Biomedical subjects

H L Jiang

Publications and source records attributed to H L Jiang.

At least 19 recordsLinked to original sources

PubMed2006

Regulation of adipocyte differentiation by PEGylated all-trans retinoic acid: reduced cytotoxicity and attenuated lipid accumulation.

Obesity is major risk factor for many disorders, including diabetes, hypertension and heart disease. Unfortunately, there is a dearth of therapeutic agents available to clinicians for the treatment of obesity. The principal aim of this study was to investigate whether PEGylated all-trans retinoic acid (PRA) can have favorable stability and biological activity in 3T3-L1 preadipocytes as an antiobesity drug. Here, we found that PRA inhibits the process of adipogenesis, including survival of adipocytes and differentiation to mature adipocytes. The results showed that RA nanoparticles (NPs) were prepared by PEGylation; below 200 nm, PRA-NPs were obtained. Moreover, PRA decreased glycerol-3-phosphate dehydrogenase activity in 3T3-L1 preadipocytes by acting with major adipocyte marker proteins such as PPARgamma2, C/EBPalpha and aP2 modulators. Apoptosis, in addition, increased as the level of RA increased from 10 to 20 microM, whereas PRA reduced apoptosis with increasing concentrations. Our data suggest that PRA-NP has potential as an antiobesity drug carrier due to its small particle size and PEGylated core-shell structure. In addition, our results suggest that PRA inhibits the process of adipogenesis and may be developed to treat obesity. Based on these results, PRA is suitable for adipocyte studies, and an enhanced effect of PRA with adipocyte differentiation offers a challenging approach for pharmaceutical applications.

3T3 Cells↗

PubMed2005

Preparation, characterization and nasal delivery of alpha-cobrotoxin-loaded poly(lactide-co-glycolide)/polyanhydride microspheres.

In this study, alpha-cobrotoxin was incorporated into the microspheres composed of poly(lactide-co-glycolide) (PLGA) and poly[1,3-bis(p-carboxy-phenoxy) propane-co-p-(carboxyethylformamido) benzoic anhydride] (P(CPP:CEFB)) and intranasally delivered to model rats in order to improve its analgesic activity. The microspheres with high entrapment efficiency (>80%) and average diameter of about 25 microm could be prepared by a modified water-in-oil-in-oil (w/o/o) emulsion solvent evaporation method. Scanning electron micrograph (SEM) study indicated that P(CPP:CEFB) content played a considerable role on the morphology and degradation of the microspheres. The presence of P(CPP:CEFB) in the microspheres increased their residence time at the surface of the nasal rat mucosa. The toxicity of the composite microspheres to nasal mucosa was proved to be mild and reversible. A tail flick assay was used to evaluate the antinociceptive activity of the microspheres after nasal administration. Compared with the free alpha-cobrotoxin and PLGA microspheres, PLGA/P(CPP:CEFB) microspheres showed an apparent increase in the strength and duration of the antinociceptive effect at the same dose of alpha-cobrotoxin (80 microg/kg body weight).

Administration, Intranasal↗

PubMed2005

In vitro and in vivo studies of cyclosporin A-loaded microspheres based on copolymers of lactide and epsilon-caprolactone: comparison with conventional PLGA microspheres.

A hydrophobic peptide, cyclosporin A (CyA), was incorporated in microspheres based on poly(lactide-b-epsilon-caprolactone) (P(LA-b-CL), LA/CL (in molar ratio): 78.7/21.3 and 48.1/51.9) and poly(lactide-co-glycolide) (PLGA, LA/GA: 80/20) using oil-in-water (O/W) emulsion solvent evaporation method. The microspheres were characterized by SEM, DSC and X-ray diffraction, and CyA release rate was determined by HPLC. It was revealed that CyA can be efficiently loaded into all the microspheres (exceed 96%). Compared to PLGA microspheres, P(LA-b-CL) microspheres liberated CyA more rapidly. Within the first day, about 75, 50 and 12% of CyA released from P(LA-b-CL) (48.1/51.9), P(LA-b-CL) (78.7/21.3) and PLGA microspheres, respectively, which can be attributed to the partial crystallization occurring in P(LA-b-CL) microspheres. CyA levels in whole blood were also tested. In comparison with PLGA microspheres, P(LA-b-CL) microspheres provided a higher blood level of CyA. The maximum CyA concentration in whole blood (approximately 520, 450 and 400 ng ml(-1) for P(LA-b-CL) (48.1/51.9) P(LA-b-CL) (78.7/21.3) and PLGA microspheres, respectively) was reached at the second day post administration. And then P(LA-b-CL) microspheres showed a constant CyA level (about 100-200 ng ml(-1)) for extended periods of time (several weeks). Such CyA-loaded P(LA-b-CL) microspheres displaying higher CyA concentration during the first few days and similar constant blood CyA level thereafter showed more advantages than those prepared with PLGA and could meet clinical needs more efficiently.

Animals↗

PubMed2005

Preparation, characterization and in vitro release properties of ibuprofen-loaded microspheres based on polylactide, poly(epsilon-caprolactone) and their copolymers.

In this paper, ibuprofen was encapsulated into microspheres by oil-in-water (o/w) emulsion solvent evaporation method. Biodegradable polymers with certain compositions and characteristics such as polylactide (PLA), poly(epsilon-caprolactone) (PCL) and their block copolymer were used to prepare the microspheres. The results indicate that, under the same processing conditions, the drug entrapment efficiency was similar (approximately 80%) for microspheres prepared with PLA and P(LA-b-CL) (78.7/21.3 by mole), but it was only 25.4% for PCL microspheres. The in vitro drug release rate decreased in the order of PCL, P(LA-b-CL) (78.7/21.3 by mole) and PLA microspheres. PCL microspheres showed more serious burst release during the first day (almost 80%) than P(LA-b-CL) (50%) and PLA microspheres (18%). The complete ibuprofen release duration from the last two kinds of microspheres exceeded 1 month. Characterization of the microspheres by differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and polarized optical microscope (POM) revealed that ibuprofen was amorphous in PCL microspheres and partially crystalline in P(LA-b-CL) and PLA microspheres. The different release behaviour of ibuprofen from the three kinds of microspheres could be attributed to the different crystallinity of the studied polymers and drug dispersion state in polymer matrices. All the above results suggest that the copolymer with a certain ratio of lactide to -caprolactone could have potential applications for long-term ibuprofen release.

Absorption↗

PubMed2004

Improvement of protein loading and modulation of protein release from poly(lactide-co-glycolide) microspheres by complexation of proteins with polyanions.

A novel method was proposed to incorporate and modulate protein release from poly(lactide-co-glycolide) (PLGA) microspheres by a modified w/o/w emulsion solvent evaporation technique with poly(methacrylic acid) (PMAA)/insulin complex suspension as the inner aqueous phase instead of the neat protein solution. It was found that a reversible, water-insoluble complex could be formed between PMAA and insulin by electrostatic interactions. A great increase in insulin entrapment efficiency was observed as the PMAA/insulin complex was adopted to prepare PLGA microspheres. A large number of the complex particles adsorbed at the surface of the microspheres, resulting in the more rapid insulin release. The complexation and microencapsulation processes have little effect on insulin bioactivity, which was revealed by examination of the plasma glucose levels of the diabetic rats administrated with the microspheres.

Animals↗

PubMed2004

Functional analysis of microbial community in phenol-degrading aerobic granules cultivated in SBR.

Phenol-degrading aerobic granules were cultivated in a sequencing batch reactor with an influent phenol concentration of 500 mg l(-1). Eight strains were isolated from aerobic granules to characterize the functional redundancy of the microbial community in the granules. The specific oxygen utilization kinetics show the eight strains possessed different phenol-degrading activities, with half-saturation constants (Ks) ranging from 0.4 to 70.5 mg phenol l(-1). Two isolates belonging to dominant populations expressed differing functions. The first strain was linked to the function of phenol degradation as this strain has the highest phenol-degrading ability among all isolates, while the second strain was linked to the maintenance of the granule structure because of its strong self-flocculation activity. This study could be used to exploit the granule-based system for treating high-strength wastewaters.

Aerobiosis↗

PubMed2004

Removal of micro-particles by microbial granules used for aerobic wastewater treatment.

Microbial granules with a diameter from 0.4 mm to 3.0 mm have been produced by fast sedimentation and retention of microbial aggregates in sequencing batch airlift reactors used for model wastewater treatment. The wastewater was with or without addition of calcium salt. The granules were able not only to degrade organic matter but to remove nano- and micro-particles from wastewater due to microchannels and pores in the matrix of the granules. To detect the removal of 0.1 microm, 0.6 pm, 4.2 microm fluorescent microspheres, and cells of Escherichia coli, stained by permeable nucleic acid stain SYTO9, the granules were incubated with these particles. The rate of particle removal and their accumulation in the granules was measured by a Fluoview300 confocal laser scanning microscope (CLSM) (Olympus, Japan); a FACSCalibur flow cytometer (Becton Dickinson, CA, USA), and a fluorescence spectrometer LS-50B (Perkin-Elmer, UK). The release or removal of biological and non-biological particles was analyzed by a flow cytometer after DNA staining. Total number of the particles bigger than 0.1 microm in the reactors was approximately 4 x 10(7) per ml, and 23% of these particles were bacterial cells. The 0.1 microm and 4.2. microm microbeads were accumulated within 250 microm in the upper layer of the microbial granule but externally added cells of Escherichia coli penetrated to the depth of approximately 800 microm in the granules without calcium addition. Microbial granules contained also attached ciliates but accumulation of the particles in protozoan cells was smaller than in the granule matrix. Kinetics of particle sorption was revealed by flow cytometry and fluorescence spectrometry. Almost half of the stained cells of E. coli can be removed by the granules for one hour. The ability of the microbial granules to remove the particles can enhance their function in aerobic treatment of wastewater.

Aerobiosis↗

PubMed2002

X-ray structures of Torpedo californica acetylcholinesterase complexed with (+)-huperzine A and (-)-huperzine B: structural evidence for an active site rearrangement.

Kinetic and structural data are presented on the interaction with Torpedo californica acetylcholinesterase (TcAChE) of (+)-huperzine A, a synthetic enantiomer of the anti-Alzheimer drug, (-)-huperzine A, and of its natural homologue (-)-huperzine B. (+)-Huperzine A and (-)-huperzine B bind to the enzyme with dissociation constants of 4.30 and 0.33 microM, respectively, compared to 0.18 microM for (-)-huperzine A. The X-ray structures of the complexes of (+)-huperzine A and (-)-huperzine B with TcAChE were determined to 2.1 and 2.35 A resolution, respectively, and compared to the previously determined structure of the (-)-huperzine A complex. All three interact with the "anionic" subsite of the active site, primarily through pi-pi stacking and through van der Waals or C-H.pi interactions with Trp84 and Phe330. Since their alpha-pyridone moieties are responsible for their key interactions with the active site via hydrogen bonding, and possibly via C-H.pi interactions, all three maintain similar positions and orientations with respect to it. The carbonyl oxygens of all three appear to repel the carbonyl oxygen of Gly117, thus causing the peptide bond between Gly117 and Gly118 to undergo a peptide flip. As a consequence, the position of the main chain nitrogen of Gly118 in the "oxyanion" hole in the native enzyme becomes occupied by the carbonyl of Gly117. Furthermore, the flipped conformation is stabilized by hydrogen bonding of Gly117O to Gly119N and Ala201N, the other two functional elements of the three-pronged "oxyanion hole" characteristic of cholinesterases. All three inhibitors thus would be expected to abolish hydrolysis of all ester substrates, whether charged or neutral.

Acetylcholinesterase↗

PubMed2002

Novel fluorescent copolyanhydrides as potential visible matrices for drug delivery.

Two classes of fluorescent copolyanhydrides were synthesized by melt copolycondensation of the fluorophoric diacid, p-(carboxyethylformamido)benzoic acid (CEFB), with sebacic acid (SA) or N-trimellitylimidoglycine (TMA-gly). Alternate copolyanhydride based on SA and CEFB was also prepared by solution polycondensation of CEFB and sebacoyl chloride. 'H NMR spectra of the copolymers confirm their structures. Fluorescence was observed for all the copolymers, the intensity of which increases with the CEFB fraction. Either blue (ca. 429 nm) or green (ca. 520 nm) light can be emitted from the copolymers with the excitation of UV (356 nm) and visible (470 nm) light, respectively. The polymers were further fabricated to microsphere formulation, which can be clearly visualized by fluorescent microscopy.

Anhydrides↗

PubMed2001

Synthesis, characterization and in vitro degradation of a new family of alternate poly(ester-anhydrides) based on aliphatic and aromatic diacids.

A new family of alternate poly(ester-anhydrides) containing aliphatic and aromatic diacids were synthesized. The dicarboxylic acids were obtained by derivatization of p-hydroxy benzoic acid at the hydroxy terminus with cyclic anhydride (adipic anhydride and succinic anhydride) and subsequently polymerized via the corresponding mixed anhydrides by melt polycondensation. DSC traces revealed that the polymers had low Tg (< 40 degrees C) and no crystallinity. The static contact angle measurements indicated that the poly(ester-anhydrides) were more hydrophobic than poly(D,L-lactide) and poly(adipic anhydride). In vitro degradation of the polymers was also investigated in pH 7.4 PBS at 37 degrees C. It was found that degradation rate of the poly(ester-anhydrides) increased with p-carboxy phenyl adipic monoester (CPA) content in the polymers and the degradation duration could be adjusted from ca. 20 days to ca. 2 months. Erosion curve of poly(p-carboxy phenyl adipic monoester anhydride) (PCPA) was characterized by a linear region of weight loss at nearly constant rate in the first 7 days (ca. 80% of weight loss) followed by a gradual decrease region. IR and SEM analysis showed that significant erosion of PCPA occurred in the outer layer and no apparent erosion could be seen in the inner layer of the degrading sample after 7-day degradation. The poly(ester-anhydrides) may be used as either anti-infective polymeric prodrugs or matrices for drug delivery.

Acids↗

PubMed2001

Preparation and release characteristics of protein-loaded polyanion/gelatin complex.

PURPOSE: This paper describes preparation of polymethacrylic acid/gelatin complex and Myoglobin release characteristics in order to evaluate the polyanion/gelatin complexes as matrices that can release proteins at a near zero-order kinetics over a long period of time. METHODS: Mb-loaded PMAA/gelatin complex was prepared by two different titration methods. Mb entrapment efficiency and PMAA/gelatin ratio in the complex were determined by HPLC. The release of Mb and gelatin from the complex was followed by HPLC. Mb conformation was detected by UV-vis spectrophotometer and capillary electrophoresis apparatus. RESULTS: Polyanion/gelatin feed ratio of the polyanion/gelatin/Mb mixed solution has great effects on complex yield and protein entrapment efficiency when "Type I" titration method is adopted, while for the colloid titration method the complex yield and protein entrapment efficiency are hardly influenced by preparative conditions (ca. 100%). Mb release rate could be adjusted by the complex composition (e.g., PMAA MW, hydrophobilization of PMAA, Mb loading and PMAA/gelatin ratio, etc.). Moreover, by coating of high MW PMAA/gelatin complex cylinder in a hydrophobic membrane with one open-end left, the period of protein release can extend to ca. 20 days and the release displays a near zero-order pattern. The protein release profiles can be described by the dissociation/erosion mechanism. The entrapment process has little effect on Mb conformation. CONCLUSIONS: The studied polyanion/gelatin complex is promising to be used as protein carriers to release proteins at a near zero-order kinetics over a long period of time by selecting suitable polyanions and designing the device structure.

Gelatin↗

PubMed2001

In vivo degradation and biocompatibility of a new class of alternate poly(ester-anhydrides) based on aliphatic and aromatic diacids.

The degradation, tissue compatibility, and toxicology of a novel class of alternate poly(ester-anhydrides) were assessed in rats. It was observed that the degradation rate of the polymers in vivo was slower than that in vitro. In addition, erosion and intact zone were observed for all the polymers. IR and SEM analysis of the outer erosion and inner intact zone revealed that the outer zone degraded more rapidly than the inner zone. Such results were similar to that in vitro. All the studied poly(ester-anhydrides) produced mild inflammatory reactions and tissue encapsulation by layers of fibroblastic cells in vivo. Observation of liver and kidney tissue by light microscopy suggested the hydrolytic products of the studied poly(ester-anhydrides) had no harmful effects on the normal tissue/organs. In addition, the polymer and the breakdown products were found to be non-mutagenic by examination of micronucleus in bone marrow.

Absorbable Implants↗

PubMed2001

A 3D structural model of memapsin 2 protease generated from theoretical study.

AIM: To build a 3D structural model of memapsin 2 (M2) protease for theoretical study and drug design. METHODS: Structural alignment was performed based on multiple and pairwise sequence alignment of three templates. After the initial model was generated, energy minimization was completed by applying molecular mechanics method. Molecular dynamics (MD) technique was used to do further structural optimization. RESULTS: The 3D structural model of memapsin 2 was constructed. The model is reasonable according to several validation criteria. The active-site motifs of M2 are structurally supported by a beta-sheet rich domain and linked together with this domain through alpha helices. Tyr132 contained in beta-hairpin is a general characteristic of aspartic protease. The Calpha atom superimposing result is a direct verification that M2 is structurally unique but still belongs to the aspartic protease superfamily. CONCLUSION: The 3D-structure model from our study is informative to guide future molecular biology study about M2 and drug design based on database searching.

Amino Acid Sequence↗

PubMed2000

Structural characterization of the catalytic active site in the latent and active natural gelatinase B from human neutrophils.

Matrix metalloproteinases are endopeptidases that have a leading role in the catabolism of the macromolecular components of the extracellular matrix in a variety of normal and pathological processes. Human gelatinase B is a zinc-dependent proteinase and a member of the matrix metalloproteinase family that is involved in inflammation, tissue remodeling, and cancer. We have conducted x-ray absorption spectroscopy, atomic emission, and quantum mechanics studies of natural and activated human gelatinase B. Our results show that the natural enzyme contains one catalytic zinc ion that is central to catalysis. In addition, upon enzyme activation, the catalytic zinc site exhibits a conformation change that results in the expansion of the bond distances around the zinc ion and the replacement of one sulfur with oxygen. Interestingly, quantum mechanics calculations show that oxygen ligation at the catalytic zinc ion exhibits a greater affinity to the binding of an oxygen from an amino acid residue rather than from an external water molecule. These results suggest that the catalytic zinc ion plays a key role in both substrate binding and catalysis.

Binding Sites↗

PubMed2000

Pulsatile protein release from a laminated device comprising polyanhydrides and pH-sensitive complexes.

A laminated device comprising of polyanhydrides as isolating layers and pH-sensitive complexes as protein-loaded layers was designed to deliver proteins in a pulsatile manner. Poly(sebacic anhydride)-b-polyethylene glycol (PSA-b-PEG) and poly(trimellitylimidoglycine-co-sebacic anhydride)-b-polyethylene glycol (P(TMA-gly-co-SA)-b-PEG) were synthesized as isolating layers for their good processing properties at room temperature and suitable erosion duration. During the erosion period, pH of the dissolution fluid decreases to a low value (3.8-5.8). Poly(methacrylic acid)/polyethoxazoline (PMAA/PEOx) complex was used as protein-loaded layers, which could dissociate and release model proteins, Myoglobin (Mb) and Bovine Serum Albumin (BSA), at pH 7.4 while become stable and retained the drugs below pH 5.0. The protein release from the device showed a typical pulsatile fashion. The lag time prior to the pulsatile protein release correlated with the hydrolytic duration of the polyanhydrides, which varied from 30 to 165 h by selecting polyanhydride type and isolating layer thickness. In addition, the pulse duration could be adjusted from 18.5 to 40 h by varying the mass of the complex. The results can be attributed to the synergistic effects between the degrading polyanhydrides, pH-sensitive complexes and proteins.

Anhydrides↗

PubMed2000

Molecular modeling on solvent effect and interaction mechanism of fentanyl analogs to mu-opioid receptor.

AIM: To do theoretical study about solvation effect and interaction mechanism of fentanyl analogs (FA) to mu opioid receptor (microOR). METHODS: Flexible docking (FlexiDock) was performed by using the possible active conformations of FA and optimized 3D structure of mu opioid receptor. Binding energies were calculated. Comparative molecular force field analysis (CoMFA) and quantitative structure activity relationship (QSAR) studies were carried out based on results of flexible docking. Solvation effects were considered by studying interaction of FA with water molecules. Partial least square (PLS) analysis was used to calculate regression equation for analgesic activities using binding energies as descriptive factor. RESULTS: 1) Binding conformations of these analogs derived by flexible docking were reasonable. 2) It was most possible for the FA to exist in water solution in the form of binding conformations. 3) Energetic calculation and QSAR analysis showed a good correlation between the calculated binding energies of FA and their analgesic activities. 4) Based on the 3D-model, the possible interaction mechanism of FA with mu opioid receptor can be illustrated reasonably. CONCLUSION: The nature of the correlation between the binding affinities and analgesic activities of FA was explained by our modeling result.

Analgesics↗

PubMed2000

Building three-dimensional structures of HIV-1 coreceptor CCR5 and its interaction with antagonist TAK779 by comparative molecular modeling.

AIM: To study the mechanism of interaction of CCR5 receptor with its antagonist TAK779. METHODS: Comparative molecular modeling has been used to develop the 3D-structural models of CCR5 receptor and its complex with TAK779. Molecular mechanics has been applied to optimize the above molecular models. Quantum mechanics has been utilized to calculate the structural information of TAK779. DOCK4.0 program is employed to dock the TAK779 molecular into the binding site of CCR5 receptor. RESULTS: The 3D-structural model of CCR5 receptor is constructed using the 3D-model of frog rhodopsin as a template. The binding pocket is situated in the transmembrane helices 3, 5, 6, and 7, and it is composed of conserved residues of Tyr108, Gly111, Ser114, Glu283, Gly286, and Cys290, and conservatively varied residues including Thr105, Leu107, Phe112, Gly115, Lys197, and Met287. O1, N7, N17, and O19 of TAK779 are the active center of TAK779. The pyran cycle and the aminium group of TAK779 interact with residues in the binding pocket of CCR5 receptor, the other part of TAK779 interacts with residues from the extracellular loops of CCR5. The binding energy of TAK779 with CCR5 is -51.606 kcal/mol. CONCLUSION: The model constructed and the interaction mode reported in the present study are useful in further understanding the molecular mechanism of receptor-virus recognition and designing new inhibitors of HIV-1 infection.

Amides↗

PubMed2000

Comparative molecular modeling on 3D-structure of opioid receptor-like 1 receptor.

AIM: To build the three-dimensional structure of opioid receptor-like 1 (ORL1) receptor. METHODS: Structural elements of ORL1 receptor were predicted from sequence alignments of opioid and related receptors of G protein-coupled receptor (GPCR) based on (i) the consensus, biophysical interpretations of alignment-derived properties, and (ii) tertiary structural homology to frog rhodopsin; The extracellular loops of ORL1 were built by self-constructed database searching based on geometrical constraints; initial model was refined computationally with energy minimization by molecular mechanics method. RESULTS: The calculated structure of ORL1 receptor has clusters of hydrogen bonds existing in interhelices and extracellular loops; the ORL1 receptor has a possible ligand-binding "crevice" situated on the extraside of the transmembrane domains between helices 3, 5, 6, and 7, which is partially covered by the extracellular loop 2 (EL-2); The binding cavity may consist of a "highly conserved region" involving the residues of Asp130, Tyr131, and an outer "conservatively variable region" containing the residues near the interface of transmembrane (TM) helices-EL loops; The molecular model obtained is qualitatively consistent with ligand affinities, hybrid peptide studies, and other experimental data. CONCLUSION: The structural model of ORL1 receptor from this study is helpful for clarifying experimental observations of ligands interacting with opioid receptors, and for designing new biological investigations.

Amino Acid Sequence↗