurements. HPβCD was determined to be a more suitable solubilizer of TPCS 2a than HPγCD in aqueous media both in the absence and presence of salt. The complexation stoichiometry between TPCS 2a /HPβCD at micromolar to millimolar concentrations of TPCS 2a was determined to be 1:3 and 1:2 in the absence and presence of isotonic NaCl, respectively. The network of TPCS 2a (10 mM) was broken down in the presence of 3% w/v (= 20 mM) HPβCD, i.e. a 1:2 molar ratio between TPCS 2a and the cyclodextrin. Formation of the inclusion complex resulted in low viscosity samples both in water and in the presence of isotonic NaCl or phosphate buffered saline (PBS) at 25 °C and 37 °C.

Substitution of egg yolk by a cyclodextrin-cholesterol complex allows a reduction of the glycerol concentration into the freezing medium of equine sperm.

PubMed

Blommaert, Didier; Franck, Thierry; Donnay, Isabelle; Lejeune, Jean-Philippe; Detilleux, Johann; Serteyn, Didier

2016-02-01

The aim of this work was to completely replace the egg yolk a classical diluent for freezing equine semen by a cyclodextrin-cholesterol complex. At the same time, the reduction in the glycerol content used for cryopreservation and the incubation time between sperm and the freezing media were evaluated. Horse ejaculates were frozen with four different freezing extenders: a frozen reference medium (IF) containing egg yolk and 2.5% glycerol and media without egg yolk but supplemented with 1.5 mg 2-hydroxypropyl-beta-cyclodextrin cholesterol (HPβCD-C) complex and containing either 1% (G1), 2% (G2) or 3% glycerol (G3). Three incubation times (90, 120 and 180 min) at 4 °C between the fresh semen and the different media were tested before freezing. Viability and motility analyses were performed with computer assisted semen analysis (CASA). Results showed that the freezing media containing the HPβCD-C complex with 1%, 2% and 3% glycerol significantly improve the 3 in vitro parameters of post thawing semen quality (viability, progressive and total mobilities) compared to IF. The best improvement of the parameters was obtained with G1 medium and the longest contact time. The substitution of egg yolk by HPβCD-C complex allows the decrease of protein charge of the medium while favouring the cholesterol supply to membrane spermatozoa offering it a better resistance to osmotic imbalance and a better tolerance to the glycerol toxicity. Our results highlight that the egg yolk of an extender for the freezing of horse semen can be completely substituted by HPβCD-C complex. Copyright © 2015. Published by Elsevier Inc.

Chiral separation of 3,4-methylenedioxymeth- amphetamine and related compounds in clandestine tablets and urine samples by capillary electrophoresis/fluorescence spectroscopy.

PubMed

Huang, Yu-San; Liu, Ju-Tsung; Lin, Li-Chang; Lin, Cheng-Huang

2003-03-01

The R-(-)- and S-(+)-isomers of 3,4-methylenedioxymethamphetamine (MDMA) and its metabolite 3,4-methylenedioxyamphetamine (MDA) were prepared, identified by gas chromatography/mass spectrometry (GC/MS) and then used as standards in a series of capillary electrophoresis (CE) experiments. Using these R-(-)- and S-(+)-isomers, the distribution of (RS)-MDA and (RS)-MDMA stereoisomers in clandestine tablets and suspect urine samples were identified. Several electrophoretic parameters, such as the concentration of beta-cyclodextrin used in the electrophoretic separation and the amount of organic solvents required for the separation, were optimized.

Reconstituted high-density lipoprotein suppresses leukocyte NADPH oxidase activation by disrupting lipid rafts.

PubMed

Peshavariya, Hitesh; Dusting, Gregory J; Di Bartolo, Belinda; Rye, Kerry-Anne; Barter, Philip J; Jiang, Fan

2009-08-01

Reconstituted discoidal high-density lipoprotein (rHDL) has potent vascular protective actions. Native HDL suppresses cellular generation of reactive oxygen species, whereas this antioxidant effect of rHDL is less clear. This study examined the effects of rHDL on NADPH oxidase, a major source of cellular superoxide generation, in both leukocytes and human umbilical vein endothelial cells. Superoxide was measured with lucigenin-enhanced chemiluminescence. Expression of NADPH oxidase sub-units was determined by real-time PCR. Pre-treatment of HL-60 cells with rHDL (10 and 25 microM) for 1 h significantly reduced phorbol 12-myristate 13-acetate-stimulated superoxide production. Treatment with rHDL for up to 24 h did not change the mRNA expression of NADPH oxidase sub-units. In HL-60 cells, depletion of cholesterol from the plasma membrane by methyl-beta-cyclodextrin mimicked the effect of rHDL, whereas cholesterol repletion blunted the effects of rHDL. Treatment with rHDL induced disruption of the lipid raft structures and blunted PMA-induced redistribution of p47phox into lipid rafts. In contrast, treatment of endothelial cells with rHDL for up to 18 h had no effect on either basal or tumour necrosis factor-alpha-stimulated NADPH oxidase activity, but markedly suppressed the cytokine-induced expression of proinflammatory adhesion molecules. The results suggest that rHDL inhibits NADPH oxidase activation in leukocytes, probably by interrupting the assembly of NADPH oxidase sub-units at the lipid rafts. This effect may contribute to the vascular protective actions of rHDL against inflammation-mediated oxidative damage.

The lipid composition modulates the influence of the bovine seminal plasma protein PDC-109 on membrane stability.

PubMed

Tannert, Astrid; Töpfer-Petersen, Edda; Herrmann, Andreas; Müller, Karin; Müller, Peter

2007-10-16

The bovine seminal plasma protein PDC-109 exerts an essential influence on the sperm cell plasma membrane during capacitation. However, by any mechanism, it has to be ensured that this function of the protein on sperm cells is not initiated too early, that is, upon ejaculation when PDC-109 and sperm cells come into first contact, but rather at later stages of sperm genesis in the female genital tract. To answer the question of whether changes of the bovine sperm lipid composition can modulate the effect of PDC-109 on sperm membranes, we have investigated the influence of PDC-109 on the integrity of (i) differently composed lipid vesicles and of (ii) membranes from human red blood cells and bovine spermatozoa. PDC-109 most effectively disturbed lipid membranes composed of choline-containing phospholipids and in the absence of cholesterol. The impact of the protein on lipid vesicles was attenuated in the presence of cholesterol or of noncholine-containing phospholipids, such as phosphatidylethanolamine or phosphatidylserine. An extraction of cholesterol from lipid or biological membranes using methyl-beta-cyclodextrin caused an increased membrane perturbation by PDC-109. Our results argue for a oppositional effect of PDC-109 during sperm cell genesis. We hypothesize that the lipid composition of ejaculated bull sperm cells allows a binding of PDC-109 without leading to an impairment of the plasma membrane. At later stages of sperm cell genesis upon release of cholesterol from sperm membranes, PDC-109 triggers a destabilization of the cells.

Synaptic proteins associate with a sub-set of lipid rafts when isolated from nerve endings at physiological temperature.

PubMed

Gil, Carles; Cubí, Roger; Blasi, Juan; Aguilera, José

2006-10-06

Although the high presence of cholesterol in nerve terminals is well documented, specific roles of this lipid in transmitter release have remained elusive. Since cholesterol is a highly enriched component in the membrane microdomains known as lipid rafts, it is probable that these domains are very important in synaptic function. The extraction of lipid rafts using Brij 98 at 37 degrees C avoids the formation of nonspecific membrane aggregates at low temperature, allowing the isolation of more physiologically relevant lipid rafts. In the present work, we examine, by means of buoyancy analysis in sucrose gradients after solubilization of the membranes with Brij 98 or with Lubrol WX, the presence of proteins involved in exocytosis in detergent-resistant membranes (DRM) using rat brain synaptosomes as a neurological model. Significant proportions of the proteins tested in the present work, which are involved in neurotransmitter release, are found in Brij 98 raft fractions, demonstrating that significant pools of synaptic proteins are segregated in specific parts of the membrane at physiological temperature. On the other hand, Lubrol WX is unable to solubilize the major fraction of the proteins tested. Treatment of synaptosomes with methyl-beta-cyclodextrin (mbetaCD) causes alteration in the buoyancy properties of proteins initially present in Brij- as well as in Lubrol-resistant membranes, indicating the cholesterol-dependency of both kinds of microdomains. Finally, we detect the depolarization-induced enhancement of the cholesterol-dependent association of syntaxin 1 with Brij 98-rafts, under the same conditions in which prolonged neurotransmitter release is stimulated.

Effect of cholesterol depletion on exocytosis of alveolar type II cells.

PubMed

Chintagari, Narendranath Reddy; Jin, Nili; Wang, Pengcheng; Narasaraju, Telugu Akula; Chen, Jiwang; Liu, Lin

2006-06-01

Alveolar epithelial type II cells secrete lung surfactant via exocytosis. Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) are implicated in this process. Lipid rafts, the cholesterol- and sphingolipid-rich microdomains, may offer a platform for protein organization on the cell membrane. We tested the hypothesis that lipid rafts organize exocytotic proteins in type II cells and are essential for the fusion of lamellar bodies, the secretory granules of type II cells, with the plasma membrane. The lipid rafts, isolated from type II cells using 1% Triton X-100 and a sucrose gradient centrifugation, contained the lipid raft markers, flotillin-1 and -2, whereas they excluded the nonraft marker, Na+-K+ ATPase. SNAP-23, syntaxin 2, and VAMP-2 were enriched in lipid rafts. When type II cells were depleted of cholesterol, the association of SNAREs with the lipid rafts was disrupted and the formation of fusion pore was inhibited. Furthermore, the cholesterol-depleted plasma membrane had less ability to fuse with lamellar bodies, a process mediated by annexin A2. The secretagogue-stimulated secretion of lung surfactant from type II cells was also reduced by methyl-beta-cyclodextrin. When the raft-associated cell surface protein, CD44, was cross-linked using anti-CD44 antibodies, the CD44 clusters were observed. Syntaxin 2, SNAP-23, and annexin A2 co-localized with the CD44 clusters, which were cholesterol dependent. Our results suggested that lipid rafts may form a functional platform for surfactant secretion in alveolar type II cells, and raft integrity was essential for the fusion between lamellar bodies with the plasma membrane.

Nanosilica sol leads to further increase in polyethylene glycol (PEG) 1000-enhanced thermostability of β-cyclodextrin glycosyltransferase from Bacillus circulans.

PubMed

Li, Caiming; Huang, Min; Gu, Zhengbiao; Hong, Yan; Cheng, Li; Li, Zhaofeng

2014-04-02

A major disadvantage of cyclodextrin production is the limited thermostability of cyclodextrin glycosyltransferase. The ability of combinations of nanosilica sol with polyethylene glycol (PEG) 1000 to enhance the thermostability of the β-cyclodextrin glycosyltransferase from Bacillus circulans was investigated. It was found that 10% PEG 1000 combined with 0.05% nanosilica sol could activate the β-cyclodextrin glycosyltransferase by 17.2%. Furthermore, 0.05% nanosilica sol leads to further increase in PEG 1000-enhanced thermostability of β-cyclodextrin glycosyltransferase. With the simultaneous addition of 10% PEG 1000 and 0.05% nanosilica into the enzyme solution, which was allowed to incubate for 60 min at 60 °C, 61.3% of β-cyclodextrin-forming activity could be retained, which was much higher than that with only 10% PEG 1000 added. Atomic force microscopy, fluorescence spectroscopy, and circular dichroism analysis indicated that silica nanoparticles helped PEG 1000 further protect the tertiary and secondary structures of β-cyclodextrin glycosyltransferase. This study provides an effective approach for improving the thermostability of cyclodextrin glycosyltransferase and related enzymes.

Novel combined stir bar sorptive extraction coupled with ultrasonic assisted extraction for the determination of brominated flame retardants in environmental samples using high performance liquid chromatography.

PubMed

Yu, Chunhe; Hu, Bin

2007-08-10

A combined stir bar coated with poly (dimethysiloxane)-beta-cyclodextrin (PDMS-beta-CD) on single side has been prepared for the first time by sol-gel method and was coupled with ultrasonic assisted extraction (UAE) for the determination of some brominated flame-retardant compounds (BFRs) in soil and dust samples by high performance liquid chromatography (HPLC). Four different kinds of coatings including PDMS-beta-CD, PDMS, carbowax (CW)-PDMS-poly (vinyl alcohol) (PVA) and PDMS-PVA were evaluated for stir bar sorptive extraction of BFRs by orthogonal experiment design. The experimental results reveal that the PDMS-beta-CD combined stir bar exhibited the best extraction efficiency for the target analytes. The reproducibility for the preparation of PDMS-beta-CD combined stir bar ranged from 1.3% to 15.7% in one batch, and 7.2% to 15.1% among batches. Extraction time, desorption solvent, concentration of methanol and NaCl in the matrix, pH, temperature and stirring speed were optimized. The combined stir bar can avoid direct friction of the coating with the bottom of the vessel, and could be used for more than 100 times. Linearity (>0.993), repeatability (<10.5%), reproducibility (<16.5%), recovery (56-118%) and detection limits (2.9-4.2 microg L(-1)) were proper to determine the seven BFRs. The developed method was applied to the determination of BFRs in soil and dust with satisfactory results.

Synthesis, cytotoxic effect and antiviral activity of 1-(beta-D-arabinofuranosyl)-5-bromo-N4-substituted cytosine and 1-(beta-D-arabinofuranosyl)-5-bromo-4-methoxypyrimidin-2(1H)-one derivatives.

PubMed

Saladino, R; Mezzetti, M; Mincione, E; Palamara, A T; Savini, P; Marini, S

1999-01-01

A convenient and mild synthesis of 5-bromo-N4-substituted-1-(beta-D-arabinofuranosyl)cytosine and 5-bromo-O4-methyl-1-(beta-D-arabinofuranosyl)pyrimidin-2(1H)-one derivatives by selective oxyfunctionalization of the corresponding 4-thionucleosides with 3,3-dimethyldioxirane is reported. The cytotoxicity and the antiviral activity against parainfluenza 1 (Sendai virus) of all new synthesized products are also reported.

Pharmaceutical applications of cyclodextrins: effects on drug permeation through biological membranes.

PubMed

Loftsson, Thorsteinn; Brewster, Marcus E

2011-09-01

Cyclodextrins are useful solubilizing excipients that have gained currency in the formulator's armamentarium based on their ability to temporarily camouflage undesirable physicochemical properties. In this context cyclodextrins can increase oral bioavailability, stabilize compounds to chemical and enzymatic degradation and can affect permeability through biological membranes under certain circumstances. This latter property is examined herein as a function of the published literature as well as work completed in our laboratories.   Cyclodextrins can increase the uptake of drugs through biological barriers if the limiting barrier component is the unstirred water layer (UWL) that exists between the membrane and bulk water. This means that cyclodextrins are most useful when they interact with lipophiles in systems where such an UWL is present and contributes significantly to the barrier properties of the membrane. Furthermore, these principles are used to direct the optimal formulation of drugs in cyclodextrins. A second related critical success factor in the formulation of cyclodextrin-based drug product is an understanding of the kinetics and thermodynamics of complexation and the need to optimize the cyclodextrin amount and drug-to-cyclodextrin ratios. Drug formulations, especially those targeting compartments associated with limited dissolution (i.e. the eye, subcutaneous space, etc.), should be carefully designed such that the thermodynamic activity of the drug in the formulation is optimal meaning that there is sufficient cyclodextrin to solubilize the drug but not more than that. Increasing the cyclodextrin concentration decreases the formulation 'push' and may reduce the bioavailability of the system. A mechanism-based understanding of cyclodextrin complexation is essential for the appropriate formulation of contemporary drug candidates. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

Post monitoring of a cyclodextrin remeditated chlorinated solvent contaminated aquifer

NASA Astrophysics Data System (ADS)

Blanford, W. J.

2006-12-01

Hydroxypropyl-â-cyclodextrin (HPâCD) has been tested successfully in the laboratory and in the field for enhanced flushing of low-polarity contaminants from aquifers. The cyclodextrin molecule forms a toroidal structure, which has a hydrophobic cavity. Within this cavity, organic compounds of appropriate shape and size can form inclusion complexes, which is the basis for the use of cyclodextrin in groundwater remediation. The hydrophilic exterior of the molecule makes cyclodextrin highly water-soluble. The solubility of cyclodextrins can be further enhanced by adding functional groups, such as hydroxypropyl groups, to the cyclodextrin core. The aqueous solubility of HPâCD exceeds 950 g/L. These high solubilities are advantageous for field applications because they permit relatively high concentrations of the flushing agent. In order for cyclodextrin to become a feasible remediative alternative, it must be demonstrate a short term resistance to biodegradation during field application, but ultimately biodegrade so as not to pose a long term presence in the aquifer. The potential for degradation of cyclodextrin as well as changes in the chlorinated solvents and groundwater geochemistry were examined during the post monitoring of a field demonstration in a shallow aquifer at Little Creek Naval Amphibious Base in Virginia. It was found that a portion of the cyclodextrin remaining in the aquifer after the cessation of field activities biodegraded during the 425 days of post monitoring. This degradation also led to the degradation of the chlorinated solvents trichloroethylene and 1,1-trichloroethane through both biological and chemical processes. The aquifer remained anaerobic with average dissolved oxygen levels below 0.5 mg/L. Dissolved nitrate and sulfate concentrations within the cyclodextrin plume decreased due their being used as terminal electron acceptors during the degradation of the cyclodextrin. The concentrations of total iron at the field site showed no change over time. It can be concluded from this research that cyclodextrin remaining in the subsurface after cessation of active remediation will degrade due to microbial processes. The chlorinated solvents will also degrade through both chemical and biological processes to their daughter products. The terminal electron acceptors present within the cyclodextrin plume will also be used for energy during the degradation processes.

Differential effects of arginine methylation on diastolic dysfunction and disease progression in patients with chronic systolic heart failure

PubMed Central

Wilson Tang, Wai Hong; Tong, Wilson; Shrestha, Kevin; Wang, Zeneng; Levison, Bruce S.; Delfraino, Brian; Hu, Bo; Troughton, Richard W.; Klein, Allan L.; Hazen, Stanley L.

2008-01-01

Aims To investigate the association of arginine methylation with myocardial function and prognosis in chronic systolic heart failure patients. Methods and results Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), as well as N-mono-methylarginine (MMA) and methyl-lysine, were simultaneously measured by tandem mass spectrometry in 132 patients with chronic systolic heart failure with echocardiographic evaluation and follow-up. Increasing ADMA and SDMA levels were associated with elevated natriuretic peptide levels (both P < 0.001), and increasing SDMA levels were associated with worsening renal function (P < 0.001). Higher plasma levels of methylated arginine metabolites (but not methyl-lysine) were associated with the presence of left ventricular (LV) diastolic dysfunction (E/septal E′, Spearman's r = 0.31–0.36, P < 0.001). Patients taking beta-blockers had lower ADMA levels than those not taking beta-blockers [0.42 (0.33, 0.50) vs. 0.51 (0.40, 0.58), P < 0.001]. Only increasing ADMA levels were associated with advanced right ventricular (RV) systolic dysfunction. Elevated ADMA levels remained a consistent independent predictor of adverse clinical events (hazard ratio = 1.64, 95% CI: 1.20–2.22, P = 0.002). Conclusion In chronic systolic heart failure, accumulation of methylated arginine metabolites is associated with the presence of LV diastolic dysfunction. Among the methylated derivatives of arginine, ADMA provides the strongest independent prediction of disease progression and adverse long-term outcomes. PMID:18687662

The epigenetic effect of glucosamine and a nuclear factor-kappa B (NF-kB) inhibitor on primary human chondrocytes - Implications for osteoarthritis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Imagawa, Kei, E-mail: k.Imagawa@soton.ac.uk; Tohoku University School of Medicine, Sendai; Andres, MC de

Research highlights: {yields} Glucosamine and a NF-kB inhibitor reduce inflammation in OA. {yields} Cytokine induced demethylation of CpG site in IL1{beta} promoter prevented by glucosamine. {yields} Glucosamine and NF-kB inhibitor have epigenetic effects on human chondrocytes. -- Abstract: Objective: Idiopathic osteoarthritis is the most common form of osteoarthritis (OA) world-wide and remains the leading cause of disability and the associated socio-economic burden in an increasing aging population. Traditionally, OA has been viewed as a degenerative joint disease characterized by progressive destruction of the articular cartilage and changes in the subchondral bone culminating in joint failure. However, the etiology of OAmore » is multifactorial involving genetic, mechanical and environmental factors. Treatment modalities include analgesia, joint injection with steroids or hyaluronic acid, oral supplements including glucosamine and chondroitin sulfate, as well as physiotherapy. Thus, there is significant interest in the discovery of disease modifying agents. One such agent, glucosamine (GlcN) is commonly prescribed even though the therapeutic efficacy and mechanism of action remain controversial. Inflammatory cytokines, including IL-1{beta}, and proteinases such as MMP-13 have been implicated in the pathogenesis and progression of OA together with an associated CpG demethylation in their promoters. We have investigated the potential of GlcN to modulate NF-kB activity and cytokine-induced abnormal gene expression in articular chondrocytes and, critically, whether this is associated with an epigenetic process. Method: Human chondrocytes were isolated from the articular cartilage of femoral heads, obtained with ethical permission, following fractured neck of femur surgery. Chondrocytes were cultured for 5 weeks in six separate groups; (i) control culture, (ii) cultured with a mixture of 2.5 ng/ml IL-1{beta} and 2.5 ng/ml oncostatin M (OSM), (iii) cultured with 2 mM N-acetyl GlcN (Sigma-Aldrich), (iv) cultured with a mixture of 2.5 ng/ml IL-1{beta}, 2.5 ng/ml OSM and 2 mM GlcN, (v) cultured with 1.0 {mu}M BAY 11-7082 (BAY; NF-kB inhibitor: Calbiochem, Darmstadt, Germany) and, (vi) cultured with a mixture of 2.5 ng/ml IL-1{beta}, 2.5 ng/ml OSM and 1.0 {mu}M BAY. The levels of IL1B and MMP13 mRNA were examined using qRT-PCR. The percentage DNA methylation in the CpG sites of the IL1{beta} and MMP13 proximal promoter were quantified by pyrosequencing. Result:IL1{beta} expression was enhanced over 580-fold in articular chondrocytes treated with IL-1{beta} and OSM. GlcN dramatically ameliorated the cytokine-induced expression by 4-fold. BAY alone increased IL1{beta} expression by 3-fold. In the presence of BAY, IL-1{beta} induced IL1B mRNA levels were decreased by 6-fold. The observed average percentage methylation of the -256 CpG site in the IL1{beta} promoter was 65% in control cultures and decreased to 36% in the presence of IL-1{beta}/OSM. GlcN and BAY alone had a negligible effect on the methylation status of the IL1B promoter. The cytokine-induced loss of methylation status in the IL1B promoter was ameliorated by both GlcN and BAY to 44% and 53%, respectively. IL-1{beta}/OSM treatment increased MMP13 mRNA levels independently of either GlcN or BAY and no change in the methylation status of the MMP13 promoter was observed. Conclusion: We demonstrate for the first time that GlcN and BAY can prevent cytokine-induced demethylation of a specific CpG site in the IL1{beta} promoter and this was associated with decreased expression of IL1{beta}. These studies provide a potential mechanism of action for OA disease modifying agents via NF-kB and, critically, demonstrate the need for further studies to elucidate the role that NF-kB may play in DNA demethylation in human chondrocytes.« less

Regulation of endothelial nitric oxide synthase: involvement of protein kinase G 1 beta, serine 116 phosphorylation and lipid structures.

PubMed

John, Theresa A; Ibe, Basil O; Raj, J Usha

2008-02-01

1. Endothelial nitric oxide synthase (NOS3) is important for vascular homeostasis. The role of protein kinase G (PKG) in regulation of NOS3 activity was studied in primary cultures of newborn lamb lung microvascular endothelial cells (LMVEC). 2. We determined the presence of PKG in fetal and neonatal LMVEC as well as subcellular localization of PKG isoforms in the neonatal cells by fluorescence immunohistochemistry. We used diaminofluorescein (DAF) fluorophore to measure nitric oxide (NO) production from neonatal LMVEC. We confirmed that NO measured was from constitutive NOS3 by inhibiting it with NOS inhibitors. 3. To identify a role for PKG in basal NO production, we measured NO release from LMVEC cells using 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM; 0.5-0.8 micromol/L) with and without prior stimulation with the PKG activator 8-bromo-cGMP (8-Br-cGMP; 0.3 and 3 micromol/L) or prior PKG inhibition with beta-phenyl-1,N2-etheno-8-bromoguanosine-3',5'-cyclic monophosphorothionate (BPC; 0.3 and 3 micromol/L). With the same drugs, we determined the role of PKG on cellular expression of NOS3 and serine 116 phosphorylated NOS (pSer116-NOS) by qualitative and quantitative immunofluorescence assays, as well as western blotting. 4. Because PKG 1 beta was distributed throughout the cytosol in a punctate expression, we used 2 mmol/L cyclodextrin, a cholesterol extractor, to determine a role for lipid vesicles in PKG regulation of NO production. 5. Protein kinase G 1 beta gave a punctate appearance, indicating its presence in intracellular vesicles. Nitric oxide production decreased by approximately 20% with 300 nmol/L and 3 micromol/L 8-Br cGMP (P < 0.05) and increased by 20.8 +/- 3.7% with 3 micromol/L BPC (P < 0.001), indicating that both stimulated and basal PKG activity has inhibitory effects on basal NOS3 function. Nitric oxide synthase immunofluorescence and immunoblot expression were decreased and pSer116-NOS immunofluorescence was increased by 800 nmol/L 8-Br-cGMP and 170 micromol/L (Z)-1-[2-(2-aminoethyl)-N-(2-ammonio-ethyl)amino]diazen-1-ium-1, 2-diolate (DETANONOate). The effect of cyclodextrin indicated that cholesterol extraction interfered with PKG inhibition of NOS. Further examination of pSer116-NOS by immunohistochemistry showed it abundant in the endoplasmic reticulum and colocalized with PKG 1 beta, especially in nuclear vesicles. 6. We conclude that endothelial PKG is involved in endogenous regulation of basal NOS3 activity with the involvement of lipid structures, the endoplasmic reticulum and the nucleus. Protein kinase G 1 beta is colocalized with pSer116-NOS, indicating that PKG action may involve serine 116 phosphorylation on NOS.

β-Cyclodextrin's orientation onto TiO2 and its paradoxical role in guest's photodegradation.

PubMed

Zhang, Xu; Yang, Zixin; Li, Xuankun; Deng, Nansheng; Qian, Shahua

2013-01-28

This work revealed that β-cyclodextrin was attached onto the surface of TiO(2) predominately by its secondary ring side, which caused paradoxical functions of β-cyclodextrin in the photodegradation of the four bisphenols. The equilibrium between the guest adsorbed through β-cyclodextrin onto TiO(2) and the one locked in β-CD in water could also change the role of β-cyclodextrin in the degradation of a certain guest.

A new synthesis of certain 7-(beta-D-ribofuranosyl) and 7-(2-deoxy-beta-D-ribofuranosyl) derivatives of 3-deazaguanine via the sodium salt glycosylation procedure.

PubMed Central

Gupta, P K; Robins, R K; Revankar, G R

1985-01-01

A facile synthesis of 7-beta-D-ribofuranosyl-3-deazaguanine (1) and certain 8-substituted derivatives of 1 via the sodium salt glycosylation method has been developed. Glycosylation of the sodium salt of methyl 2-chloro(or methylthio)-4(5)-cyanomethylimidazole-5(4)-carboxylate (5 and 13b) with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide (6) gave exclusively methyl 2-chloro(or methylthio)-4-cyanomethyl-1-(2,3, 5-tri-O-benzoyl-beta-D-ribofuranosyl)imidazole-5-carboxylate (7 and 14a), respectively. Ammonolysis of 7 and 14a provided 6-amino-2-chloro(or methylthio)-3-beta-D-ribofuranosylimidazo-[4,5-c]pyridin-4(5H)-one (11 and 17), which on subsequent dehalogenation (or dethiation) gave 1. Similarly, reaction of the sodium salt of 5 and 13b with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-alpha-D-erythro-pentofuranose (8), and ammonolysis of the glycosylated imidazole precursors (9 and 16) gave 6-amino-2-chloro(or methylthio)-3-(2-deoxy-beta-D-erythro-pentofuranosyl) imidazo[4,5-c]-pyridin-4(5H)-one (10a and 15), respectively. Dehalogenation of 10a or dethiation of 15 gave 2'-deoxy-7-beta-D-ribofuranosyl-3-deazaguanine (10b). This procedure provided a direct method of obtaining 10b without the contaminating 9-glycosyl isomer 4. PMID:4022783

Preparation and Physicochemical Characterization of an Inclusion Complex Between Dimethylated β-Cyclodextrin and a Drug Lead From a New Class of Orally Active Antimalarial 3,5-Diaryl-2-Aminopyridines.

PubMed

Joseph, Laurelle M; Chibale, Kelly; Caira, Mino R

2016-11-01

Cyclodextrins (CDs) were used to increase the aqueous solubility of a recently discovered orally active 3,5-diaryl-2-aminopyridine antimalarial drug lead (MMP). Phase-solubility studies using β-CD, hydroxypropyl-β-CD, and heptakis(2,6-di-O-methyl)-β-CD (DIMEB) as potential solubilizers for MMP yielded solubility enhancement factors of 17, 49, and 65, respectively, at 25°C with CD concentrations ∼20 mM. A crystalline complex, DIMEB⋅MMP⋅2H 2 O, was prepared and characterized by thermal and single-crystal X-ray analyses. The latter technique revealed preferential encapsulation of the hydrophobic methylsulfonylphenyl moiety of MMP within the CD cavity and protrusion of the more polar methoxypyridinyl and aminopyridine residues from the cavity. This inclusion mode results in a DIMEB complex with a new packing arrangement and an intricate network of intermolecular hydrogen bonds linking guest residues that protrude from 2 1 -related host cavities. A summary of the results of the performance of the inclusion complex in preliminary pharmacokinetic and efficacy tests in mouse models is provided. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Catching TFSI: A Computational-Experimental Approach to β-Cyclodextrin-Based Host-Guest Systems as electrolytes for Li-Ion Batteries.

PubMed

Jeschke, Steffen; Jankowski, Piotr; Best, Adam S; Johansson, Patrik

2018-03-12

Cyclodextrins (CDs) are pyranoside-based macromolecules with a hydrophobic cavity to encapsulate small molecules. They are used as molecular vehicles, for instance in pharmaceutical drug delivery or as solubility enhancer of monomers for their polymerization in aqueous solution. In this context, it was discovered about 10 years ago that the bis(trifluoromethylsulonyl)imide (TFSI) anion forms host-guest complexes with βCD in aqueous media. This sparked interest in using the TFSI anion in lithium-based battery electrolytes open for its encapsulation by βCD as an attractive approach to increase the contribution of the cation to the total ion conductivity. By using semi-empirical quantum mechanical (SQM) methods and the conductor-like screening model for a real solvent (COSMO-RS), a randomly methylated βCD (RMβCD) is here identified as a suitable host for TFSI when using organic solvents often used in battery technology. By combining molecular dynamics (MD) simulations with different NMR and FTIR experiments, the formation of the corresponding RMβCD-TFSI complex was investigated. Finally, the effects of the addition RMβCD to a set of electrolytes on the ion conductivity are measured and explained using three distinct scenarios. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

N-Methyl-D-aspartate receptor antagonist MK-801 and radical scavengers protect cholinergic nucleus basalis neurons against beta-amyloid neurotoxicity.

PubMed

Harkany, T; Mulder, J; Sasvári, M; Abrahám, I; Kónya, C; Zarándi, M; Penke, B; Luiten, P G; Nyakas, C

1999-04-01

Previous experimental data indicate the involvement of Ca(2+)-related excitotoxic processes, possibly mediated by N-Methyl-D-Aspartate (NMDA) receptors, in beta-amyloid (beta A) neurotoxicity. On the other hand, other lines of evidence support the view that free radical generation is a critical step in the beta A-induced neurodegenerative cascade. In the present study, therefore, a neuroprotective strategy was applied to explore the contributions of each of these pathways in beta A toxicity. beta A(1-42) was injected into the magnocellular nucleus basalis of rats, while neuroprotection was achieved by either single or combined administration of the NMDA receptor antagonist MK-801 (2.5 mg/kg) and/or a vitamin E and C complex (150 mg/kg). The degree of neurodegeneration was determined by testing the animals in consecutive series of behavioral tasks, including elevated plus maze, passive avoidance learning, small open-field and open-field paradigms, followed by acetylcholinesterase (AChE), choline-acetyltransferase (ChAT), and superoxide dismutase (SOD) biochemistry. beta A injected in the nucleus basalis elicited significant anxiety in the elevated plus maze, derangement of passive avoidance learning, and altered spontaneous behaviors in both open-field tasks. A significant decrease in both AChE and ChAT accompanied by a similar decrement of MnSOD, but not of Cu/ZnSOD provided neurochemical substrates for the behavioral changes. Each of the single drug administrations protected against the neurotoxic events, whereas the combined treatment failed to ameliorate beta A toxicity.

(+)-4 beta-hydroxyhernandulcin, a new sweet sesquiterpene from the leaves and flowers of Lippia dulcis.

PubMed

Kaneda, N; Lee, I S; Gupta, M P; Soejarto, D D; Kinghorn, A D

1992-08-01

From the leaves and flowers of Lippia dulcis collected in Panama, a new sweet sesquiterpene identified as (+)-4 beta-hydroxyhernandulcin [2] was isolated, accompanied by (+)-hernandulcin [1], (-)-epihernandulcin [3] (a novel natural product), and 6-methyl-5-hepten-2-one [4]. Acteoside (verbascoside) [5], a known bitter phenylpropanoid glycoside, was isolated from the flowers of L. dulcis. The structure of (+)-4 beta-hydroxyhernandulcin was established by interpretation of its spectral data.

Are [O-methyl-11C]derivatives of ICI 89,406 beta1-adrenoceptor selective radioligands suitable for PET?

PubMed

Law, Marilyn P; Wagner, Stefan; Kopka, Klaus; Pike, Victor W; Schober, Otmar; Schäfers, Michael

2008-01-01

Radioligand binding studies show that beta(1)-adrenoceptor (beta(1)-AR) density may be reduced in heart disease without down regulation of beta(2)-ARs. Radioligands are available for measuring total beta-AR density non-invasively with clinical positron emission tomography (PET) but none are selective for beta(1)- or beta(2)-ARs. The aim was to evaluate ICI 89,406, a beta(1)-AR-selective antagonist amenable to labelling with positron emitters, for PET. The S-enantiomer of an [O-methyl-(11)C] derivative of ICI 89,406 ((S)-[(11)C]ICI-OMe) was synthesised. Tissue radioactivity after i.v. injection of (S)-[(11)C]ICI-OMe (< 2 nmol x kg(-1)) into adult Wistar rats was assessed by small animal PET and post mortem dissection. Metabolism was assessed by HPLC of extracts prepared from plasma and tissues and by measuring [(11)C]CO(2) in exhaled air. The heart was visualised by PET after injection of (S)-[(11)C]ICI-OMe but neither unlabelled (S)-ICI-OMe nor propranolol (non-selective beta-AR antagonist) injected 15 min after (S)-[(11)C]ICI-OMe affected myocardial radioactivity. Ex vivo dissection showed that injecting unlabelled (S)-ICI-OMe, propranolol or CGP 20712A (beta(1)-selective AR antagonist) at high dose (> 2 mumol x kg(-1)) before (S)-[(11)C]ICI-OMe had a small effect on myocardial radioactivity. HPLC demonstrated that radioactivity in myocardium was due to unmetabolised (S)-[(11)C]ICI-OMe although (11)C-labelled metabolites rapidly appeared in plasma and liver and [(11)C]CO(2) was detected in exhaled air. Myocardial uptake of (S)-[(11)C]ICI-OMe after i.v. injection was low, possibly due to rapid metabolism in other tissues. Injection of unlabelled ligand or beta-AR antagonists had little effect indicating that binding was mainly to non-specific myocardial sites, thus precluding the use of (S)-[(11)C]ICI-OMe to assess beta(1)-ARs with PET.

Cyclodextrins as excipients in tablet formulations.

PubMed

Conceição, Jaime; Adeoye, Oluwatomide; Cabral-Marques, Helena Maria; Lobo, José Manuel Sousa

2018-04-22

This paper aims to provide a critical review of cyclodextrins as excipients in tablet formulations, highlighting: (i) the principal pharmaceutical applications of cyclodextrins; (ii) the most relevant technological aspects in pharmaceutical formulation development; and (iii) the actual regulatory status of cyclodextrins. Moreover, several illustrative examples are presented. Cyclodextrins can be used as complexing excipients in tablet formulations for low-dose drugs. By contrast, for medium-dose drugs and/or when the complexation efficiency is low, the methods to enhance the complexation efficiency play a key part in reducing the cyclodextrin quantity. In addition, these compounds are used as fillers, disintegrants, binders and multifunctional direct compression excipients of the tablets. Copyright © 2018 Elsevier Ltd. All rights reserved.

Cyclodextrins as new formulation entities and therapeutic agents.

PubMed

Sikharam, Sreevalli; Egan, Talmage D; Kern, Steven E

2005-08-01

This review is focused on recent advances in the application of cyclodextrins to new drug formulations, with emphasis on the field of anesthesia. Cyclodextrins are well-known excipients in the pharmaceutical industry. Their recent application to the anesthetic induction agent propofol as a means of creating a non-lipid formulation may lead to their introduction into anesthesia pharmacology. The development of a novel cyclodextrin as specific reversal agent for the neuromuscular blocker rocuronium (that acts as an in-vivo scavenging system to bind free rocuronium in the circulation) will also increase the likelihood that cyclodextrins will have a greater clinical presence in anesthesiology in the future. Cyclodextrin-containing polymers are also finding a role in the delivery of nucleic acids and protein therapeutic agents. Recent developments in cyclodextrins as excipients for anesthetics may soon culminate in their introduction into anesthesiology, although more research is necessary to better define their potential.

Cyclodextrin Nanoparticles Bearing 8-Hydroxyquinoline Ligands as Multifunctional Biomaterials.

PubMed

Oliveri, Valentina; Bellia, Francesco; Vecchio, Graziella

2017-03-28

Cyclodextrins are used as building blocks for the development of a host of polymeric biomaterials. The cyclodextrin polymers have found numerous applications as they exhibit unique features such as mechanical properties, stimuli responsiveness and drug loading ability. Notwithstanding the abundance of cyclodextrin polymers studied, metal-chelating polymers based on cyclodextrins have been poorly explored. Herein we report the synthesis and the characterization of the first metal-chelating β-cyclodextrin polymer bearing 8-hydroxyquinoline ligands. The metal ions (Cu 2+ or Zn 2+ ) can modulate the assembly of the polymer nanoparticles. Moreover, the protective activity of the new chelating polymer against self- and metal-induced Aβ aggregation and free radical species are significantly higher than those of the parent compounds. These synergistic effects suggest that the incorporation of hydroxyquinoline moieties into a soluble β-cyclodextrin polymer could represent a promising strategy to design multifunctional biomaterials. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Sensitizing of pyrene fluorescence by β-cyclodextrin-modified TiO2 nanoparticles.

PubMed

Shown, Indrajit; Ujihara, Masaki; Imae, Toyoko

2010-12-15

TiO(2) nanoparticles were synthesized by hydrolysis of tetraisopropyl orthotitanate in an aqueous solution of cyclodextrin. The β-cyclodextrin-modified spherical TiO(2) nanoparticles were water-dispersible and had an average particle diameter of 4.4 ± 1 nm. Pyrene fluorescence was enhanced by increasing the concentration of β-cyclodextrin-modified TiO(2) nanoparticle and the sensitization effect was triply stronger than the case of the β-cyclodextrin only. The increase in a concentration of host (β-cyclodextrin) changes its microenvironment for guest (pyrene), that is, the interaction of pyrene with apolar cavity of β-cyclodextrin increases, resulting in enhancement of fluorescence. The sensitization behavior of pyrene fluorescence in the presence of TiO(2) nanoparticles occurs from the increase in the extinction coefficient of pyrene, demonstrating the charge transfer between pyrene and metal oxide nanoparticle. Crown Copyright © 2010. Published by Elsevier Inc. All rights reserved.

A STUDY OF THE EFFECT OF SUBSTITUENTS AND OF SOLVENT ON THE REACTIVITY OF THE NORMAL AND ABNORMAL POSITIONS OF UNSYMMETRICAL ORGANIC EPOXIDES

DTIC Science & Technology

determined by a kinetic study of the reactions of m-chloro- and 3,4-dimethylbenzylamine with styrene oxide in ethanol at 3 temperatures. The results...and o-methyl-styrene oxide with benzylamine in ethanol showed that the beta-methyl group reduces the rate of attack at both positions very...considerably, while the alpha-methyl group reduces the rate of normal attack slightly and that of abnormal attack considerably, and the o-methyl group has surprisingly little effect of the rate of attack at either position. (Author)

The Role of Placental 11-Beta Hydroxysteroid Dehydrogenase Type 1 and Type 2 Methylation on Gene Expression and Infant Birth Weight.

PubMed

Green, Benjamin B; Armstrong, David A; Lesseur, Corina; Paquette, Alison G; Guerin, Dylan J; Kwan, Lauren E; Marsit, Carmen J

2015-06-01

Maternal stress has been linked to infant birth weight outcomes, which itself may be associated with health later in life. The placenta acts as a master regulator for the fetal environment, mediating intrauterine exposures to stress through the activity of genes regulating glucocorticoids, including the 11beta-hydroxysteroid dehydrogenase (HSD11B) type 1 and 2 genes, and so we hypothesized that variation in these genes will be associated with infant birth weight. We investigated DNA methylation levels at six sites across the two genes, as well as mRNA expression for each, and the relationship to infant birth weight. Logistic regressions correcting for potential confounding factors revealed a significant association between methylation at a single CpG site within HSD11B1 and being born large for gestational age. In addition, our analysis identified correlations between methylation and gene expression, including sex-specific transcriptional regulation of HSD11B2. Our work is one of the first comprehensive views of DNA methylation and expression in the placenta for both HSD11B types 1 and 2, linking epigenetic alterations with the regulation of fetal stress and birth weight outcomes. © 2015 by the Society for the Study of Reproduction, Inc.

Effects of cyclodextrin glycosiltransferase modified starch and cyclodextrins on plasma glucose and lipids metabolism in mice

USDA-ARS?s Scientific Manuscript database

The potential functional and nutritional benefits of granular starch treated with cyclodextrin glycosyltransferase (CGTase) and the released cyclodextrins (CDs) were explored in in vivo studies. The metabolic effects of diets in the C57BL/6J mouse containing native and enzymatically modified corn st...

Amyloid protein-mediated differential DNA methylation status regulates gene expression in Alzheimer's disease model cell line

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sung, Hye Youn; Choi, Eun Nam; Ahn Jo, Sangmee

2011-11-04

Highlights: Black-Right-Pointing-Pointer Genome-wide DNA methylation pattern in Alzheimer's disease model cell line. Black-Right-Pointing-Pointer Integrated analysis of CpG methylation and mRNA expression profiles. Black-Right-Pointing-Pointer Identify three Swedish mutant target genes; CTIF, NXT2 and DDR2 gene. Black-Right-Pointing-Pointer The effect of Swedish mutation on alteration of DNA methylation and gene expression. -- Abstract: The Swedish mutation of amyloid precursor protein (APP-sw) has been reported to dramatically increase beta amyloid production through aberrant cleavage at the beta secretase site, causing early-onset Alzheimer's disease (AD). DNA methylation has been reported to be associated with AD pathogenesis, but the underlying molecular mechanism of APP-sw-mediated epigenetic alterationsmore » in AD pathogenesis remains largely unknown. We analyzed genome-wide interplay between promoter CpG DNA methylation and gene expression in an APP-sw-expressing AD model cell line. To identify genes whose expression was regulated by DNA methylation status, we performed integrated analysis of CpG methylation and mRNA expression profiles, and identified three target genes of the APP-sw mutant; hypomethylated CTIF (CBP80/CBP20-dependent translation initiation factor) and NXT2 (nuclear exporting factor 2), and hypermethylated DDR2 (discoidin domain receptor 2). Treatment with the demethylating agent 5-aza-2 Prime -deoxycytidine restored mRNA expression of these three genes, implying methylation-dependent transcriptional regulation. The profound alteration in the methylation status was detected at the -435, -295, and -271 CpG sites of CTIF, and at the -505 to -341 region in the promoter of DDR2. In the promoter region of NXT2, only one CpG site located at -432 was differentially unmethylated in APP-sw cells. Thus, we demonstrated the effect of the APP-sw mutation on alteration of DNA methylation and subsequent gene expression. This epigenetic regulatory mechanism may contribute to the pathogenesis of AD.« less

The Periplasmic Cyclodextrin Binding Protein CymE from Klebsiella oxytoca and Its Role in Maltodextrin and Cyclodextrin Transport

PubMed Central

Pajatsch, Markus; Gerhart, Maria; Peist, Ralf; Horlacher, Reinhold; Boos, Winfried; Böck, August

1998-01-01

Klebsiella oxytoca M5a1 has the capacity to transport and to metabolize α-, β- and γ-cyclodextrins. Cyclodextrin transport is mediated by the products of the cymE, cymF, cymG, cymD, and cymA genes, which are functionally homologous to the malE, malF, malG, malK, and lamB gene products of Escherichia coli. CymE, which is the periplasmic binding protein, has been overproduced and purified. By substrate-induced fluorescence quenching, the binding of ligands was analyzed. CymE bound α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, with dissociation constants (Kd) of 0.02, 0.14 and 0.30 μM, respectively, and linear maltoheptaose, with a Kd of 70 μM. In transport experiments, α-cyclodextrin was taken up by the cym system of K. oxytoca three to five times less efficiently than maltohexaose by the E. coli maltose system. Besides α-cyclodextrin, maltohexaose was also taken up by the K. oxytoca cym system, but because of the inability of maltodextrins to induce the cym system, growth of E. coli mal mutants on linear maltodextrin was not observed when the cells harbored only the cym uptake system. Strains which gained this capacity by mutation could easily be selected, however. PMID:9573146

A stereochemical examination of the equine metabolism of 17alpha-methyltestosterone.

PubMed

McKinney, Andrew R; Suann, Craig J; Stenhouse, Allen M

2007-01-09

An investigation was conducted into the stereochemistry of the equine urinary metabolites of 17alpha-methyltestosterone observed after oral administration. Standards of the complete range of C3/C5/C16 stereoisomeric 17alpha-methylandrostane-3,17beta-diols, 17alpha-methylandrostane-3,16,17beta-triols and 17alpha-hydroxymethylandrostane-3,17beta-diols were purchased or synthesised, and were used to unequivocally identify the absolute structures of the metabolites. Phase I metabolism was found to involve combinations of Delta(4)-3-ketone reduction with both 5alpha,3beta- and 5beta,3alpha-stereochemistry, hydroxylation at C16 with both 16alpha- and 16beta-stereochemistry and hydroxylation of the 17alpha-methyl substituent. Phase II metabolism involved mainly sulfation with a lesser degree of beta-glucuronidation.

Sources and transport of silicone NVR

NASA Technical Reports Server (NTRS)

Harvey, Gale A.

1992-01-01

The retrieved LDEF had varying amounts of visible contamination films (brown stains) at many locations. FTIR spectra of heavy film deposits at vents and of optical windows from tray E5 indicated methyl silicone and silica in the contaminant films. Two possible sources of the methyl silicone are DC-710 phenyl methyl silicone in the shuttle-bay-liner beta cloth, and the shuttle tile waterproofing silane. It is concluded that much of the silicon and silica contamination came from ground operations and the orbiter.

Anticancer and antioxidant tannins from Pimenta dioica leaves.

PubMed

Marzouk, Mohamed S A; Moharram, Fatma A; Mohamed, Mona A; Gamal-Eldeen, Amira M; Aboutabl, Elsayed A

2007-01-01

Two galloylglucosides, 6-hydroxy-eugenol 4-O-(6'-O-galloyl)-beta-D-4C1-glucopyranoside (4) and 3-(4-hydroxy-3-methoxyphenyl)-propane-1,2-diol-2-O-(2',6'-di-O-galloyl)-beta-D -4C1-glucopyranoside (7), and two C-glycosidic tannins, vascalaginone (10) and grandininol (14), together with fourteen known metabolites, gallic acid (1), methyl gallate (2), nilocitin (3), 1-O-galloyl-4,6-(S)-hexahydroxydiphenoyl-(alpha/beta)-D-glucopyranose (5), 4,6-(S)-hexahydroxydiphenoyl-(alpha/beta)-D-glucopyranose (6), 3,4,6-valoneoyl-(alpha/beta)-D-glucopyranose (8), pedunculagin (9), casuariin (11), castalagin (12), vascalagin (13), casuarinin (15), grandinin (16), methyl-flavogallonate (17) and ellagic acid (18), were identified from the leaves of Pimenta dioica (Merr.) L. (Myrtaceae) on the basis of their chemical and physicochemical analysis (UV, HRESI-MS, 1D and 2D NMR). It was found that 9 is the most cytotoxic compound against solid tumour cancer cells, the most potent scavenger against the artificial radical DPPH and physiological radicals including ROO*, OH*, and O2-*, and strongly inhibited the NO generation and induced the proliferation of T-lymphocytes and macrophages. On the other hand, 3 was the strongest NO inhibitor and 16 the highest stimulator for the proliferation of T-lymphocytes, while 10 was the most active inducer of macrophage proliferation.

Driving forces and the influence of the buffer composition on the complexation reaction between ibuprofen and HPCD.

PubMed

Perlovich, German L; Skar, Merete; Bauer-Brandl, Annette

2003-10-01

Cyclodextrins are often used in order to increase the aqueous solubility of drug substances by complexation. In order to investigate the complexation reaction of ibuprofen and hydroxypropyl-beta-cyclodextrin, titration calorimetry was used as a direct method. The thermodynamic parameters of the complexation process (stability constant, K(11); complexation enthalpy, deltaH(c) degrees ) were obtained in two different buffer systems (citric acid/sodium-phosphate and phosphoric acid) at various pH values. Based on these data the relative contributions of the enthalpic and entropic terms of the Gibbs energy to the complexation process have been analyzed. In both buffers the enthalpic and entropic terms are of different sign and this case corresponds to a 'nonclassical' model of hydrophobic interaction. In citric buffer, the main driving force of complexation is the entropy, which increases from 60 to 67% while the pH of the solution increases from 3.2 to 8.0. However, for the phosphoric buffer the entropic term decreases from 60 to 45%, while the pH-value of the solution increases from 5.0 to 8.2, and the driving force of the complexation process changes from entropy to enthalpy. The experimental data of the present study are compared to results of other authors and discrepancies discussed in detail.

Enantioselectivity of anteiso-fatty acids in hitherto uninspected sample matrices.

PubMed

Eibler, Dorothee; Seyfried, Carolin; Vetter, Walter

2017-09-01

Anteiso-fatty acids (aFAs) are chiral molecules due to a methyl substituent on the antepenultimate carbon of the otherwise straight acyl chain. 12-Methyltetradecanoic acid (a15:0) and 14-methylhexadecanoic acid (a17:0) are the predominant aFAs in nature but their individual contributions e.g. to food lipids are usually low. Enantioselective data has been collected in fish, bovine milk/cheese, and Brussels sprouts. In this study, we determined the enantioselectivity of a15:0 and a17:0 in shea butter, moose and camel milk, two soil samples and mold (collected from contaminated cheese). For this purpose, sample lipids were extracted and containing fatty acids were converted into methyl esters. Methyl esters of aFAs were selectively enriched by hydrogenation, urea complexation and/or RP-HPLC-fractionation. Enantioselective gas chromatography with mass spectrometry operated in the selected ion monitoring mode using a chiral stationary phase consisting of 66% tert.-butyldimethylsilylated β-cyclodextrin in OV-1701. While a15:0 and a17:0 in moose milk were (S)-enantiopure, all other determined samples contained up to 10% (R)-aFAs. The highest proportions of (R)-enantiomers were detected in the soil samples (ee=80%). Copyright © 2017 Elsevier B.V. All rights reserved.

Beta-cryptoxanthin reduced lung tumor multiplicity and inhibited lung cancer cell motility by downregulating nicotinic acetylcholine receptor alpha7 signaling

USDA-ARS?s Scientific Manuscript database

Despite the consistent association between a higher intake of the provitamin A carotenoid beta-cryptoxanthin (BCX) and a lower risk of lung cancer among smokers, potential mechanisms supporting BCX as a chemopreventive agent are needed. We first examined the effects of BCX on 4-[methyl nitrosamino]-...

Thermodynamics and binding mode of novel structurally related 1,2,4-thiadiazole derivatives with native and modified cyclodextrins

NASA Astrophysics Data System (ADS)

Terekhova, Irina V.; Chislov, Mikhail V.; Brusnikina, Maria A.; Chibunova, Ekaterina S.; Volkova, Tatyana V.; Zvereva, Irina A.; Proshin, Alexey N.

2017-03-01

Study of complex formation of cyclodextrins with 1,2,4-thiadiazole derivatives intended for Alzheimer's disease treatment was carried out using 1H NMR, ITC and phase solubility methods. Structure of cyclodextrins and thiadiazoles affects the binding mode and thermodynamics of complexation. The larger cavity of β- and γ-cyclodextrins is more appropriate for deeper insertion of 1,2,4-thiadiazole derivatives which is accompanied by intensive dehydration and solvent reorganization. Benzene ring of the thiadiazoles is located inside macrocyclic cavity while piperidine ring is placed outside the cavity and can form H-bonds with cyclodextrin exterior. Complexation with cyclodextrins induces the enhancement of aqueous solubility of 1,2,4-thiadiazole derivatives.

Lanthanide-cyclodextrin complexes as probes for elucidating optical purity by NMR spectroscopy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wenzel, T.J.; Bogyo, M.S.; Lebeau, E.L.

1994-06-01

A multidentate ligand is bonded to cyclodextrins by the reaction of diethylenetriaminepentaacetic dianhydride with 6-mono- and 2-mono(ethylenediamine) derivatives of cyclodextrin. Adding Dy(III) to the cyclodextrin derivatives enhances the enantiomeric resolution in the [sup 1]H NMR spectra of carbionoxamine maleate, doxylamine succinate, pheniramine maleate, propranolol hydrochloride, and tryptophan. The enhancement is more pronounced with the secondary derivative. The Dy(III)-induced shifts can be used to elucidate the geometry of cyclodextrin-substrate inclusion complexes. Lanthanide-induced shifts are reported for complexes of aspartame, tryptophan, propranolol, and 1-anilino-8-naphthalenesulfonate with cyclodextrins, and the relative magnitudes of the shifts agree with previously reported structures of the complexes. 37more » refs., 9 figs., 5 tabs.« less

Cyclodextrin-modified MEKC for enantioseparation of hexaconazole, penconazole, and myclobutanil.

PubMed

Wan Ibrahim, Wan Aini; Hermawan, Dadan; Sanagi, M Marsin; Aboul-Enein, Hassan Y

2009-02-01

A CD-modified micellar EKC (CD-MEKC) method with 2-hydroxypropyl-gamma-CD (HP-gamma-CD) as chiral selector for the enantioseparation of three chiral triazole fungicides, namely hexaconazole, penconazole, and myclobutanil, is reported for the first time. Simultaneous enantioseparation of the three triazole fungicides was successfully achieved using a CD-MEKC system containing 40 mM HP-gamma-CD and 50 mM SDS in 25 mM phosphate buffer (pH 3.0) solution with resolutions (R(s)) greater than 1.60, peak efficiencies (N) greater than 200,000 for all enantiomers and an analysis time within 15 min compared to 36 min as previously reported using sulfated-beta-CD.

Cyclodextrins sequester neuroactive steroids and differentiate mechanisms that rate limit steroid actions

PubMed Central

Shu, H-J; Zeng, C-M; Wang, C; Covey, D F; Zorumski, C F; Mennerick, S

2006-01-01

Background and purpose: Neuroactive steroids are potent modulators of GABAA receptors and are thus of interest for their sedative, anxiolytic, anticonvulsant and anaesthetic properties. Cyclodextrins may be useful tools to manipulate neuroactive effects of steroids on GABAA receptors because cyclodextrins form inclusion complexes with at least some steroids that are active at the GABAA receptor, such as (3α,5α)-3-hydroxypregnan-20-one (3α5αP, allopregnanolone). Experimental approach: To assess the versatility of cyclodextrins as steroid modulators, we investigated interactions between γ-cyclodextrin and neuroactive steroids of different structural classes. Key results: Both a bioassay based on electrophysiological assessment of GABAA receptor function and optical measurements of cellular accumulation of a fluorescent steroid analogue suggest that γ-cyclodextrin sequesters steroids rather than directly influencing GABAA receptor function. Neither a 5β-reduced A/B ring fusion nor a sulphate group at carbon 3 affected the presumed inclusion complex formation between steroid and γ-cyclodextrin. Apparent dissociation constants for interactions between natural steroids and γ-cyclodexrin ranged from 10-60 μM. Although γ-cyclodextrin accommodates a range of natural and synthetic steroids, C11 substitutions reduced inclusion complex formation. Using γ-cyclodextrin to remove steroid not directly bound to GABAA receptors, we found that cellular retention of receptor-unbound steroid rate limits potentiation by 3α- hydroxysteroids but not inhibition by sulphated steroids. Conclusions and implications: We conclude that γ-cyclodextrins can be useful, albeit non-specific, tools for terminating the actions of multiple classes of naturally occurring neuroactive steroids. PMID:17160009

A Tau Class Glutathione-S-Transferase is Involved in Trans-Resveratrol Transport Out of Grapevine Cells

PubMed Central

Martínez-Márquez, Ascensión; Martínez-Esteso, María J.; Vilella-Antón, María T.; Sellés-Marchart, Susana; Morante-Carriel, Jaime A.; Hurtado, Elias; Palazon, Javier; Bru-Martínez, Roque

2017-01-01

Vitis vinifera cell cultures respond to pathogens and elicitors by synthesizing and extracellularly accumulating stilbenoid phytoalexins. Large amounts of trans-resveratrol (t-R) are produced when a cell culture is elicited with methylated cyclodextrins (MBCD), either alone or combined with methyl jasmonate (MeJA). t-R transport to the extracellular medium, which represents the apoplastic space, would place this antifungal defense right in the battlefield to efficiently fight against pathogen attack. Yet despite their physiological relevance, these transport pathways are mostly unknown. A broad hypothesis-free DIGE-based proteomic experiment of a temporal series of elicited grapevine cell cultures was performed to explore the expression profiles of t-R biosynthetic proteins and other co-expressing proteins potentially involved in such a cell response. A correlation between two tau class glutathione-S-transferases (GSTs) with several stilbene synthase and phenylalanine ammonia-lyase isoforms, and with the t-R metabolite itself, was found and further assessed by a qRT-PCR gene expression analysis. The best candidate, GSTU-2, was cloned from the cDNA of the MBCD + MeJA-elicited grapevine cells and used for Agrobacterium-mediated grapevine cell transformation. The non-elicited lines that overexpressed GSTU-2 displayed an extracellular t-R accumulating phenotype, but stabilization of t-R required the addition to culture medium of adsorbent compounds, e.g., PVP or β-cyclodextrin. The wild-type cell cultures accumulated no t-R, not even in the presence of adsorbents. The transient expression of the GSTU-2-GFP fusion proteins in grapevine cells showed localisation in the plasma membrane, and the immunoprecipitation of HA-tagged GSTU-2 revealed its interaction with HIR, a plasma membrane-bound protein. These findings are consistent with a functional role in transport. This is the first report providing several pieces of experimental evidence for the involvement of a specific tau class GST in t-R transport to the extracellular medium. PMID:28878794

Optimization of methyl jasmonate and β-cyclodextrin for enhanced production of taraxerol and taraxasterol in (Taraxacum officinale Weber) cultures.

PubMed

Sharma, Kiran; Zafar, Rasheeduz

2016-06-01

Taraxacum officinale Weber (TO) commonly known as "dandelion", is a tropical Asian medicinal plant which contains taraxasterol (TX) and taraxerol (TA) in its roots, which are reported to be commercially important anticancer compounds. The main objective of the present study was to evaluate the increase in yield of TX and TA through elicitation by addition of abiotic elictors like methyl jasmonate (MJ) and β-cyclodextrin (CD), to the root callus suspension cultures of TO. The root callus suspension was maintained on Murashige and Skoog's (MS) medium MS + IAA + BA + 2, 4-D (0.5 ppm + 1 ppm + 0.5 ppm). The concentrations of the abiotic elicitors MJ and CD were optimized using central composite design (CCD) and quantification of TA and TX in elicited cultures was done by High Performance Liquid Chromatography (HPLC) analysis. It was observed that MJ at a concentration of 0.2 mM showed good increase in content of TX to 0.032% w/w and at concentrations 0.05 mM, 0.1 mM and 0.2 mM showed similar increase in TA content to 0.018% w/w, whereas CD at the concentration of 25 mM showed highest increase in TX content to 0.036% w/w and at the concentrations of 25 mM, 50 mM showed increase in TA content to 0.023% w/w as compared to the plant root (PR) which showed content of TX as 0.0299% w/w and TA as 0.0169% w/w. From the present investigation it was concluded that out of the two abiotic elicitors MJ and CD, CD was found to be more effective to increase TA and TX content in Dandelion cell cultures. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Sol-Gel Synthesis of Ordered β-Cyclodextrin-Containing Silicas

NASA Astrophysics Data System (ADS)

Trofymchuk, Iryna Mykolaivna; Roik, Nadiia; Belyakova, Lyudmila

2016-03-01

New approaches for β-cyclodextrin-containing silicas synthesis were demonstrated. Materials with hexagonally ordered mesoporous structure were prepared by postsynthesis grafting and by co-condensation methods. β-Cyclodextrin activated by a N, N'-carbonyldiimidazole was employed for postsynthesis treatment of 3-aminopropyl-modified MCM-41 support as well as for sol-gel synthesis with β-cyclodextrin-containing organosilane and tetraethyl orthosilicate participation in the presence of cetyltrimethylammonium bromide. The successful incorporation of cyclic oligosaccharide moieties in silica surface layer was verified by means of FT-IR spectroscopy and chemical analysis. Obtained β-cyclodextrin-containing materials were characterized by X-ray diffraction, transmission electron microscopy, and low-temperature adsorption-desorption of nitrogen. In spite of commensurable loading of β-cyclodextrin groups attained by both proposed approaches (up to 0.028 μmol · m-2), it was found that co-condensation procedure provides uniform distribution of β-cyclodextrin functionalities in silica framework, whereas postsynthesis grafting results in modification of external surface of silica surface. Adsorption of benzene from aqueous solutions onto the surface of β-cyclodextrin-containing materials prepared by co-condensation method was studied as the function of time and equilibrium concentration. Langmuir and Freundlich models were used to evaluate adsorption processes and parameters. Adsorption experiments showed that β-cyclodextrin-containing silicas could be promising for the trace amount removal of aromatics from water.

Regioselective self-acylating cyclodextrins in organic solvent

NASA Astrophysics Data System (ADS)

Cho, Eunae; Yun, Deokgyu; Jeong, Daham; Im, Jieun; Kim, Hyunki; Dindulkar, Someshwar D.; Choi, Youngjin; Jung, Seunho

2016-03-01

Amphiphilic cyclodextrins have been synthesized with self-acylating reaction using vinyl esters in dimethylformamide. In the present study no base, catalyst, or enzyme was used, and the structural analyses using thin layer chromatography, nuclear magnetic resonance spectroscopy and mass spectrometry show that the cyclodextrin is substituted preferentially by one acyl moiety at the C2 position of the glucose unit, suggesting that cyclodextrin functions as a regioselective catalytic carbohydrate in organic solvent. In the self-acylation, the most acidic OH group at the 2-position and the inclusion complexing ability of cyclodextrin were considered to be significant. The substrate preference was also observed in favor of the long-chain acyl group, which could be attributed to the inclusion ability of cyclodextrin cavity. Furthermore, using the model amphiphilic building block, 2-O-mono-lauryl β-cyclodextrin, the self-organized supramolecular architecture with nano-vesicular morphology in water was investigated by fluorescence spectroscopy, dynamic light scattering and transmission electron microscopy. The cavity-type nano-assembled vesicle and the novel synthetic methods for the preparation of mono-acylated cyclodextrin should be of great interest with regard to drug/gene delivery systems, functional surfactants, and carbohydrate derivatization methods.

Synthesis and Utilization of Trialkylammonium-Substituted Cyclodextrins as Water-Soluble Chiral NMR Solvating Agents for Anionic Compounds.

PubMed

Dowey, Alison E; Puentes, Cira Mollings; Carey-Hatch, Mira; Sandridge, Keyana L; Krishna, Nikhil B; Wenzel, Thomas J

2016-04-01

Cationic trialkylammonium-substituted α-, β-, and γ-cyclodextrins containing trimethyl-, triethyl-, and tri-n-propylammonium substituent groups were synthesized and analyzed for utility as water-soluble chiral nuclear magnetic resonance (NMR) solvating agents. Racemic and enantiomerically pure (3-chloro-2-hydroxypropyl)trimethyl-, triethyl-, and tri-n-propyl ammonium chloride were synthesized from the corresponding trialkyl amine hydrochloride and either racemic or enantiomerically pure epichlorohydrin. The ammonium salts were then reacted with α-, β-, and γ-cyclodextrins at basic pH to provide the corresponding randomly substituted cationic cyclodextrins. The (1) H NMR spectra of a range of anionic, aromatic compounds was recorded with the cationic cyclodextrins. Cyclodextrins with a single stereochemistry at the hydroxy group on the (2-hydroxypropyl)trialkylammonium chloride substituent were often but not always more effective than the corresponding cyclodextrin in which the C-2 position was racemic. In several cases, the larger triethyl or tri-n-propyl derivatives were more effective than the corresponding trimethyl derivative at causing enantiomeric differentiation. None of the cyclodextrin derivatives were consistently the most effective for all of the anionic compounds studied. © 2016 Wiley Periodicals, Inc.

Promising applications in drug delivery systems of a novel β-cyclodextrin derivative obtained by green synthesis.

PubMed

García, Agustina; Leonardi, Darío; Lamas, María C

2016-01-15

An efficient and green method has been developed for the synthesis of succinyl-β-cyclodextrin in aqueous media obtaining very good yield. Acidic groups have been introduced in the synthesized carrier molecule to improve the guest-host affinity. To evaluate the suitability of the novel excipient focused to develop oral dosage forms, albendazole, a BSC class II compound, was chosen as a model drug. The β-cyclodextrin derivative and the inclusion complex were thoroughly characterized in solution and solid state by phase solubility studies, FT-IR spectroscopy, SEM, XRD, ESI-MS, DSC, 1D (1)H NMR, 1D (13)C NMR, selective 1D TOCSY, 2D COSY, 2D HSQC, 2D HMBC and ROESY NMR spectroscopy. Phase solubility studies indicated that both of them β-cyclodextrin and succinyl-β-cyclodextrin formed 1:1 inclusion complexes with albendazole, and the stability constants were 68M(-1) (β-cyclodextrin), 437M(-1) (succinyl-β-cyclodextrin), respectively. Water solubility and dissolution rate of albendazole were significantly improved in complex forms. Thus, the succinyl-β-cyclodextrin derivative could be a promising excipient to design oral dosage forms. Copyright © 2015 Elsevier Ltd. All rights reserved.

Evaluation of the potential toxicity of unmodified and modified cyclodextrins on murine blood-brain barrier endothelial cells.

PubMed

Shityakov, Sergey; Salmas, Ramin Ekhteiari; Salvador, Ellaine; Roewer, Norbert; Broscheit, Jens; Förster, Carola

2016-04-01

In this study, we investigated the cytotoxic effects of unmodified α-cyclodextrin (α-CD) and modified cyclodextrins, including trimethyl-β-cyclodextrin (TRIMEB) and hydroxypropyl-β-cyclodextrin (HPβCD), on immortalized murine microvascular endothelial (cEND) cells of the blood-brain barrier (BBB). A CellTiter-Glo viability test, performed on the cEND cells showed significant differences among the different cyclodextrins. After 24 hr of incubation, TRIMEB was the most cytotoxic, and HPβCD was non-toxic. α-CD and TRIMEB exhibited greater cytotoxicity in the Dulbecco's modified Eagle's medium than in heat-inactivated human serum indicating protective properties of the human serum. The predicted dynamic toxicity profiles (Td) for α-CD and TRIMEB indicated higher cytotoxicity for these cyclodextrins compared to the reference compound (dimethylsulfoxide). Molecular dynamics simulation of cholesterol binding to the CDs suggested that not just cholesterol but phospholipids extraction might be involved in the cytotoxicity. Overall, the results demonstrate that HPβCD has the potential to be used as a candidate for drug delivery vector development and signify a correlation between the in vitro cytotoxic effect and cholesterol binding of cyclodextrins.

In vitro investigations of α-amylase mediated hydrolysis of cyclodextrins in the presence of ibuprofen, flurbiprofen, or benzo[a]pyrene.

PubMed

Lumholdt, Ludmilla Riisager; Holm, René; Jørgensen, Erling Bonne; Larsen, Kim Lambertsen

2012-11-15

In vitro studies of α-amylase degradation of α-, β- and γ-cyclodextrins and 2-hydroxypropyl-β- and -γ-cyclodextrins were investigated spectrophotometrically by measuring the formation of reducing sugars, the reaction products of α-amylase degradation. This was done to evaluate potential degradation and thereby biological conversion of the cyclodextrins if dosed orally, as the intestinal tract contains α-amylase for digestive purposes. The results demonstrated that only γ- and 2-hydroxypropyl-γ-cyclodextrins can be degraded by α-amylase to a relevant extent, that is, γ- and 2-hydroxypropyl-γ-cyclodextrins have different biopharmaceutical behaviours than the other evaluated cyclodextrins. The rate of degradation was affected by the addition of the inclusion complex forming additives flurbiprofen, ibuprofen and benzo[a]pyrene. This effect between the degradation dynamics and the included additives was caused by a correlation between solubility of the additives and the stability of the complex. Copyright © 2012 Elsevier Ltd. All rights reserved.

Host-guest chemistry of cyclodextrin carbamates and cellulose derivatives in aqueous solution.

PubMed

Guo, Xin; Jia, Xiangxiang; Du, Jiaojiao; Xiao, Longqiang; Li, Feifei; Liao, Liqiong; Liu, Lijian

2013-10-15

Supramolecular polymer micelles were prepared on basis of the inclusion complexation between cyclodextrin carbamates and cellulose derivatives in aqueous media. Cyclodextrin carbamates were synthesized by microwave-assisted method from cyclodextrin and urea. The urea modified cyclodextrin shows the higher yield than the physical mixture of urea/cyclodextrin in the micellization with cellulose derivatives. The supramolecular structure of the core-shell micelles was demonstrated by (1)H NMR spectra, TEM images, and fluorescence spectra. The drug release behavior of the supramolecular polymer micelles was evaluated using prednisone acetate as a model drug. The drug loaded micelles showed steady and long time drug release behavior. With these properties, the supramolecular polymer micelles are attractive as drug carriers for pharmaceutical applications. Copyright © 2013 Elsevier Ltd. All rights reserved.

alpha-Amino-3-hydroxy-5-methyl-4-isoxazole propionate attenuates glutamate-induced caspase-3 cleavage via regulation of glycogen synthase kinase 3beta.

PubMed

Nishimoto, Takaaki; Kihara, Takeshi; Akaike, Akinori; Niidome, Tetsuhiro; Sugimoto, Hachiro

2008-04-01

Preconditioning of sublethal ischemia exhibits neuroprotection against subsequent ischemia-induced neuronal death. It has been indicated that glutamate, an excitatory amino acid, is involved in the pathogenesis of ischemia-induced neuronal death or neurodegeneration. To elucidate whether prestimulation of glutamate receptor could counter ischemia-induced neuronal death or neurodegeneration, we examined the effect of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), an ionotropic subtype of glutamate receptor, on excess glutamate-induced excitotoxicity using primary cortical neuronal cultures. We found that AMPA exerted a neuroprotective effect in a time- and concentration-dependent manner. A blocker of phosphatidylinositol-3 kinase (PI3K), LY294002 (10 microM), significantly attenuated AMPA-induced protection. In addition, Ser473 of Akt/PKB, a downstream target of PI3K, was phosphorylated by AMPA administration (10 microM). Glycogen synthase kinase 3beta (GSK3beta), which has been reported to be inactivated by Akt, was phosphorylated at Ser9 by AMPA. Ser9-phosphorylated GSK3beta or inactivated form would be a key molecule for neuroprotection, insofar as lithium chloride (100 microM) and SB216763 (10 microM), inhibitors of GSK3beta, also induced phosphorylation of GSK3beta at Ser9 and exerted neuroprotection, respectively. Glutamate (100 microM) increased cleaved caspase-3, an apoptosis-related cysteine protease, and caspase-3 inhibitor (Ac-DEVD-CHO; 1 microM) blocked glutamate-induced excitotoxicity in our culture. AMPA (10 microM, 24 hr) and SB216763 (10 microM) prominently decreased glutamate-induced caspase-3 cleavage. These findings suggest that AMPA activates PI3K-Akt and subsequently inhibits GSK3beta and that inactivated GSK3beta attenuates glutamate-induced caspase-3 cleavage and neurotoxicity.

Involvement of the glucose moiety in the molecular recognition of methyl beta-lactoside by ricin: synthesis, conformational analysis, and binding studies of different derivatives at the C-3 region.

PubMed

Fernández, P; Jiménez-Barbero, J; Martín-Lomas, M; Solís, D; Díaz-Mauriño, T

1994-04-01

Syntheses of the 3-aminodeoxy (4), 3-deoxy-3-methyl (5), and 3-epi (6) derivatives of methyl beta-lactoside (1) have been achieved from 1 in a straightforward way, and their solution conformations in water and dimethyl sulfoxide analysed through molecular mechanics and dynamics calculations and nuclear magnetic resonance data. The overall shape of all the compounds studied is fairly similar and may be described by conformers included in a low energy region with phi = 15 +/- 45 degrees and psi = -25 +/- 30 degrees, that is ca. 5% of the total potential energy surface for the glycosidic linkages of the disaccharides. The binding of the different compounds to ricin, the galactose-specific toxin from Ricinus communis, has been investigated. The results confirm the involvement of the C-3 region in a nonpolar interaction with the protein at the periphery of the combining site.

Conformational free energies of methyl-alpha-L-iduronic and methyl-beta-D-glucuronic acids in water.

PubMed

Babin, Volodymyr; Sagui, Celeste

2010-03-14

We present a simulation protocol that allows for efficient sampling of the degrees of freedom of a solute in explicit solvent. The protocol involves using a nonequilibrium umbrella sampling method, in this case, the recently developed adaptively biased molecular dynamics method, to compute an approximate free energy for the slow modes of the solute in explicit solvent. This approximate free energy is then used to set up a Hamiltonian replica exchange scheme that samples both from biased and unbiased distributions. The final accurate free energy is recovered via the weighted histogram analysis technique applied to all the replicas, and equilibrium properties of the solute are computed from the unbiased trajectory. We illustrate the approach by applying it to the study of the puckering landscapes of the methyl glycosides of alpha-L-iduronic acid and its C5 epimer beta-D-glucuronic acid in water. Big savings in computational resources are gained in comparison to the standard parallel tempering method.

The interaction of caffeine with substituted cyclodextrins in water

NASA Astrophysics Data System (ADS)

Terekhova, I. V.; Kumeev, R. S.; Al'Per, G. A.

2007-07-01

The interaction of caffeine with hydroxypropyl-and methylcyclodextrins in water was studied by the calorimetry, spectroscopy, and solubility methods at 298.15 K. The interaction of caffeine with these cyclodextrins did not result in the formation of stable inclusion complexes and was mostly accompanied by predominantly endothermic effects of particle dehydration. The introduction of substituents and changes in the size of cyclodextrin molecular cavity did not influence the ability of cyclodextrins to form complexes with caffeine. The conclusion was drawn that substituted cyclodextrins could not be used for increasing the solubility of caffeine in water.

Adsorption of environmental pollutants using magnetic hybrid nanoparticles modified with β-cyclodextrin

NASA Astrophysics Data System (ADS)

Wang, Niejun; Zhou, Lilin; Guo, Jun; Ye, Qiquan; Lin, Jin-Ming; Yuan, Jinying

2014-06-01

Graft through strategy was utilized to coat magnetic Fe3O4 nanoparticles with poly(glycidyl methacrylate) using ordinary radical polymerization and then β-cyclodextrin was linked onto the surface of nanoparticles. With these nanoparticles modified with cyclodextrin groups, adsorption of two model environmental pollutants, bisphenol A and copper ions, was studied. Host-guest interactions between cyclodextrin and aromatic molecules had a great contribution to the adsorption of bisphenol A, while multiple hydroxyls of cyclodextrin also helped the adsorption of copper ions. These magnetic nanoparticles could be applied in the elimination, enrichment and detection of some environmental pollutants.

Efficacy and Safety Profile of Diclofenac/Cyclodextrin and Progesterone/Cyclodextrin Formulations: A Review of the Literature Data.

PubMed

Scavone, Cristina; Bonagura, Angela Colomba; Fiorentino, Sonia; Cimmaruta, Daniela; Cenami, Rosina; Torella, Marco; Fossati, Tiziano; Rossi, Francesco

2016-06-01

According to health technology assessment, patients deserve the best medicine. The development of drugs associated with solubility enhancers, such as cyclodextrins, represents a measure taken in order to improve the management of patients. Different drugs, such as estradiol, testosterone, dexamethasone, opioids, non-steroidal anti-inflammatories (NSAIDs; i.e. diclofenac), and progesterone are associated with cyclodextrins. Products containing the association of diclofenac/cyclodextrins are available for subcutaneous, intramuscular, and intravenous administration in doses that range from 25 to 75 mg. Medicinal products containing the association of progesterone/cyclodextrins are indicated for intramuscular and subcutaneous injection at a dose equal to 25 mg. The effects of cyclodextrins have been discussed in the solubility profile and permeability through biological membranes of drug molecules. A literature search was performed in order to give an overview of the pharmacokinetic characteristics, and efficacy and safety profiles of diclofenac/hydroxypropyl-β-cyclodextrin (HPβCD) and progesterone/HPβCD associations. The results of more than 20 clinical studies were reviewed. It was suggested that the new diclofenac/HPβCD formulation gives a rapid and effective response to acute pain and, furthermore, has pharmacokinetic and efficacy/safety profiles comparable to other medicinal products not containing cyclodextrins. One of the principal aspects of these new diclofenac formulations is that in lowering the dose (lower than 50 mg) the drugs could be more tolerable, especially in patients with comorbid conditions. Moreover, results of studies investigating the characteristics of progesterone and cyclodextrins showed that the new formulation (progesterone/HPβCD 25 mg solution) has the same bioavailability as other products containing progesterone. It is more rapidly absorbed and allows the achievement of peak plasma concentrations in a shorter time. Finally, the new formulation of progesterone was shown to be safe and not inferior to other products already on the market, with the exception of progesterone administered vaginally. As shown by the results of clinical studies presented in this review, the newly approved medicines containing cyclodextrins have been found to be as effective and as well-tolerated as other medicinal products that do not contain cyclodextrins. Moreover, the newly approved lower dose of diclofenac associated with cyclodextrins is consistent with the European Medicines Agency recommendations reported in the revision of the Assessment Report for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Cardiovascular Risk. Finally, the use of cyclodextrins led to significant increases in solubility and bioavailability of drugs, such as diclofenac and progesterone, and improvement in the efficacy and safety of these drugs.

Stereocontrolled reduction of alpha- and beta-keto esters with micro green algae, Chlorella strains.

PubMed

Ishihara, K; Yamaguchi, H; Adachi, N; Hamada, H; Nakajima, N

2000-10-01

The stereocontrolled reduction of alpha- and beta-keto esters using micro green algae was accomplished by a combination of the cultivation method and the introduction of an additive. The reduction of ethyl pyruvate and ethyl benzoylformate by the photoautotrophically cultivated Chlorella sorokiniana gave the corresponding alcohol in high e.e. (>99% e.e. (S) and >99% e.e. (R), respectively). In the presence of glucose as an additive, the reduction of ethyl 3-methyl-2-oxobutanoate by the heterotrophically cultivated C. sorokiniana afforded the corresponding (R)-alcohol. On the other hand, the reduction in the presence of ethyl propionate gave the (S)-alcohol. Ethyl 2-methyl-3-oxobutanoate was reduced in the presence of glycerol by the photoautotrophically cultivated C. sorokiniana or the heterotrophically cultivated C. sorokiniana to the corresponding syn-(2R,3S)-hydroxy ester with high diastereo- and enantiomeric excess (e.e.). Some additives altered the stereochemical course in the reduction of alpha- and beta-keto esters.

A silica monolithic column prepared by the sol-gel process for enantiomeric separation by capillary electrochromatography.

PubMed

Kang, Jingwu; Wistuba, Dorothee; Schurig, Volker

2002-04-01

A method for the preparation of a silica monolithic capillary electrochromatography (CEC) column for the separation of enantiomers has been developed. The porous silica monolith was fabricated inside a fused-silica capillary column by using the sol-gel process. After gelation for 24 h, hydrothermal treatment at 100 degrees C for 24 h was performed to prevent the sol-gel matrix from cracking. The prepared monolith was then coated with Chirasil-beta-Dex which represents a chiral polymer prepared by grafting permethyl-beta-cyclodextrin to polymethylsiloxane with an octamethylene spacer. Immobilization of Chirasil-beta-Dex was performed by heat treatment at 120 degrees C for 48 h to give a nonextractable coating. The column performance was evaluated by using racemic hexobarbital as a model compound. The efficiency of 9.2 x 10(4) theoretical plates/m for the first eluted enantiomer of hexobarbital was obtained at an optimal flow rate of the mobile phase. The effect of mobile phase composition on enantiomeric separation of hexobarbital was also investigated. The column proved to be stable for more than one hundreds of runs during a two-months period. The enantiomers of several neutral and negatively charged chiral compounds were baseline separated on this column.

H NMR studies of substrate hydrogen exchange reactions catalyzed by L-methionine gamma-lyase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Esaki, N.; Nakayama, T.; Sawada, S.

Hydrogen exchange reactions of various L-amino acids catalyzed by L-methionine gamma-lyase (EC 4.4.1.11) have been studied. The enzyme catalyzes the rapid exchange of the alpha- and beta-hydrogens of L-methionine and S-methyl-L-cysteine with deuterium from the solvent. The rate of alpha-hydrogen exchange was about 40 times faster than that of the enzymatic elimination reaction of the sulfur-containing amino acids. The enzyme also catalyzes the exchange reaction of alpha- and beta-hydrogens of the straight-chain L-amino acids which are not susceptible to elimination. The exchange rates of the alpha-hydrogen and the total beta-hydrogens of L-alanine and L-alpha-aminobutyrate with deuterium followed first-order kinetics. Formore » L-norvaline, L-norleucine, S-methyl-L-cysteine, and L-methionine, the rate of alpha-hydrogen exchange followed first-order kinetics, but the rate of total beta-hydrogen exchange decreased due to a primary isotope effect at the alpha-position. L-Phenylalanine and L-tryptophan slowly underwent alpha-hydrogen exchange. The pro-R hydrogen of glycine was deuterated stereospecifically.« less

Functional characterization of the beta-adrenergic receptor subtypes expressed by CA1 pyramidal cells in the rat hippocampus.

PubMed

Hillman, Kristin L; Doze, Van A; Porter, James E

2005-08-01

Recent studies have demonstrated that activation of the beta-adrenergic receptor (AR) using the selective beta-AR agonist isoproterenol (ISO) facilitates pyramidal cell long-term potentiation in the cornu ammonis 1 (CA1) region of the rat hippocampus. We have previously analyzed beta-AR genomic expression patterns of 17 CA1 pyramidal cells using single cell reverse transcription-polymerase chain reaction, demonstrating that all samples expressed the beta2-AR transcript, with four of the 17 cells additionally expressing mRNA for the beta1-AR subtype. However, it has not been determined which beta-AR subtypes are functionally expressed in CA1 for these same pyramidal neurons. Using cell-attached recordings, we tested the ability of ISO to increase pyramidal cell action potential (AP) frequency in the presence of subtype-selective beta-AR antagonists. ICI-118,551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol] and butoxamine [alpha-[1-(t-butylamino)ethyl]-2,5-dimethoxybenzyl alcohol) hydrochloride], agents that selectively block the beta2-AR, produced significant parallel rightward shifts in the concentration-response curves for ISO. From these curves, apparent equilibrium dissociation constant (K(b)) values of 0.3 nM for ICI-118,551 and 355 nM for butoxamine were calculated using Schild regression analysis. Conversely, effective concentrations of the selective beta1-AR antagonists CGP 20712A [(+/-)-2-hydroxy-5-[2-([2-hydroxy-3-(4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]phenoxy)propyl]amino)ethoxy]-benzamide methanesulfonate] and atenolol [4-[2'-hydroxy-3'-(isopropyl-amino)propoxy]phenylacetamide] did not significantly affect the pyramidal cell response to ISO. However, at higher concentrations, atenolol significantly decreased the potency for ISO-mediated AP frequencies. From these curves, an apparent atenolol K(b) value of 3162 nM was calculated. This pharmacological profile for subtype-selective beta-AR antagonists indicates that beta2-AR activation is mediating the increased AP frequency. Knowledge of functional AR expression in CA1 pyramidal neurons will aid future long-term potentiation studies by allowing selective manipulation of specific beta-AR subtypes.

X-ray investigations of sulfur-containing fungicides. IV. 4'-[[Benzoyl(4-chlorophenylhydrazono)methyl]sulfonyl]acetanilide and 4'-[[benzoyl(4-methoxyphenylhydrazono)methyl]sulfonyl]acetanilide.

PubMed

Wolf, W M

2001-09-01

The conformations of the two approximately isomorphous structures 4'-[[benzoyl(4-chlorophenylhydrazono)methyl]sulfonyl]acetanilide, C(22)H(18)ClN(3)O(4)S, and 4'-[[benzoyl(4-methoxyphenylhydrazono)methyl]sulfonyl]acetanilide, C(23)H(21)N(3)O(5)S, are stabilized by resonance-assisted intramolecular hydrogen bonds linking the hydrazone moieties and sulfonyl groups. The stronger bond is observed in the former compound. The difference in electronic properties between the Cl atom and the methoxy group is too small to significantly alter the non-bonding interactions of the sulfonyl and beta-carbonyl groups.

Cytotoxic principles from the formosan milkweed, Asclepias curassavica.

PubMed

Roy, Michael C; Chang, Fang-Rong; Huang, Hsiao-Chu; Chiang, Michael Y-N; Wu, Yang-Chang

2005-10-01

A series of cardenolides and related compounds have been isolated from the aerial parts and roots of the ornamental milkweed, Asclepias curassavica. Their structures were determined by spectroscopic and chemical methods. Among them, three derivatives of calactinic acid methyl ester (13-15), 19-nor-16 alpha-acetoxy-10 beta-hydroxyasclepin (16), 20 beta,21-dihydroxypregna-4,6-dien-3-one (19), and 3,4-seco-urs-20(30)-en-3-oic acid (22) are new compounds. The relative configuration of calactinic acid methyl ester (12) has been confirmed by X-ray diffraction analysis on its derivative 13. Most of the cardenolides obtained showed pronounced cytotoxicity against four cancer cell lines (IC(50) 0.01 to 2.0 microg/mL).

Cyclodextrins in eye drop formulations: enhanced topical delivery of corticosteroids to the eye.

PubMed

Loftsson, Thorsteinn; Stefánsson, Einar

2002-04-01

Cyclodextrins are cylindrical oligosaccharides with a lipophilic central cavity and hydrophilic outer surface. They can form water-soluble complexes with lipophilic drugs, which 'hide' in the cavity. Cyclodextrins can be used to form aqueous eye drop solutions with lipophilic drugs, such as steroids and some carbonic anhydrase inhibitors. The cyclodextrins increase the water solubility of the drug, enhance drug absorption into the eye, improve aqueous stability and reduce local irritation. Cyclodextrins are useful excipients in eye drop formulations of various drugs, including steroids of any kind, carbonic anhydrase inhibitors, pilocarpine, cyclosporins, etc. Their use in ophthalmology has already begun and is likely to expand the selection of drugs available as eye drops. In this paper we review the properties of cyclodextrins and their application in eye drop formulations, of which their use in the formulation of dexamethasone eye drops is an example. Cyclodextrins have been used to formulate eye drops containing corticosteroids, such as dexamethasone, with levels of concentration and ocular absorption which, according to human and animal studies, are many times those seen with presently available formulations. Cyclodextrin-based dexamethasone eye drops are well tolerated in the eye and seem to provide a higher degree of bioavailability and clinical efficiency than the steroid eye drop formulations presently available. Such formulations offer the possibility of once per day application of corticosteroid eye drops after eye surgery, and more intensive topical steroid treatment in severe inflammation. While cyclodextrins have been known for more than a century, their use in ophthalmology is just starting. Cyclodextrins are useful excipients in eye drop formulations for a variety of lipophilic drugs. They will facilitate eye drop formulations for drugs that otherwise might not be available for topical use, while improving absorption and stability and decreasing local irritation.

Redox signaling via lipid raft clustering in homocysteine-induced injury of podocytes.

PubMed

Zhang, Chun; Hu, Jun-Jun; Xia, Min; Boini, Krishna M; Brimson, Christopher; Li, Pin-Lan

2010-04-01

Our recent studies have indicated that hyperhomocysteinemia (hHcys) may induce podocyte damage, resulting in glomerulosclerosis. However, the molecular mechanisms mediating hHcys-induced podocyte injury are still poorly understood. In the present study, we first demonstrated that an intact NADPH oxidase system is present in podocytes as shown by detection of its membrane subunit (gp91(phox)) and cytosolic subunit (p47(phox)). Then, confocal microscopy showed that gp91(phox) and p47(phox) could be aggregated in lipid raft (LR) clusters in podocytes treated with homocysteine (Hcys), which were illustrated by their colocalization with cholera toxin B, a common LR marker. Different mechanistic LR disruptors, either methyl-beta-cyclodextrin (MCD) or filipin abolished such Hcys-induced formation of LR-gp91(phox) or LR-p47(phox) transmembrane signaling complexes. By flotation of detergent-resistant membrane fractions we found that gp91(phox) and p47(phox) were enriched in LR fractions upon Hcys stimulation, and such enrichment of NADPH oxidase subunits and increase in its enzyme activity were blocked by MCD or filipin. Functionally, disruption of LR clustering significantly attenuated Hcys-induced podocyte injury, as shown by their inhibitory effects on Hcys-decreased expression of slit diaphragm molecules such as nephrin and podocin. Similarly, Hcys-increased expression of desmin was also reduced by disruption of LR clustering. In addition, inhibition of such LR-associated redox signaling prevented cytoskeleton disarrangement and apoptosis induced by Hcys. It is concluded that NADPH oxidase subunits aggregation and consequent activation of this enzyme through LR clustering is an important molecular mechanism triggering oxidative injury of podocytes induced by Hcys. 2009 Elsevier B.V. All rights reserved.

Regulation of Hsp27 and Hsp70 expression in human and mouse skin construct models by caveolae following exposure to the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Black, Adrienne T.; Hayden, Patrick J.; Casillas, Robert P.

Dermal exposure to the vesicant sulfur mustard causes marked inflammation and tissue damage. Basal keratinocytes appear to be a major target of sulfur mustard. In the present studies, mechanisms mediating skin toxicity were examined using a mouse skin construct model and a full-thickness human skin equivalent (EpiDerm-FT{sup TM}). In both systems, administration of the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide (CEES, 100-1000 {mu}M) at the air surface induced mRNA and protein expression of heat shock proteins 27 and 70 (Hsp27 and Hsp70). CEES treatment also resulted in increased expression of caveolin-1, the major structural component of caveolae. Immunohistochemistry revealedmore » that Hsp27, Hsp70 and caveolin-1 were localized in basal and suprabasal layers of the epidermis. Caveolin-1 was also detected in fibroblasts in the dermal component of the full thickness human skin equivalent. Western blot analysis of caveolar membrane fractions isolated by sucrose density centrifugation demonstrated that Hsp27 and Hsp70 were localized in caveolae. Treatment of mouse keratinocytes with filipin III or methyl-{beta}-cyclodextrin, which disrupt caveolar structure, markedly suppressed CEES-induced Hsp27 and Hsp70 mRNA and protein expression. CEES treatment is known to activate JNK and p38 MAP kinases; in mouse keratinocytes, inhibition of these enzymes suppressed CEES-induced expression of Hsp27 and Hsp70. These data suggest that MAP kinases regulate Hsp 27 and Hsp70; moreover, caveolae-mediated regulation of heat shock protein expression may be important in the pathophysiology of vesicant-induced skin toxicity.« less

Novel Extracellular PHB Depolymerase from Streptomyces ascomycinicus: PHB Copolymers Degradation in Acidic Conditions

PubMed Central

García-Hidalgo, Javier; Hormigo, Daniel; Arroyo, Miguel; de la Mata, Isabel

2013-01-01

The ascomycin-producer strain Streptomyces ascomycinicus has been proven to be an extracellular poly(R)-3-hydroxybutyrate (PHB) degrader. The fkbU gene, encoding a PHB depolymerase (PhaZSa), has been cloned in E. coli and Rhodococcus sp. T104 strains for gene expression. Gram-positive host Rhodococcus sp. T104 was able to produce and secrete to the extracellular medium an active protein form. PhaZSa was purified by two hydrophobic interaction chromatographic steps, and afterwards was biochemically as well as structurally characterized. The enzyme was found to be a monomer with a molecular mass of 48.4 kDa, and displayed highest activity at 45°C and pH 6, thus being the first PHB depolymerase from a gram-positive bacterium presenting an acidic pH optimum. The PHB depolymerase activity of PhaZSa was increased in the presence of divalent cations due to non-essential activation, and also in the presence of methyl-β-cyclodextrin and PEG 3350. Protein structure was analyzed, revealing a globular shape with an alpha-beta hydrolase fold. The amino acids comprising the catalytic triad, Ser131-Asp209-His269, were identified by multiple sequence alignment, chemical modification of amino acids and site-directed mutagenesis. These structural results supported the proposal of a three-dimensional model for this depolymerase. PhaZSa was able to degrade PHB, but also demonstrated its ability to degrade films made of PHB, PHBV copolymers and a blend of PHB and starch (7∶3 proportion wt/wt). The features shown by PhaZSa make it an interesting candidate for industrial applications involving PHB degradation. PMID:23951224

Novel extracellular PHB depolymerase from Streptomyces ascomycinicus: PHB copolymers degradation in acidic conditions.

PubMed

García-Hidalgo, Javier; Hormigo, Daniel; Arroyo, Miguel; de la Mata, Isabel

2013-01-01

The ascomycin-producer strain Streptomyces ascomycinicus has been proven to be an extracellular poly(R)-3-hydroxybutyrate (PHB) degrader. The fkbU gene, encoding a PHB depolymerase (PhaZ Sa ), has been cloned in E. coli and Rhodococcus sp. T104 strains for gene expression. Gram-positive host Rhodococcus sp. T104 was able to produce and secrete to the extracellular medium an active protein form. PhaZ Sa was purified by two hydrophobic interaction chromatographic steps, and afterwards was biochemically as well as structurally characterized. The enzyme was found to be a monomer with a molecular mass of 48.4 kDa, and displayed highest activity at 45°C and pH 6, thus being the first PHB depolymerase from a gram-positive bacterium presenting an acidic pH optimum. The PHB depolymerase activity of PhaZ Sa was increased in the presence of divalent cations due to non-essential activation, and also in the presence of methyl-β-cyclodextrin and PEG 3350. Protein structure was analyzed, revealing a globular shape with an alpha-beta hydrolase fold. The amino acids comprising the catalytic triad, Ser(131)-Asp(209)-His(269), were identified by multiple sequence alignment, chemical modification of amino acids and site-directed mutagenesis. These structural results supported the proposal of a three-dimensional model for this depolymerase. PhaZ Sa was able to degrade PHB, but also demonstrated its ability to degrade films made of PHB, PHBV copolymers and a blend of PHB and starch (7∶3 proportion wt/wt). The features shown by PhaZ Sa make it an interesting candidate for industrial applications involving PHB degradation.

Toxicology and drug delivery by cucurbit[n]uril type molecular containers.

PubMed

Hettiarachchi, Gaya; Nguyen, Duc; Wu, Jing; Lucas, Derick; Ma, Da; Isaacs, Lyle; Briken, Volker

2010-05-06

Many drug delivery systems are based on the ability of certain macrocyclic compounds - such as cyclodextrins (CDs) - to act as molecular containers for pharmaceutical agents in water. Indeed beta-CD and its derivatives have been widely used in the formulation of hydrophobic pharmaceuticals despite their poor abilities to act as a molecular container (e.g., weak binding (K(a)<10(4) M(-1)) and their challenges toward chemical functionalization. Cucurbit[n]urils (CB[n]) are a class of molecular containers that bind to a variety of cationic and neutral species with high affinity (K(a)>10(4) M(-1)) and therefore show great promise as a drug delivery system. In this study we investigated the toxicology, uptake, and bioactivity of two cucurbit[n]urils (CB[5] and CB[7]) and three CB[n]-type containers (Pentamer 1, methyl hexamer 2, and phenyl hexamer 3). All five containers demonstrated high cell tolerance at concentrations of up to 1 mM in cell lines originating from kidney, liver or blood tissue using assays for metabolic activity and cytotoxicity. Furthermore, the CB[7] molecular container was efficiently internalized by macrophages indicating their potential for the intracellular delivery of drugs. Bioactivity assays showed that the first-line tuberculosis drug, ethambutol, was as efficient in treating mycobacteria infected macrophages when loaded into CB[7] as when given in the unbound form. This result suggests that CB[7]-bound drug molecules can be released from the container to find their intracellular target. Our study reveals very low toxicity of five members of the cucurbit[n]uril family of nanocontainers. It demonstrates the uptake of containers by cells and intracellular release of container-loaded drugs. These results provide initial proof-of-concept towards the use of CB[n] molecular containers as an advanced drug delivery system.

Dopamine-induced programmed cell death is associated with cytochrome c release and caspase-3 activation in snail salivary gland cells.

PubMed

Pirger, Zsolt; Rácz, Boglárka; Kiss, Tibor

2009-02-01

PCD (programmed cell death) is a common mechanism to remove unwanted and excessive cells from organisms. In several exocrine cell types, PCD mode of release of secretory products has been reported. The molecular mechanism of the release, however, is largely unknown. Our aim was to study the molecular mechanism of saliva release from cystic cells, the specific cell type of snail SGs (salivary glands). SG cells in active feeding animals revealed multiple morphological changes characteristic of PCD. Nerve stimulation and DA (dopamine) increased the number of TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling)-positive cells both in inactive and feeding animals. The DA-induced PCD was prevented by TEA (tetraethylammonium chloride) and eticlopride, emphasizing the role of K channels and D2 receptors in the PCD of cystic cells. DA enhanced cyto-c (cytochrome c) translocation into the cytosol and methyl-beta-cyclodextrin prevented it, suggesting apoptosome formation and ceramide involvement in the PCD linking of the surface DA receptor to mitochondria. Western blot analysis revealed that the release of cyto-c was under the control of Bcl-2 and Bad. DA also increased the active caspase-3 in gland cells while D2 receptor antagonists and TEA attenuated it. Our results provide evidence for a type of transmitter-mediated pathway that regulates the PCD of secretory cells in a mitochondrial-caspase-dependent manner. The activation of specific molecules, such as K channels, DA receptors, cyto-c, ceramide, Bcl-2 proteins and caspase-3, but not caspase-8, was demonstrated in cells involved in the DA-induced PCD, suggesting that PCD is a physiological method for the release of saliva from SG cells.

Alternative mechanism by which IFN-gamma enhances tumor recognition: active release of heat shock protein 72.

PubMed

Bausero, Maria A; Gastpar, Robert; Multhoff, Gabriele; Asea, Alexzander

2005-09-01

IFN-gamma exhibits differential effects depending on the target and can induce cellular activation and enhance survival or mediate cell death via activation of apoptotic pathways. In this study, we demonstrate an alternative mechanism by which IFN-gamma enhances tumor recognition, mediated by the active release of Hsp72. We demonstrate that stimulation of 4T1 breast adenocarcinoma cells and K562 erythroleukemic cells with IFN-gamma triggers the cellular stress response, which results in the enhanced expression of total Hsp72 expression without a significant increase in cell death. Intracellular expression of Hsp72 was abrogated in cells stably transfected with a mutant hsf-1 gene. IFN-gamma-induced Hsp72 expression correlated with enhanced surface expression and consequent release of Hsp72 into the culture medium. Pretreatment of tumors with compounds known to the block the classical protein transport pathway, including monensin, brefeldin A, tunicamycin, and thapsigargin, did not significantly block Hsp72 release. However, pretreatment with intracellular calcium chelator BAPTA-AM or disruption of lipid rafts using methyl beta-cyclodextrin completely abrogated IFN-gamma-induced Hsp72 release. Biochemical characterization revealed that Hsp72 is released within exosomes and has the ability to up-regulate CD83 expression and stimulate IL-12 release by naive dendritic cells. Pretreatment with neutralizing mAb or depletion of Hsp72 completely abrogated its chaperokine function. Taken together, these findings are indicative of an additional previously unknown mechanism by which IFN-gamma promotes tumor surveillance and furthers our understanding of the central role of extracellular Hsp72 as an endogenous adjuvant and danger signal.