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At least 1,153 records · Page 64Linked to original sources
PubMed1996

Systemic administration of cellular IL-10 induces an effective, specific, and long-lived immune response against established tumors in mice.

Cellular IL-10 (cIL-10), the collective term for human and murine IL-10, has both stimulatory and inhibitory effects on diverse cell types, including costimulation of T cell proliferation, chemoattraction of CD8+ T cells, and stimulation of lymphokine-activated killer cell activity. Human IL-10 (hIL-10) differs from its EBV homolog viral IL-10 (vIL-10) by only 16% at the amino acid level; however, vIL-10 shares with cIL-10 predominantly inhibitory effects, such as macrophage deactivation. We administered cIL-10 systemically to mice bearing established (day 7) sarcomas, melanomas, or colorectal carcinomas. At high doses (20 to 60 micrograms/day x 7 days), cIL-10 induced rejection of tumors, delaying tumor outgrowth or resulting in complete cure. Sublethal irradiation (500 rad) of mice prior to tumor inoculation abrogated the IL-10 effect. Cured mice were immune to subsequent rechallenge with 10-fold higher inoculation with the same, but not a different, tumor. IL-12 also has potent antitumor activity and interacts with IL-10 in both complementary and antagonistic ways; co-administration of both cytokines resulted in additive antitumor activity. To compare cIL-10 vs vIL-10 effects in vivo, we engineered CL8-1 melanoma transfectants bearing the vIL-10 or the murine IL-10 (mIL-10) gene. Local secretion of mIL-10 induced rejection of tumors, while vIL-10 resulted in accelerated outgrowth. Subsequent systemic administration of cIL-10 to mice bearing vIL-10-transduced tumors completely reversed the local suppressive effects, leading to rejection, suggesting distinct pathways for cIL-10 and vIL-10 effects. That cIL-10 can stimulate the acquisition of an effective, specific, and long-lived antitumor immune response in murine models and can reverse the local immunosuppressive effects of vIL-10 indicates a potential role for cIL-10 administration in the biologic therapy of cancer and suggests a broader interpretation of IL-10 biology.

Adenocarcinoma↗
PubMed2006

Development of an in vitro pancreatic tissue model to study regulation of islet neogenesis associated protein expression.

Restoration of a functional beta-cell mass in a patient with diabetes may hold the key for curing the disease. In recent years, there has been increasing interest in the development of new strategies to induce beta-cell regeneration and new islet formation in situ and a role for Reg proteins has been suggested. One such protein, islet neogenesis associated protein (INGAP), is a member of the Reg3 family of proteins and has been shown to induce islet neogenesis. Elucidation of the mechanisms and factors involved in the regulation of expression of INGAP and related proteins is, therefore, of great importance. Here, we report the establishment of the first in vitro tissue model of INGAP expression that consists of epithelial cystic structures derived from hamster pancreatic acinar tissue cultured in collagen matrix. The objective of this study was to characterize INGAP expression in this model and to investigate the role of pro-inflammatory cytokines and growth factors. Using quantitative reverse transcriptase PCR, we show that INGAP expression correlates with cyst formation and size suggesting the involvement of intra-luminal pressure associated with cyst growth. We also demonstrate for the first time that INGAP gene expression was significantly induced by treatment with interleukin (IL)-6 and further enhanced by a combination of IL-6 with dexamethazone and nicotinamide. Additionally, our data suggest that the effect of IL-6 on INGAP expression is mediated via the JAK/STAT3 signaling pathway. In summary, the in vitro model of INGAP expression described here represents an important step in the development of strategies for the use of INGAP and related proteins as islet neogenic agents in the pharmacotherapy of both type-1 and type-2 diabetes.

Animals↗
PubMed1994

An in vitro ligation and transfection system for inserting DNA sequences into the latency-associated transcripts (LATs) gene of herpes simplex virus type 1.

This report describes a simple, rapid and highly efficient method for introducing specific DNA sequences into a defined locus of the herpes simplex virus type 1 (HSV-1) genome by restriction enzyme cleavage and ligation. The genome of the HSV-1 strain HFEM contains a 4.1 kb deletion in one copy of the RL region, deleting one copy of the latency-associated transcript (LAT) gene. It does not contain any site for restriction enzyme PacI. Two unique PacI restriction enzyme sites flanking an HSV-1 ICP6 promoter-LacZ reporter gene cassette were engineered into the LAT region to generate a recombinant virus HFEM/ICP6-LacZ which produced blue plaques in the presence of X-gal. This viral vector allowed the insertion of foreign genes directly into the HSV-1 genome by restriction enzyme digestion and ligation. The system was tested by digesting the HFEM/ICP6-LacZ DNA with PacI and with SwaI (an endogenous unique restriction enzyme site upstream of the LAT promoter locus and inserting by in vitro ligation a LAT promoter-LacZ gene cassette into the HFEM/ICP6-LacZ genome. The new recombinant virus HFEM/LAT-LacZ was detected as white plaques in the presence of X-gal, since beta-galactosidase expression, when driven by the LAT promoter, is not detectable during viral replication in tissue culture. The high yield (approximately 100%) of the recombinant virus obtainable from this in vitro ligation and transfection procedure coupled with a blue-white or reversible white-blue plaque detection scheme makes this a powerful method for constructing HSV-1 vectors around the LAT promoter locus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Temperature adaptation of proteins: engineering mesophilic-like activity and stability in a cold-adapted alpha-amylase.

Two multiple mutants of a psychrophilic alpha-amylase were produced, bearing five mutations (each introducing additional weak interactions found in pig pancreatic alpha-amylase) with or without an extra disulfide bond specific to warm-blooded animals. Both multiple mutants display large modifications of stability and activity arising from synergic effects in comparison with single mutations. Newly introduced weak interactions and the disulfide bond confer mesophilic-like stability parameters, as shown by increases in the melting point t(m), in the calorimetric enthalpy DeltaH(cal) and in protection against heat inactivation, as well as by decreases in cooperativity and reversibility of unfolding. In addition, both kinetic and thermodynamic activation parameters of the catalyzed reaction are shifted close to the values of the porcine enzyme. This study confirms the central role of weak interactions in regulating the balance between stability and activity of an enzyme in order to adapt to the environmental temperature.

Animals↗
PubMed2005

A predominantly articular cartilage-associated gene, SCRG1, is induced by glucocorticoid and stimulates chondrogenesis in vitro.

OBJECTIVE: Cartilage tissue engineering using multipotential human mesenchymal stem cells (hMSCs) is a promising approach to develop treatment for degenerative joint diseases. A key requirement is that the engineered tissues maintain their hyaline articular cartilage phenotype and not proceed towards hypertrophy. It is noteworthy that osteoarthritic articular cartilage frequently contains limited regions of reparative cartilage, suggesting the presence of bioactive factors with regenerative activity. Based on this idea, we recently performed cDNA microarray analysis to identify genes that are strongly expressed only in articular cartilage and encode secreted gene products. One of the genes that met our criteria was SCRG1. This study aims to analyze SCRG1 function in cartilage development using an in vitro mesenchymal chondrogenesis system. METHODS: Full-length SCRG1 cDNA was subcloned into pcDNA5 vector, and transfected into hMSCs and murine C3H10T1/2 mesenchymal cells, placed in pellet cultures and micromass cultures, respectively. The cultures were analyzed by reverse transcription-polymerase chain reaction for the expression of SCRG1 and cartilage marker genes, and by histological staining for cartilage phenotype. RESULTS: Induction of SCRG1 expression was seen during in vitro chondrogenesis, and was dependent on dexamethasone (DEX) known to promote chondrogenesis. Immunohistochemistry revealed that SCRG1 protein was localized to the extracellular matrix. Forced expression of SCRG1 in hMSCs suppressed their proliferation, and stimulated chondrogenesis in C3H10T1/2 cells, confirmed by reduced collagen type I and elevated collagen type IIB expression. CONCLUSION: These results suggest that SCRG1 is involved in cell growth suppression and differentiation during DEX-dependent chondrogenesis. SCRG1 may be of utility in gene-mediated cartilage tissue engineering.

Aged↗
PubMed2005

Engineered Streptomyces quorum-sensing components enable inducible siRNA-mediated translation control in mammalian cells and adjustable transcription control in mice.

BACKGROUND: Recent advances in functional genomics, gene therapy, tissue engineering, drug discovery and biopharmaceuticals production have been fostered by precise small-molecule-mediated fine-tuning of desired transgenes. METHODS: Capitalizing on well-evolved quorum-sensing regulatory networks in Streptomyces coelicolor we have designed a mammalian regulation system inducible by the non-toxic butyrolactone SCB1. Fusion of the S. coelicolor SCB1 quorum-sensing receptor ScbR to the human Kox-1-derived transsilencing domain reconstituted a mammalian transsilencer (SCS) able to repress transcription from SCS-specific operator-containing promoters in a reverse SCB1-adjustable manner. RESULTS: This quorum-sensing-derived mammalian transgene control system (Q-ON) enabled precise SCB1-specific fine-tuning of (i) desired transgene transcription in a variety of mammalian/human cell lines and human primary cells, (ii) small interfering RNA-mediated posttranscriptional knockdown (siRNA) in mammalian cells, and (iii) dosing of a human glycoprotein in mice. CONCLUSIONS: As exemplified by Q-ON technology, bacterial quorum-sensing regulons may represent a near-infinite source for the design of mammalian gene control systems compatible with molecular interventions relevant to future gene therapy and tissue engineering scenarios.

4-Butyrolactone↗
PubMed2001

Three-dimensional cartilage formation by bone marrow-derived cells seeded in polylactide/alginate amalgam.

Bone marrow-derived cells are considered as candidate cells for cartilage tissue engineering by virtue of their ability to undergo chondrogenesis in vitro when cultured in high density or when embedded within a three-dimensional matrix in the presence of growth factors. This study evaluated the potential of human bone marrow-derived cells for cartilage tissue engineering by examining their chondrogenic properties within a three-dimensional amalgam scaffold consisting of the biodegradable polymer, poly-L-lactic acid (PLA) alone, and with the polysaccharide gel, alginate. Cells were suspended either in alginate or medium and loaded into porous PLA blocks. Alginate was used to improve cell loading and retention within the construct, whereas the PLA polymeric scaffold provided appropriate mechanical support and stability to the composite culture. Cells seeded in the PLA/alginate amalgams and the plain PLA constructs were treated with different concentrations of recombinant human transforming growth factor-beta1 (TGF-beta 1) either continuously (10 ng/mL) or only for the initial 3 days of culture (50 ng/mL). Chondrogenesis was assessed at weekly intervals with cultures maintained for up to 3 weeks. Histological and immunohistochemical analysis of the TGF-beta 1-treated PLA/alginate amalgam and PLA constructs showed development of a cartilaginous phenotype from day 7 to day 21 as demonstrated by colocalization of Alcian blue staining with collagen type II and cartilage proteoglycan link protein. Expression of cartilage specific genes, including collagen types II and IX, and aggrecan, was detected in TGF-beta 1-treated cultures by reverse transcription-polymerase chain reaction analysis. The initiation and progression of chondrogenic differentiation within the polymeric macrostructure occurred with both continuous and the initial 3-day TGF-beta 1 treatment regimens, suggesting that key regulatory events of chondrogenesis take place during the early period of cell growth and proliferation. Scanning electron microscopy revealed abundant cells with a rounded morphology in the PLA/alginate amalgam. These findings suggest that the three-dimensional PLA/alginate amalgam is a potential candidate bioactive scaffold for cartilage tissue engineering applications.

Alginates↗
PubMed2002

Asymmetric conductivity of engineered porins.

Positively charged peptide segments of 16 and 18 residues were inserted at a periplasmic turn of the porin from Rhodobacter blasticus in order to form an electric field-dependent plug. The X-ray diffraction analysis of a mutant confirmed that the structure of the porin had remained intact and that the insert was mobile. Incorporation experiments of single molecules into lipid bilayers showed that the distribution of electric conduction increments depended on the field polarity. The observed distributions are explained if the porin molecules enter the bilayer preferentially with their periplasmic surface first. Furthermore, the conduction of membrane-incorporated porin mutants changed reproducibly on field reversal showing asymmetries of reverse similar 15%, while the wild-type remained constant. This asymmetry is most likely caused by the electric field pressing the charged insert onto the pore eyelet in one field direction and removing it from the eyelet in the other. The results encourage attempts to improve the inserts in order to eventually reach diode characteristics.

Amino Acid Sequence↗
PubMed1986

Respiratory disease in a photographer.

Reversible airways obstruction occurred in a photographer after long-term exposure (over many years) to sulfuric and acetic acid fixers. Air-exchange recommendations for darkrooms by the Building Officials Code Administration [1981] differ markedly from those recommended by the American Society of Heating, Refrigerating, and Airconditioning Engineers [1977] and the fixer manufacturer (Eastman Kodak). Use of fume hoods or rates of air-exchange higher than are required by law may be necessary to prevent symptoms and disease in certain workers.

Adult↗
PubMed1999

Some properties of mitochondrial adrenodoxin associated with its nonconventional electron donor function toward rabbit liver microsomal cytochrome P450 2B4.

Mitochondrial adrenodoxin (Adx) was found to cross-react with microsomal cytochrome P450 2B4 (CYP2B4) as the terminal electron acceptor. When compared with NADPH-cytochrome P450 reductase (P450R), the natural redox partner of CYP2B4, Adx was less efficient both in transferring the first electron and in coupling the system. The ferredoxin yielded an unusual reverse type I spectral change with low-spin CYP2B4, which underwent transformation to a typical type I optical perturbation upon deletion of the signal anchor sequence (Delta2-27) of the hemoprotein. Truncation of CYP2B4 slightly fostered electron transfer from Adx, but was deleterious to reduction of the engineered isozyme by P450R. Addition of manganese-substituted cytochrome b5, which failed to serve as an electron donor to CYP2B4, augmented the amount of hemoprotein existing in form of a low-spin complex with Adx and affected the ferredoxin-dependent reduction kinetics through causing a proportional rise in both Km and Vmax. Conservative replacement of Asp-76 with glutamate in the Adx molecule was associated with a drastic drop in reductive efficiency toward CYP2B4, while spectral binding of the mutant to the hemoprotein was marginally changed. The results support the concept of an evolutionary relationship between the various cytochrome P450 forms as regards the conservation of surface regions participating in contacts with heterologous donor proteins.

Adrenodoxin↗
PubMed1988

Identification and isolation of methionine-cysteine rich proteins in soybean seed.

We recently developed a method to identify methionine-containing proteins and quantitate their methionine contents. We applied this method to soybeans and identified relatively methionine-rich proteins (MRP) among the albumins. By acidic methanol extraction of the albumins, we obtained a group of low molecular weight methionine-cysteine rich proteins (MCRP) that analyzed 4.0% methionine and 8.8% cysteine. MCRP made up 1-2% of the total protein in soybeans. Reversed-phase HPLC purification of MCRP yielded a protein peak that exhibited a single major band on denaturing polyacrylamide gel electrophoresis, had a molecular weight of 16 kD and contained 6.2% methionine and 18.8% cysteine. We are cloning the gene for this protein. Increasing its level through genetic engineering could increase the methionine-cysteine content of soybeans.

Amino Acids↗
PubMed2003

Beta-adrenergic stimulation induces cardiac ankyrin repeat protein expression: involvement of protein kinase A and calmodulin-dependent kinase.

OBJECTIVE: The cardiac ankyrin repeat protein (CARP), a nuclear transcription co-factor that negatively regulates cardiac gene expression, is increased in human heart failure and in animal models of cardiac hypertrophy. The mechanism by which CARP expression is regulated and the consequences of CARP overexpression on cardiac contractility are unknown. METHODS AND RESULTS: Compared to vehicle treated controls, 4-day treatment of male Wistar rats with the beta-adrenoceptor agonist isoprenaline (2.4 mg/kg per day) induced hypertrophy and significantly increased CARP mRNA and CARP protein levels in left ventricles. The signalling pathways were investigated in more detail in isolated neonatal rat cardiomyocytes. Treatment of cells with isoprenaline (1 micromol/l) caused a significant increase in CARP mRNA and protein by approximately 50%. Combined beta(1)- and beta(2)-adrenoceptor blockade, inhibition of protein kinase A (PKA; Rp-cAMPS, 100 micromol/l), and inhibition of calmodulin-dependent protein kinases (CaMK; KN-62, 10 micromol/l) completely reversed the effects of isoprenaline. To examine the consequences of CARP overexpression on contractile function, an adenovirus encoding human CARP as well as a control virus were constructed. Although the basal force of contraction was not different, contractile response to Ca(2+) and isoprenaline was significantly diminished in engineered heart tissue infected with the recombinant adenovirus that carries the CARP gene (Ad.CARP). CONCLUSIONS: Our study provides the first evidence that overexpression of CARP, which is thought to act as a transcriptional co-repressor, may deteriorate contractile function of the heart tissue. Furthermore, beta-adrenoceptor stimulation and activation of PKA and CaMK have been identified as mechanisms that induce expression of CARP in cardiomyocytes.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2000

A Salmonella detection system using an engineered DNA binding protein that specifically captured a DNA sequence.

We have developed a novel method for the detection with high selectivity of a double-stranded DNA fragment using an engineered DNA-binding protein, DnaA IV, a fusion protein of the DNA-binding domain of DnaA and glutathione S-transferase. The DNA fragment detection system is based on DNA-protein interaction and consists of sequence-specific binding of DnaA IV with a DNA fragment containing the DnaA box. DnaA IV, while not capturing other DNA fragments, specifically captured that containing the DnaA box. Because the oriC fragment containing the DnaA box could be specifically amplified by PCR from the genus Salmonella, the DNA fragment detection system was adapted for the detection of Salmonella. The Salmonella detection system using PCR amplification and the engineered DNA-binding protein could distinguish 104 cfu/mL Salmonella from 106 cfu/ mL contaminating bacteria.

Culture Media↗
PubMed2026

A reproducible three-dimensional model of human brain tissue to investigate physiological and disease-associated microglia phenotypes.

Stem-cell-based in vitro models offer promising potential to elucidate human brain cell functions and interactions, but limitations in reproducibility, maturation and cell-type diversity persist. Especially, prolonged incorporation of mature microglia and studies of neuroinflammation have proven challenging. Here, we developed a human induced pluripotent stem cell-based three-dimensional cortical brain tissue model (3BTM) containing neurons, astrocytes and microglia with high reproducibility, maturity and viability. 3BTMs show morphological, functional and proteomic maturation of all cell types, leading to high similarity to their in vivo counterparts. Incorporated microglia survive for over 6 months and display mature morphology, functions and gene expression. Importantly, when engineered to model Alzheimer's disease pathology, 3BTMs recapitulate key disease hallmarks, including amyloid deposition, increased phospho-tau levels and neuroinflammation, with microglia shifting their transcriptional landscape to disease-relevant signatures. Treatment of Alzheimer's disease 3BTMs with anti-Aβ immunotherapy cleared deposits and largely reversed disease signatures in glia. Together, our microglia-containing model provides a platform for studying physiological and pathological states of human brain tissue.

Humans↗
PubMed2003

Interleukin-2 abolishes myeloid cell accumulation induced by Lewis lung carcinoma.

Immune aberration in cancer patients can be at least partly ascribed to an accumulation of immature myeloid cells and monocytes/macrophages with immunosuppressive functions. Mice implanted with Lewis lung carcinoma 2 (LL/2) cells show marked splenomegaly as the tumors progress, and this condition is accompanied by impaired T cell activities. We characterized the cells that accumulated in the spleens of LL/2 tumor-bearing mice and attempted to restore the normal cell population by employing interleukin-2 (IL-2). Flow cytometric analysis revealed that the cells expressing Mac1, B7, NK-K1, Gra-1, and MHC class II antigens on their surfaces drastically decreased in number when LL/2 had been engineered to produce IL-2. IL-2 also restored the concanavalin A (ConA)-mediated proliferative response and IL-2 production of the spleen cells. The in vivo growth of IL-2-producing tumors was significantly slower than that of parental LL/2 cells. Therefore, local IL-2 production may reverse systemic immune abnormality by stopping myeloid cell accumulation.

Animals↗
PubMed2002

Scanning mutagenesis identifies amino acid residues essential for the in vivo activity of the Escherichia coli DnaJ (Hsp40) J-domain.

The DnaJ (Hsp40) cochaperone regulates the DnaK (Hsp70) chaperone by accelerating ATP hydrolysis in a cycle closely linked to substrate binding and release. The J-domain, the signature motif of the Hsp40 family, orchestrates interaction with the DnaK ATPase domain. We studied the J-domain by creating 42 mutant E. coli DnaJ variants and examining their phenotypes in various separate in vivo assays, namely, bacterial growth at low and high temperatures, motility, and propagation of bacteriophage lambda. Most mutants studied behaved like wild type in all assays. In addition to the (33)HisProAsp(35) (HPD) tripeptide found in all known functional J-domains, our study uncovered three new single substitution mutations (Y25A, K26A, and F47A) that totally abolish J-domain function. Furthermore, two glycine substitution mutants in an exposed flexible loop (R36G, N37G) showed partial loss of J-domain function alone and complete loss of function as a triple (RNQ-GGG) mutant coupled with the phenotypically silent Q38G. Interestingly, all the essential residues map to a small region on the same solvent-exposed face of the J-domain. Engineered mutations in the corresponding residues of the human Hdj1 J-domain grafted in E. coli DnaJ also resulted in loss of function, suggesting an evolutionarily conserved interaction surface. We propose that these clustered residues impart critical sequence determinants necessary for J-domain catalytic activity and reversible contact interface with the DnaK ATPase domain.

Amino Acid Sequence↗
PubMed2006

A base pair at the bottom of the anticodon stem is reciprocally preferred for discrimination of cognate tRNAs by Escherichia coli lysyl- and glutaminyl-tRNA synthetases.

Although the yeast amber suppressor tRNA(Tyr) is a good candidate for a carrier of unnatural amino acids into proteins, slight misacylation with lysine was found to occur in an Escherichia coli protein synthesis system. Although it was possible to restrain the mislysylation by genetically engineering the anticodon stem region of the amber suppressor tRNA(Tyr), the mutant tRNA showing the lowest acceptance of lysine was found to accept a trace level of glutamine instead. Moreover, the glutamine-acceptance of various tRNA(Tyr) transcripts substituted at the anticodon stem region varied in reverse proportion to the lysine-acceptance, similar to a 'seesaw'. The introduction of a C31-G39 base pair at the site was most effective for decreasing the lysine-acceptance and increasing the glutamine-acceptance. When the same substitution was introduced into E.coli tRNA(Lys) transcripts, the lysine-accepting activity was decreased by 100-fold and faint acceptance of glutamine was observed. These results may support the idea that there are some structural element(s) in the anticodon stem of tRNA, which are not shared by aminoacyl-tRNA synthetases that have similar recognition sites in the anticodon, such as E.coli lysyl- and glutaminyl-tRNA synthetases.

Amino Acyl-tRNA Synthetases↗
PubMed2003

Evidence for protein phosphatase inhibitor-1 playing an amplifier role in beta-adrenergic signaling in cardiac myocytes.

The protein phosphatase inhibitor-1 (PPI-1) inhibits phosphatase type-1 (PP1) only when phosphorylated by protein kinase A and could play a pivotal role in the phosphorylation/dephosphorylation balance. Rat cardiac PPI-1 was cloned by reverse transcriptase-polymerase chain reaction, expressed in Eschericia coli, evaluated in phosphatase assays, and used to generate an antiserum. An adenovirus was constructed encoding PPI-1 and green fluorescent protein (GFP) under separate cytomegalovirus promotors (AdPPI-1/GFP). A GFP-only virus (AdGFP) served as control. Engineered heart tissue (EHT) from neonatal rat cardiomyocytes and adult rat cardiac myocytes (ARCMs) were used as model systems. PPI-1 expression was determined in human ventricular samples by Northern blots. Compared with AdGFP, AdPPI-1/GFP-infected neonatal rat cardiomyocytes displayed a 73% reduction in PP1 activity. EHTs infected with AdPPI-1/GFP exhibited a fivefold increase in isoprenaline sensitivity. AdPPI-1/GFP-infected ARCMs displayed enhanced cell shortening as well as enhanced phospholamban phosphorylation when stimulated with 1 nM isoprenaline. PPI-1 mRNA levels were reduced by 57+/-12% in failing hearts with dilated and ischemic cardiomyopathy (n=8 each) compared with nonfailing hearts (n=8). In summary, increased PPI-1 expression enhances myocyte sensitivity to isoprenaline, indicating that PPI-1 acts as an amplifier in beta-adrenergic signaling. Decreased PPI-1 in failing human hearts could participate in desensitization of the cAMP pathway.

Adenoviridae↗