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At least 577 records · Page 32Linked to original sources
PubMed2003

Diversity among microbial cyclic lipopeptides: iturins and surfactins. Activity-structure relationships to design new bioactive agents.

A prominent group of bioactive lipopeptides produced by Bacillus species is constituted by iturins, surfactins and lichenysins. Interest in such substances results in their exceptional surfactant power, and their valuable antifungal, antibacterial, antitumoral and anti-Mycoplasma properties. As is typical for peptidic secondary-metabolites synthesized by the polyenzymic pathway, they are produced as mixtures of components varying in the peptidic and/or in the lipidic structure. In the context of structure-activity relationships, it is possible to take advantage of the adaptability of the biosynthesis system by systematically adding selected amino acids in the culture medium of the producing bacterium. When an amino acid is used as the sole nitrogen source, it is inserted directly into selected positions of the peptide sequence, thus amplifying the original structural microheterogeneity via a production of variants. This method revealed very efficient for increasing the amounts of preexisting variants and for building new variants of surfactins and lichenysins but totally inefficient with iturins. In this group, the peptidic diversity strictly depends on the selected strain. So far the screening remained the only method to discover new iturins. Another interesting peculiarity is the common occurrence in a single strain of two lipopeptides with different core structures such as surfactins and iturins. Taken together, these features led to an extensive metabolite pattern. Besides, engineered variants and chemical derivatives enlarged the array of available molecules. Despite the high degree of chemical similarity, the separation of variants and/or homologues was successfully achieved by reversed-phase HPLC leading to well-separated compounds ideally suited to investigation of structure-activity relationships. Improved physical techniques such as 2D-NMR and mass spectrometry allowed to describe efficiently and rapidly the composition of cyclic lipopeptides even in mixtures containing several variants. From NMR, the 3D structure and dynamics gave crucial data for fine structure-activity relationships as well as for understanding of the properties at the membrane and/or at the air/water interface. Here the role of residues was identified in the context of hydrophobic and electrostatic interactions that play a leader role. Such a comprehensive approach, based on both structural and biosynthesis knowledge, opened the way to rational design for enhanced properties and its validity was confirmed with 10 fold higher surfactant efficacy.

Anti-Bacterial Agents↗
PubMed2001

[Results of creating domestic medicinal forms of antineoplastic agents at the N. N. Blokhin Cancer Research Center of the Russian Academy of Medical Sciences].

Since there is a rise in morbidity and mortality rates due to malignant neoplasms, their drug therapy along with radiation and surgical methods remains a burning problem of modern medicine. Empirical and rational approaches to searching for new drugs have given rise to cancer agents that are widely used in clinical practice today. By taking into account the chemical and biological features of experimentally chosen active cytostatics, emphasis should be laid on the particular importance of development of effective dosage forms of antitumor substances by conducting chemical analytical, pharmacological engineering, biopharmaceutical, and pharmacokinetic studies. The purpose of the present paper is to assess the retrospective and present status of studies to design dosage forms of cancer drugs in our and foreign countries, and to pool the results of the author's own studies in designing dosage forms of antitumor substances from classes of chloroethylamines, nitrosoalkyl ureas, complex metal compounds, anthracene diones, antibiotics of plant origin, etc.

Academies and Institutes↗
PubMed2001

Combinatorial biosynthesis in microorganisms as a route to new antimicrobial, antitumor and neuroregenerative drugs.

Combinatorial biosynthesis utilizes the genes of biosynthetic pathways that produce microbial products to create novel chemical structures. The engineering of mondular polyketide synthase (PKS) genes has been the major focus of this effort and has led to the production of analogs of macrolide antibiotics like the erythromycins and their derived ketolides, and of the immunosuppressive macrolide FK-520 (Fujisawa Pharmaceutical Co Ltd). Approaches to making analogs of the promising antitumor compounds known as epothilones are also being explored. Lead compounds for further study have resulted and routes to analogs of other pharmacologically important compounds have been established. To facilitate this work, many new tools for manipulating and studying the multifunctional PKSs have been developed including the development of Escherichia coli as a PKS expression last. These developments have resulted in faster ways of engineering PKS to produce new compounds for the development of chemotherapeutic agents from natural products.

Animals↗
PubMed2006

[Isolation, sequencing analysis and characterization of the promoter of banana lectin gene].

Banana (Musa spp) is one of the most important fruit crops in the world. Banana fruit is an ideal organ for producing foreign pharmaceutical proteins and chemicals by genetic engineering. A perfect promoter driving foreign gene to express strongly and specifically in banana fruit is necessary for that. In order to isolate a banana fruit-specific expressed promoter, a fragment of 702 nt nucleotide sequence upstream 5' of banana lectin (BanLec) gene, which was demonstrated to express specifically in banana fruit previously, was isolated by using chromosomal walking in this study. Bioinformatical analysis of this sequence shows that the sequence contains some typical elements of a promoter. To identify the fruit-specific expression of this promoter, a construct was derived from pBI121, which originally CaMV 35S promoter was replaced by the 702 nt nucleotide sequence, and named as pBIL2. Transformations of pBIL2 to roots, leaves and fruit pieces of banana were carried out by using particle bombardment. The transient expression of gus showed that the gus expressed specifically in banana fruit with a little higher level compared with CaMV 35S. It is the first report that BanLec promoter is a potential fruit-specific expressed promoter which can further be used in transgenes into banana.

Cloning, Molecular↗
PubMed1995

Immunotechnological trends in radioimmunotargeting: from 'magic bullet' to 'smart bomb'.

The impact of recent advances in the chemical and genetic engineering manipulations of antibodies on radioimmunotargeting is reviewed both in relation to radioimmunoscintigraphy and radioimmunotherapy. The resulting trends are: (1) the linking of parts of the mouse/rat and human antibody molecule; (2) the creation of molecules with dual antigen or multiple antigen recognition capabilities; (3) the making of smaller and smaller antigen recognition molecules; and (4) the development of molecules with dual capabilities, e.g. antigen recognition and enzyme activity. The various methods of creating antibodies in vitro are reviewed with reference to bacteria, using phage selection and a combinatorial library, mammalian cells, yeast cells and, finally, mice containing giant yeast artificial chromosomes. The advantages and disadvantages of smaller fragments as well as of the human anti-mouse antibody (HAMA) reaction are discussed and the need for early clinical evaluation and widespread availability of the newer antibodies is emphasized. It is envisaged that these immunotechnological advances will permit the large-scale production of precisely engineered humanized antibodies, and the specificity and affinity rate constant of these antibodies can be optimized using in vitro phage selection as well as by computer modelling where the stereo chemistry of the antigen is known precisely.

Animals↗
PubMed2004

Antifouling potential of lubricious, micro-engineered, PDMS elastomers against zoospores of the green fouling alga Ulva (Enteromorpha).

The settlement and release of Ulva spores from chemically modified, micro-engineered surface topographies have been investigated using poly(dimethyl siloxane) elastomers (PDMSe) with varying additions of non-network forming poly(dimethyl siloxane) based oils. The topographic features were based on 5 microns wide pillars or ridges separated by 5, 10, or 20 microns wide channels. Pattern depths were 5 or 1.5 microns. Swimming spores showed no marked difference in settlement on smooth surfaces covered with excess PDMS oils. However, incorporation of oils significantly reduced settlement density on many of the surfaces with topographic features, in particular, the 5 microns wide and deep channels. Previous results, confirmed here, demonstrate preferences by the spores to settle in channels and against pillars with spatial dimensions of 5 microns, 10 microns and 20 microns. The combination of lubricity and pillars significantly reduced the number of attached spores compared to the control, smooth, unmodified PDMSe surfaces when exposed to turbulent flow in a flow channel. The results are discussed in relation to the energy needs for spores to adhere to various surface features and the concepts of ultrahydrophobic surfaces. A factorial, multi-level experimental design was analyzed and a 2nd order polynomial model was regressed for statistically significant effects and interactions to determine the magnitude and direction of influence on the spore density measurements between factor levels.

Analysis of Variance↗
PubMed2001

Impact of biodiesel source material and chemical structure on emissions of criteria pollutants from a heavy-duty engine.

Biodiesel is an oxygenated diesel fuel made from vegetable oils and animal fats by conversion of the triglyceride fats to esters via transesterification. In this study we examined biodiesels produced from a variety of real-world feedstocks as well as pure (technical grade) fatty acid methyl and ethyl esters for emissions performance in a heavy-duty truck engine. The objective was to understand the impact of biodiesel chemical structure, specifically fatty acid chain length and number of double bonds, on emissions of NOx and particulate matter (PM). A group of seven biodiesels produced from real-world feedstocks and 14 produced from pure fatty acids were tested in a heavy-duty truck engine using the U.S. heavy-duty federal test procedure (transient test). It was found that the molecular structure of biodiesel can have a substantial impact on emissions. The properties of density, cetane number, and iodine number were found to be highly correlated with one another. For neat biodiesels, PM emissions were essentially constant at about 0.07 g/bhp-h for all biodiesels as long as density was less than 0.89 g/cm3 or cetane number was greater than about 45. NOx emissions increased with increasing fuel density or decreasing fuel cetane number. Increasing the number of double bonds, quantified as iodine number, correlated with increasing emissions of NOx. Thus the increased NOx observed for some fuels cannot be explained by the NOx/PM tradeoff and is therefore not driven by thermal NO formation. For fully saturated fatty acid chains the NOx emission increased with decreasing chain length for tests using 18, 16, and 12 carbon chain molecules. Additionally, there was no significant difference in NOx or PM emissions for the methyl and ethyl esters of identical fatty acids.

Animals↗
PubMed2003

Chemically-bound nerve growth factor for neural tissue engineering applications.

In order to promote regeneration after spinal cord injury, growth factors have been applied in vivo to rescue ailing neurons and provide a path finding signal for regenerating neurites. We previously demonstrated that soluble growth factor concentration gradients can guide axons over long distances, but this model is inherently limited to in vitro applications. To translate the use of growth factor gradients to an implantible device for in vivo studies, we developed a photochemical method to bind nerve growth factor (NGF) to microporous poly(2-hydroxyethylmethacrylate) (PHEMA) gels and tested bioactivity in vitro. A cell adhesive photoreactive poly(allylamine) (PAA) was synthesized and characterized. This photoreactive PAA was applied to the surface of the PHEMA gels to provide both a cell adhesive layer and a photoreactive handle for further NGF immobilization. Using a direct ELISA technique, the amount of NGF immobilized on the surface of PHEMA after UV exposure was determined to be 5.65 +/- 0.82 ng/cm2 or 3.4% of the originally applied NGF. A cell-based assay was performed to determine the bioactivity of the immobilized NGF. Using pheochromocytoma (PC-12) cells, 30 +/- 7% of the cell population responded to bound NGF, a response statistically similar to that of cells cultured on collagen in the presence of 40 ng/ml soluble NGF of 39 +/- 12%. These results demonstrate that PHEMA with photochemically bound NGF is bioactive. This photochemical technique may be useful to spatially control the amount of NGF bound to PHEMA using light and thus build a stable concentration gradient.

Animals↗
PubMedDate not supplied

Influence of physical and chemical characteristics of diesel fuels and exhaust emissions on biological effects of particle extracts: a multivariate statistical analysis of ten diesel fuels.

The emission of diesel exhaust particulates is associated with potentially severe biological effects, e.g., cancer. The aim of the present study was to apply multivariate statistical methods to identify factors that affect the biological potency of these exhausts. Ten diesel fuels were analyzed regarding physical and chemical characteristics. Particulate exhaust emissions were sampled after combustion of these fuels on two makes of heavy duty diesel engines. Particle extracts were chemically analyzed and tested for mutagenicity in the Ames test. Also, the potency of the extracts to competitively inhibit the binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to the Ah receptor was assessed. Relationships between fuel characteristics and biological effects of the extracts were studied, using partial least squares regression (PLS). The most influential chemical fuel parameters included the contents of sulfur, certain polycyclic aromatic compounds (PAC), and naphthenes. Density and flash point were positively correlated with genotoxic potency. Cetane number and upper distillation curve points were negatively correlated with both mutagenicity and Ah receptor affinity. Between 61% and 70% of the biological response data could be explained by the measured chemical and physical factors of the fuels. By PLS modeling of extract data versus the biological response data, 66% of the genotoxicity could be explained, by 41% of the chemical variation. The most important variables, associated with both mutagenicity and Ah receptor affinity, included 1-nitropyrene, particle bound nitrate, indeno[1,2,3-cd]pyrene, and emitted mass of particles. S9-requiring mutagenicity was highly correlated with certain PAC, whereas S9-independent mutagenicity was better correlated with nitrates and 1-nitropyrene. The emission of sulfates also showed a correlation both with the emission of particles and with the biological effects. The results indicate that fuels with biologically less hazardous potentials should have high cetane number and contain less PAC and sulfur. The results also indicate that engine factors affect the formation and emission of nitrated PAC.

Automobiles↗
PubMed2005

Effect of passage number and matrix characteristics on differentiation of endothelial cells cultured for tissue engineering.

Cells can sense the physical and chemical properties of artificial materials used as scaffolds for tissue engineering and regulate their behavior. Therefore, biomimetic and biospecific molecules are coated on materials to regulate function of cells on the tissue-engineered product. These bioactive molecules can be attached in a defined spectrum, concentration and spatial distribution in order to control adhesion, growth, viability, differentiation, and function of the cells. When autologous cells are used for tissue engineering, initially limited cells obtained may often need an amplification of cell number by passage in tissue culture before they are seeded on a biomaterial or scaffold. We have conducted this study to understand how the characteristics of bioactive molecule coating might affect proliferation, apoptosis and differentiation when endothelial cell (EC) is serially passaged. Proliferation was assessed by proliferating cell nuclear antigen (PCNA) staining along with counting of cells harvested from confluent monolayer. Apoptosis was assessed by Annexin V staining and differentiation by semi quantitative reverse transcriptase polymerase chain reaction (RT-PCR) for von Willebrand factor (vWF) expression and quantification of its release using enzyme linked immunosorbant assay (ELISA), and thrombogenicity by comparing platelet adhesion to EC monolayer Dacron grafts (DG) with specific protein coating. The results indicate that ECs easily lose its proliferation potential when they are cultured repeatedly on gelatin, turn apoptotic and over express the prothrombotic protein- vWF. Whereas, when it is grown on a matrix composed of fibrin, fibronectin, gelatin and vascular EC growth factor (VEGF), the cells retained their ability to proliferate, remained viable and were relatively less thrombogenic, even when passage number progressed. It is concluded that if ECs are grown on the composite matrix that mimics natural vessel scaffold, the cell number can be amplified without affecting its normal physiological function and may be used to generate effective tissue-engineered cardiovascular constructs.

Cell Adhesion↗
PubMed1978

Industrial hygiene engineering in the petrochemical industry.

Industrial hygiene engineering can be utilized most effectively when it is employed in the design or construction phases of new or modified chemical manufacturing processes. Minimization of leaks, spills, fugitive emissions and other releases is the goal. Some chemical and physical agents can still be released during normal or non-normal operations and during plant turnaround procedures and these require continuous industrial hygiene surveillance. It follows that industrial hygiene principles must continue to be applied in all phases of the petrochemical industry from the beginning of the design and throughout the life of the unit.

Chemical Industry↗
PubMed1994

Drug synthesis by genetically engineered microorganisms.

The interplay between chemical and biological approaches to drug discovery and development is increasing with the advent of combinatorial methods that accelerate the output of screening programs and the development of genetically modified microorganisms able to make new metabolites and larger amounts of known ones. Actinomycetes, the most prolific microbial source of known drugs, can produce new aromatic compounds by manipulation of the Type II polyketide synthase genes as well as analogs of existing macrolide antibiotics, unavailable by chemical synthesis, through targeted mutation of specific biosynthetic genes. Genetic alteration of pathways to aminoglycoside and oligopeptide antibiotics should offer equally promising approaches to manufacturing novel metabolites. When coupled with DNA-based prescreening of microbial isolates for genes associated with known pharmacologically active agents, these new genetic-based approaches are creating an expanded role for microorganisms in drug research.

Anti-Bacterial Agents↗
PubMed1994

Survival and respiratory activity of genetically engineered Pseudomonas spp. exposed to antimicrobial agents in broth and soil.

The effectiveness of seven chemical disinfectants were tested against genetically engineered Pseudomonas spp. under optimal growth conditions. Each chemical was tested to determine how quickly 10(8) cells/ml Pseudomonas fluorescens C5t (containing Bacillus thuringiensis endotoxin gene) were killed in King's B broth at 30 degrees C. The minimal bactericidal concentrations (MBC) for calcium hypochlorite, benzalkonium chloride, Germiphene and Spectrum Clear Bath were 0.06% (w/v), 0.01% (w/v), 0.08% (v/v) and 0.044 (v/v), respectively. Virocidin X and CanLab Neutral did not kill P. fluorescens C5t at concentrations up to 20% (v/v). Baxter Bacdown was ineffective as a killing agent at concentrations up to 10% (v/v). These agents were also tested on P. aureofaciens RNL11 (lacZY), P. putida strains PaW8 and PaW340 (containing the plasmid pLV1013 encoding the xylE gene) and P. aeruginosa UG2L (lacZY and luxAB). All strains were killed by similar disinfectant concentrations with the exception of P. aeruginosa UG2L. The MBCs for this strain were double the MBCs for P. fluorescens C5t with all disinfectants used except for Spectrum Clear Bath, which was similar. Oxygen consumption and carbon dioxide evolution were used to assess the activity of P. fluorescens C5t inoculated in non-sterile soil in the presence of antimicrobial agents. Concentrations chosen were 0.1 and 1.0% (w/v) calcium hypochlorite, 0.01 and 0.1% (w/v) benzalkonium chloride, 0.1 and 1.0% (v/v) Germiphene and 0.1 and 1.0% (v/v) Spectrum Clear Bath. Over a 15-day period, the antimicrobial agents did not reduce respiratory activity of P. fluorescens C5t and indigenous soil micro-organisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Containment of Biohazards↗
PubMed1996

Engineering the gramicidin channel.

The chemical design or redesign of proteins with significant biological activity presents formidable challenges. Ion channels offer advantages for such design studies because one can examine the function of single molecular entities in real time. Gramicidin channels are attractive for study because of their known structure and exceptionally well-defined function. This article focuses on amino acid sequence changes that redesign the structure or function of gramicidin channels. New, and functional, folded states have been achieved. In some cases, a single amino acid sequence can give rise to several (up to three) functional conformations. Single amino acid substitutions confer voltage-dependent channel gating. The findings provide insight into the folding of integral membrane proteins, the importance of tryptophan residues at the membrane/water interface, and the mechanism of channel gating.

Amino Acid Sequence↗
PubMed2006

Rational design of hydrogels for tissue engineering: impact of physical factors on cell behavior.

When designing suitable biomaterials for tissue-engineering applications, biological and chemical parameters are frequently taken into account, while the equally important physical design variables have often been neglected. For a rational design of biomaterials, however, all variables influencing cell function and tissue morphogenesis have to be considered. This review will stress the development of cross-linked hydrogels and outline the impact of their physical properties on cell function and tissue morphogenesis. In the first part, the principles of cellular mechanosensitivity, as well as the influence of substrate mechanics on cell behavior, will be discussed. Afterwards, methods to characterize the mechanical properties of biomaterials will be presented. The subsequent chapters will address hydrogels that allow for the control of their physical qualities followed by a discussion of their use in tissue-engineering applications.

Biocompatible Materials↗
PubMed1999

Taking engineered anti-CEA antibodies to the clinic.

There is a need to improve on existing targeting technologies in order to develop effective cancer therapy. We have investigated this for colorectal cancer using antibodies directed against carcinoembryonic antigen (CEA). Chemical and molecular protein engineering has been used to produce antibody molecules which differ in molecular weight, affinity, valency and specificity. These have been characterised and tested in animal tumour models and clinical trials to test the parameters important for optimising tumour penetration, increasing residence time in viable areas of the tumour, accelerating clearance from normal tissues and improving therapeutic efficacy.

Animals↗
PubMed2004

Production of vitamin B12 in genetically engineered Propionibacterium freudenreichii.

Since the chemical synthesis of vitamin B12 requires more than 70 steps, the production of vitamin B12 has been achieved by microorganism fermentation with additional brief chemical modifications. In an effort to increase the productivity of vitamin B12, we tried to express 10 genes belonging to the hem, cob and cbi gene families involved in the synthesis of vitamin B12 in Propionibacterium freudenreichii, which is a known producer of vitamin B12. In a recombinant P. freudenreichii clone that harbored the expression vector containing a cobA, cbiLF, or cbiEGH, we obtained an increase in vitamin B12 production of 1.7-, 1.9-, and 1.5-fold higher, respectively, than that in the microorganism without any cloned genes in the expression vector pPK705. The cobU and cobS genes caused a slight increase in the production of vitamin B12. Furthermore, we achieved multigene expression in P. freudenreichii. In a recombinant P. freudenreichii clone that harbored an exogenous gene, hemA, from Rhodobacter sphaeroides and endogenous hemB and cobA genes, we successfully achieved the production of about 1.7 mg/l vitamin B12, 2.2-fold higher than that produced by P. freudenreichii harboring pPK705.

Journal Article↗