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1.  A lipid-rich gestational diet predisposes offspring to nonalcoholic fatty liver disease: a potential sequence of events 
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome. It affects 20%–30% of the US population, and it is increasing worldwide. Recently, the role of lipid-rich maternal gestational nutrition in spurring the development of NAFLD among offspring has been indicated. Fetal predisposition to NAFLD involves numerous physiological reroutings that are initiated by increased delivery of nonesterified fatty acids to the fetal liver. Hampered β-oxidation, uncontrolled oxidative stress, increased triacylglycerol synthesis, and the endoplasmic reticulum unfolded protein response are all implicated in sculpting a hepatic phenotype with a propensity to develop NAFLD in the postnatal state. This review suggests a mechanism that integrates outcomes reported by a variety of studies conducted in an analysis of fetal hepatic metabolic capacity amid the maternal consumption of a high-fat diet. Potential preventive measures and therapies for use both as part of prenatal nutrition and for those at risk for the development of NAFLD are also discussed.
doi:10.2147/HMER.S57500
PMCID: PMC3953741
nonalcoholic fatty liver disease; fetal–maternal diet; hepatocyte; oxidative stress
2.  Minor fibrillar collagens; variable regions alternative splicing, intrinsic disorder, and tyrosine sulfation 
Protein & cell  2012;3(6):419-433.
Minor fibrillar collagen types V and XI, are those less abundant than the fibrillar collagens types I, II and III. The alpha chains share a high degree of similarity with respect to protein sequence in all domains except the variable region. Genomic variation and, in some cases, extensive alternative splicing contribute to the unique sequence characteristics of the variable region. While unique expression patterns in tissues exist, the functions and biological relevance of the variable regions have not been elucidated. In this review, we summarize the existing knowledge about expression patterns and biological functions of the collagen types V and XI alpha chains. Analysis of biochemical similarities among the peptides encoded by each exon of the variable region suggest the potential for shared function. The alternative splicing, conservation of biochemical characteristics in light of low sequence conservation, and evidence for intrinsic disorder, suggests modulation of binding events between the surface of collagen fibrils and surrounding extracellular molecules as a shared function.
doi:10.1007/s13238-012-2917-5
PMCID: PMC3484837  PMID: 22752873
minor fibrillar collagens; variable regions; alternative splicing; fibrillogenesis; heparan sulfate binding sites; intrinsic disorder; tyrosine sulfation
3.  Proteomic analysis of Col11a1-associated protein complexes 
Proteomics  2011;11(24):4660-4676.
Cartilage plays an essential role during skeletal development within the growth plate and in articular joint function. Interactions between the collagen fibrils and other extracellular matrix molecules maintain structural integrity of cartilage, orchestrate complex dynamic events during embryonic development, and help to regulate fibrillogenesis. To increase our understanding of these events, affinity chromatography and liquid chromatography/tandem mass spectrometry were used to identify proteins that interact with the collagen fibril surface via the amino terminal domain of collagen alpha 1(XI) a protein domain that is displayed at the surface of heterotypic collagen fibrils of cartilage. Proteins extracted from fetal bovine cartilage using homogenization in high ionic strength buffer were selected based on affinity for the amino terminal noncollagenous domain of collagen alpha 1(XI). Mass spectrometry was used to determine the amino acid sequence of tryptic fragments for protein identification. Extracellular matrix molecules and cellular proteins that were identified as interacting with the amino terminal domain of collagen alpha 1(XI) directly or indirectly, included proteoglycans, collagens, and matricellular molecules, some of which also play a role in fibrillogenesis, while others are known to function in the maintenance of tissue integrity. Characterization of these molecular interactions will provide a more thorough understanding of how the extracellular matrix molecules of cartilage interact and what role collagen XI plays in the process of fibrillogenesis and maintenance of tissue integrity. Such information will aid tissue engineering and cartilage regeneration efforts to treat cartilage tissue damage and degeneration.
doi:10.1002/pmic.201100058
PMCID: PMC3463621  PMID: 22038862
arthritis; cartilage; collagen fibril; extracellular matrix; interactions
4.  Expression, Purification, and Refolding of Recombinant Collagen α1(XI) Amino Terminal Domain Splice Variants 
The amino terminal domain of collagen type XI α1 chain is a noncollagenous structure that is essential for the regulation of fibrillogenesis in developing cartilage. The amino terminal domain is alternatively spliced at the mRNA level, resulting in proteins expressed as splice variants. These splice variants, or isoforms, have unique distribution in growing tissues, alluding to distinct roles in development. We report here a rapid and straightforward method for expression, purification and in vitro folding of recombinant collagen XI isoforms α1(XI) NTD[p7] and α1(XI) NTD[p6b+7]. The recombinant isoforms were expressed in Escherichia coli as bacterial inclusion bodies. Unfolded carboxy terminal polyhistidine tagged proteins were purified via nickel affinity chromatography and refolded with specific protocols optimized for each isoform. Purity was assessed by SDS-PAGE and correct secondary structure by a comparison of circular dichroism data with that obtained for Npp. Protein expression and purification of the recombinant collagen XI splice variants will allow further studies to elucidate the structure and molecular interactions with components of the extracellular matrix. This research will clarify the mechanism of collagen XI mediated regulation of collagen fibrillogenesis.
doi:10.1016/j.pep.2006.10.016
PMCID: PMC2713663  PMID: 17166742
5.  Autism as the Early Closure of a Neuroplastic Critical Period Normally Seen in Adolescence 
Biological systems, open access  2013;1:10.4172/2329-6577.1000118.
The most severe cases of autism are diagnosed by extreme social dysfunction and other behavioral abnormalities. A number of genetic studies have been conducted to correlate behavioral phenotypes to genetic dysfunctions, but no “autism gene” has yet been discovered. In addition, environmental factors have been found to influence the development of autistic traits with high probability. This review will examine the role of a shortened period of neuroplasticity as a unifying feature of the autistic phenotype. The neuroplastic period of interest normally extends into adolescence, allowing for neural integration and the development of language and social skills. Early closure of this period may result in a shortened period of development, forcing the brain to rely on underdeveloped structures.
doi:10.4172/2329-6577.1000118
PMCID: PMC3864123  PMID: 24353985
autism spectrum disorder; critical period; plasticity; language acquisition; development
6.  The expression patterns of minor fibrillar collagens during development in zebrafish 
Gene expression patterns : GEP  2010;10(7-8):315-322.
Minor fibrillar collagens are recognized as the organizers and nucleators during collagen fibrillogenesis but likely serve additional functions. The minor fibrillar collagens include collagens type V and type XI. Mutations of collagen type V and XI can cause Ehlers Danlos, Stickler’s, and Marshall’s syndromes in human. We have characterized the spatiotemporal expression patterns of Col11a1, Col11a2, Col5a1 as well as Col5a3 in zebrafish embryos by in situ hybridization. Col5a1 is expressed in developing somites, neural crest, the head mesenchyme, developing cranial cartilage, pharyngeal arches and vertebrae. Col5a3 is detected in the notochord, mesenchyme cells in the eyes and lens. Both Col11a1 and Col11a2 have similar expression patterns, including notochord, otic vesicle, and developing cranial cartilages. Zebrafish may therefore serve as a valuable vertebrate model system for the study of diseases associated with collagens type V and XI mutations.
doi:10.1016/j.gep.2010.07.002
PMCID: PMC2956583  PMID: 20647059
minor fibrillar collagens; zebrafish; development; in situ hybridization; Danio rerio
7.  Interaction between Amino Propeptides of Type XI Procollagen α1 Chains* 
The Journal of biological chemistry  2003;279(12):10939-10945.
Type XI collagen is a quantitatively minor yet essential constituent of the cartilage extracellular matrix. The amino propeptide of the α1 chain remains attached to the rest of the molecule for a longer period of time after synthesis than the other amino propeptides of type XI collagen and has been localized to the surface of thin collagen fibrils. Yeast two-hybrid system was used to demonstrate that a homodimer of α1(XI) amino propeptide (α1(XI)Npp) could form in vivo. Interaction was also confirmed using multi-angle laser light scattering, detecting an absolute weight average molar mass ranging from the size of a monomer to the size of a dimer (25,000–50,000 g/mol), respectively. Binding was shown to be saturable by ELISA. An interaction between recombinant α1(XI)Npp and the endogenous α1(XI)Npp was observed, and specificity for α1(XI)Npp but not α2(XI)Npp was demonstrated by co-precipitation. The interaction between the recombinant form of α1(XI)Npp and the endogenous α1(XI)Npp resulted in a stable association during the regeneration of cartilage extracellular matrix by fetal bovine chondrocytes maintained in pellet culture, generating a protein that migrated with an apparent molecular mass of 50–60 kDa on an SDS-polyacrylamide gel.
doi:10.1074/jbc.M310291200
PMCID: PMC2952413  PMID: 14699108
8.  Isoform-specific Heparan Sulfate Binding within the Amino-terminal Noncollagenous Domain of Collagen α1(XI)* 
The Journal of biological chemistry  2006;281(51):39507-39516.
Collagen type XI is a constituent of the pericellular matrix of chondrocytes and plays a role in the regulation of fibrillogenesis. The amino-terminal domain of collagen type XI α1 chain is a noncollagenous structure that has been identified on the surface of cartilage collagen fibrils. The biochemical composition of the amino-terminal domain varies due to alternative splicing of the primary transcript. Recombinantly expressed α1(XI) amino-terminal domain isoforms were used in this study to investigate potential interactions. Purified products were analyzed for heparan sulfate binding properties. The results demonstrated that two additional binding sites exist within the α1(XI) amino-terminal domain, one within the amino propeptide and one within the variable region of the amino-terminal domain. Analysis of relative affinities indicated that the site located within the amino propeptide (site 1) was of similar affinity to sites that exist within the major triple helix of collagen type XI. Substitution of amino acid residues 147 to 152 within the amino propeptide by site-directed mutagenesis resulted in altered affinity for heparan sulfate. The binding site located within the variable region (site 2) demonstrated significantly higher affinity than other sites within the molecule. Displacement of collagen type XI within the pericellular matrix was observed in cell culture in the presence of excess heparan sulfate and by treatment with heparinase. These studies suggest two additional binding sites located within the noncollagenous amino-terminal domain that may play a role in the function of collagen type XI. The localization of collagen type XI within the pericellular matrix may be dependent upon interactions with heparan sulfate proteoglycans, and these are likely to take place in an isoform-specfic manner.
doi:10.1074/jbc.M608551200
PMCID: PMC2948787  PMID: 17062562
9.  Characterization of collagenous matrix assembly in a chondrocyte model system 
Collagen is a major component of the newly synthesized pericellular microenvironment of chondrocytes. Collagen types II, IX, and XI are synthesized and assembled into higher ordered complexes by a mechanism in which type XI collagen plays a role in nucleation of new fibrils, and in limiting fibril diameter. This study utilizes a cell line derived from the Swarm rat chondrosarcoma that allows the accumulation and assembly of pericellular matrix. Immunofluorescence and atomic force microscopy were used to assess early intermediates of fibril formation. Results indicate that this cell line synthesizes and secretes chondrocyte-specific pericellular matrix molecules including types II, IX, and XI collagen and is suitable for the study of newly synthesized collagen matrix under the experimental conditions used. AFM data indicate that small fibrils or assemblies of microfibrils are detectable and may represent precursors of the ~20 nm thin fibrils reported in cartilage. Treatment with hyaluronidase indicates that the dimensions of the small fibrils may be dependent upon the presence of hyaluronan within the matrix. This study provides information on the composition and organization of the newly synthesized extracellular matrix that plays a role in establishing the material properties and performance of biological materials such as cartilage.
doi:10.1002/jbm.a.32078
PMCID: PMC2842207  PMID: 18496861
cartilage; collagen; extracellular matrix; immunofluorescence; atomic force microscopy; chondrocyte; microfibril
10.  Differential Expression of Collagen Type V and XI α-1 in Human Ascending Thoracic Aortic Aneurysms 
The Annals of thoracic surgery  2009;88(2):506-513.
Background
The molecular mechanisms leading to ascending thoracic aortic aneurysms (ATAAs) remain unknown. We hypothesized that alterations in expression levels of specific fibrillar collagens occur during the aneurysmal process.
Methods
Surgical samples from ascending aortas from patients with degenerative ATAAs were subdivided by aneurysm diameter: small, 5 to 6 cm; medium, 6 to 7 cm; and large, greater than 7 cm; and compared with nonaneurysmal aortas (mean diameter, 2.3 cm).
Results
Histology, immunofluorescence, and electron microscopy demonstrated greater disorganization of extracellular matrix constituents in ATAAs as compared with control with an increase in collagen α1(XI) within regions of cystic medial degenerative lesions. Real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) showed collagens type V and α1(XI) were significantly and linearly increased in ATAAs as compared with control (p < 0.001). There was no change in the messenger ribonucleic acid (mRNA) expression levels of collagens type I and III. Western blot analysis showed collagens type I and III were significantly decreased and collagens α1(XI) and V were significantly increased and were linearly correlated with the size of the aneurysm (p < 0.001 for both).
Conclusions
These results demonstrate that increased collagen α1(XI) and collagen V mRNA and protein levels are linearly correlated with the size of the aneurysm and provide a potential mechanism for the generation and progression of aneurysmal enlargement.
doi:10.1016/j.athoracsur.2009.04.030
PMCID: PMC2834780  PMID: 19632402

Results 1-10 (10)