148 research outputs found
Widespread Occurrence of Secondary Lipid Biosynthesis Potential in Microbial Lineages
Bacterial production of long-chain omega-3 polyunsaturated fatty acids (PUFAs),
such as eicosapentaenoic acid (EPA, 20:5n-3) and
docosahexaenoic acid (DHA, 22:6n-3), is constrained to a narrow
subset of marine γ-proteobacteria. The genes responsible for de
novo bacterial PUFA biosynthesis, designated
pfaEABCD, encode large, multi-domain protein complexes akin
to type I iterative fatty acid and polyketide synthases, herein referred to as
“Pfa synthases”. In addition to the archetypal Pfa synthase gene
products from marine bacteria, we have identified homologous type I FAS/PKS gene
clusters in diverse microbial lineages spanning 45 genera representing 10 phyla,
presumed to be involved in long-chain fatty acid biosynthesis. In total, 20
distinct types of gene clusters were identified. Collectively, we propose the
designation of “secondary lipids” to describe these
biosynthetic pathways and products, a proposition consistent with the
“secondary metabolite” vernacular. Phylogenomic analysis reveals a
high degree of functional conservation within distinct biosynthetic pathways.
Incongruence between secondary lipid synthase functional clades and taxonomic
group membership combined with the lack of orthologous gene clusters in closely
related strains suggests horizontal gene transfer has contributed to the
dissemination of specialized lipid biosynthetic activities across disparate
microbial lineages
PDGF-C Induces Maturation of Blood Vessels in a Model of Glioblastoma and Attenuates the Response to Anti-VEGF Treatment
Recent clinical trials of VEGF inhibitors have shown promise in the treatment of recurrent glioblastomas (GBM). However, the survival benefit is usually short-lived as tumors escape anti-VEGF therapies. Here we tested the hypothesis that Platelet Derived Growth Factor-C (PDGF-C), an isoform of the PDGF family, affects GBM progression independent of VEGF pathway and hinders anti-VEGF therapy.We first showed that PDGF-C is present in human GBMs. Then, we overexpressed or downregulated PDGF-C in a human GBM cell line, U87MG, and grew them in cranial windows in nude mice to assess vessel structure and function using intravital microscopy. PDGF-C overexpressing tumors had smaller vessel diameters and lower vascular permeability compared to the parental or siRNA-transfected tumors. Furthermore, vessels in PDGF-C overexpressing tumors had more extensive coverage with NG2 positive perivascular cells and a thicker collagen IV basement membrane than the controls. Treatment with DC101, an anti-VEGFR-2 antibody, induced decreases in vessel density in the parental tumors, but had no effect on the PDGF-C overexpressing tumors.These results suggest that PDGF-C plays an important role in glioma vessel maturation and stabilization, and that it can attenuate the response to anti-VEGF therapy, potentially contributing to escape from vascular normalization
Methamphetamine-Induced Dopamine-Independent Alterations in Striatal Gene Expression in the 6-Hydroxydopamine Hemiparkinsonian Rats
Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle are used extensively as a model of Parkinson's disease. The present experiments sought to identify genes that were affected in the dopamine (DA)–denervated striatum after 6-hydroxydopamine-induced destruction of the nigrostriatal dopaminergic pathway in the rat. We also examined whether a single injection of methamphetamine (METH) (2.5 mg/kg) known to cause changes in gene expression in the normally DA-innervated striatum could still influence striatal gene expression in the absence of DA. Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle resulted in METH-induced rotational behaviors ipsilateral to the lesioned side and total striatal DA depletion on the lesioned side. This injection also caused decrease in striatal serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels. DA depletion was associated with increases in 5-HIAA/5-HT ratios that were potentiated by the METH injection. Microarray analyses revealed changes (± 1.7-fold, p<0.025) in the expression of 67 genes on the lesioned side in comparison to the intact side of the saline-treated hemiparkinsonian animals. These include follistatin, neuromedin U, and tachykinin 2 which were up-regulated. METH administration caused increases in the expression of c-fos, Egr1, and Nor-1 on the intact side. On the DA-depleted side, METH administration also increased the expression of 61 genes including Pdgf-d and Cox-2. There were METH-induced changes in 16 genes that were common in the DA-innervated and DA-depleted sides. These include c-fos and Nor-1 which show greater changes on the normal DA side. Thus, the present study documents, for the first time, that METH mediated DA-independent changes in the levels of transcripts of several genes in the DA-denervated striatum. Our results also implicate 5-HT as a potential player in these METH-induced alterations in gene expression because the METH injection also caused significant increases in 5-HIAA/5-HT ratios on the DA-depleted side
Platelet-Derived Growth Factor (PDGF) in primary brain tumours of neuroglial origin
It has become clear that disruptions in the genome of somatic cells play a causative role in tumour development. We know that the ultimate formation of a malignancy is the result of a multistep process in which the functional loss andlor the altered or increased expression of genes play important roles. One such family of genes are the oncogenes, encoding protein products with mainly growth stimulating effects. Platelet-derived growth factor (PDGF) belongs to the family of oncogenes. It is likely that PDGF plays an essential role in the development of at least a subgroup of malignant astrocytic tumours that do not contain amplification of the EGF-receptor. The expression of PDGF a-receptors is related to tumour progression in these tumours, and some of the most malignant tumours were shown to contain amplification of the PDGF areceptor. It is also clear now from several experimental studies that PDGF can drive the transformed phenotype, and that PDGF antagonists, by blocking the PDGF autocrine pathway revert the transformed phenotype of certain tumour cells. Because of the findings that receptor protein tyrosine kinases such as the EGF- and the PDGF-receptor play a crucial role in the development of gliomas, it is possible that inhibitors of the phosphorylation of the protein tyrosine kinases will be future candidates for glioma therapy. They might be able to at least delay the development of a fully malignant glioma. The role of PDGF in other tumours of neuroglial origin in the central nervous system has not been studied as extensively as its role in gliomas. Recent data suggest that also for the primitive neuroectodermal tumours overexpression of the PDGF a-receptor is related to malignancy of the tumours. For other tumours, such as neuroblastomas, PDGF exerts a differentiating rather than a mitogenic function and is an important survival factor. Further studies are needed to elucidate the role of PDGF in these non-glial primary brain tumours. Moreover, for a complete understanding of the role of PDGF in malignancies of the CNS, it is important to explore its function in the development of the normal CNS further
Platelet-Derived Growth Factor PDGF in primary brain tumours of neuroglial origin
It has become clear that disruptions in the
genome of somatic cells play a causative role in tumour
development. We know that the ultimate formation of a
malignancy is the result of a multistep process in which
the functional loss andlor the altered or increased
expression of genes play important roles. One such
family of genes are the oncogenes, encoding protein
products with mainly growth stimulating effects.
Platelet-derived growth factor (PDGF) belongs to the
family of oncogenes. It is likely that PDGF plays an
essential role in the development of at least a subgroup
of malignant astrocytic tumours that do not contain
amplification of the EGF-receptor. The expression of
PDGF a-receptors is related to tumour progression in
these tumours, and some of the most malignant tumours
were shown to contain amplification of the PDGF areceptor.
It is also clear now from several experimental
studies that PDGF can drive the transformed phenotype,
and that PDGF antagonists, by blocking the PDGF
autocrine pathway revert the transformed phenotype of
certain tumour cells. Because of the findings that
receptor protein tyrosine kinases such as the EGF- and
the PDGF-receptor play a crucial role in the development
of gliomas, it is possible that inhibitors of the
phosphorylation of the protein tyrosine kinases will be
future candidates for glioma therapy. They might be able
to at least delay the development of a fully malignant
glioma. The role of PDGF in other tumours of neuroglial
origin in the central nervous system has not been studied
as extensively as its role in gliomas. Recent data suggest
that also for the primitive neuroectodermal tumours
overexpression of the PDGF a-receptor is related to
malignancy of the tumours. For other tumours, such as
neuroblastomas, PDGF exerts a differentiating rather
than a mitogenic function and is an important survival
factor. Further studies are needed to elucidate the role of
PDGF in these non-glial primary brain tumours.
Moreover, for a complete understanding of the role of
PDGF in malignancies of the CNS, it is important to
explore its function in the development of the normal
Offprint requests to: Dr. Anja Smits, Department of Neurology,
University Hospital Uppsala, S-751 85 Uppsala, Sweden
CNS further
Autocrine endothelial regulation in brain stem vessels of newborn piglets
Vasoactive intestinal peptide (VIP) is known as a potent regulator for the development of the central nervous system (CNS). The neonatal period of brain development is characterised by rapid cellular proliferation in parallel with neuronal differentiation and angiogenesis. We examined the expression of native VIP and the VIP receptor-associated protein by immunohistochemistry as well as the expression of VIP mRNA by in situ hybridisation in the brain stem of newborn piglets. We found both the mRNA and the protein of VIP as well as the VIP receptor-associated protein in endothelial cells of veins, arteries and capillaries in the marginal zone of brain stem tissue sections, especially in pons and mesencephalon, as well as in pia1 vessels. The coexpression of native VIP, VIP mRNA and the VIP receptor-associated protein within the endothelium suggests the presence of an autocrine loop, which has been detected so far only in neuroblastoma cells. This expression pattern gives evidence to the immaturity of endothelial cells at birth and the presence of an adaptive response in the VIP-regulated system during the change from intra- to extrauterine life
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