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Nutrition is an important regulator of the tempo of growth and obesity is usually associated with tall childhood stature and earlier pubertal development. Several longitudinal studies have demonstrated that timing of puberty is most closely linked to infancy weight gain: suggesting an early window for programming of growth and development. Earlier puberty in the UK MRC 1946 birth cohort was related to smaller size at birth and rapid growth between 0 and 2 years. Rapid early weight gain leads to taller childhood stature and higher insulin-like growth factor I (IGF-I) levels, possibly through early induction of growth hormone (GH) receptor numbers, and such children are also at risk of childhood obesity. In the Avon Longitudinal Study of Parents and Children, rapid infancy weight gain was associated with increased risk of obesity at 5 and 8 years, with evidence of insulin resistance, exaggerated adrenarche and reduced levels of sex hormone binding globulin (SHBG). Potentially the elevated IGF-I and adrenal androgen levels, increased aromatase activity and increased 'free' sex steroid levels consequent to lower SHBG levels could all promote activity of the GnRH pulse generator. In addition obese children have higher leptin levels, a proven permissive factor in initiating LH pulsatility. Obesity could also affect the rate of progression through puberty as nutrition and SHBG may act respectively as an accelerator and brake on peripheral sex steroid action. Early weight gain and early pubertal development might also be associated with loss of the pubertal growth spurt perhaps through obesity-related suppression of GH secretion. Trans-generational recurrence of low birth weight, early catch-up weight gain, earlier menarche, and shorter adult stature have been observed in women, and could contribute to the strong heritability in age at menarche.
Mol Cell Endocrinol 2006 Jul 25
PMID:Early and late weight gain and the timing of puberty. 1682 79

Airway remodeling is a structural alteration associated with chronic inflammatory and obstructive airway diseases, wherein fibroblasts are crucially involved. The present study investigates whether lung fibroblast proliferation is influenced by muscarinic mechanisms. For this purpose, expression of muscarinic receptors in MRC-5 human lung fibroblasts was characterized by semiquantitative RT-PCR, and the effects of muscarinic agonists and antagonists on ((3)H)-thymidine incorporation as a measure of proliferative activity were studied under different culture conditions. MRC-5 fibroblasts express mRNA encoding different subtypes of muscarinic receptors (M(2) > M(3) > M(4), traces for M(5) and no M(1)). Expression of M(2) and M(3) receptors was confirmed at the protein level by immunoblot analysis. Under different culture conditions, carbachol (up to 10 microM) or oxotremorine (10 microM) stimulated ((3)H)-thymidine incorporation, with maximum increases between about 40 and 100%. The stimulatory effect of 10 microM carbachol was prevented by pretreatment with pertussis toxin and antagonized in a concentration-dependent manner by the muscarinic receptor antagonists tiotropium, AQ-RA 741, AF-DX 384, 4-diphenylacetoxy-N-methylpiperidine methoiodide, himbacine, p-fluorohexahydrosiladifenidol, and pirenzepine, with concentrations producing 50% inhibition of 14 pM, 24, 64, 127, 187, 452 nM, and 1.5 microM, respectively. Primary human lung fibroblasts were also found to express mRNA for muscarinic receptors (M(2) > M(1) > M(3), traces for M(4) and no M(5)), and showed a pertussis toxin-sensitive proliferative response to muscarinic receptor stimulation. In conclusion, proliferation of human lung fibroblasts can be stimulated by activation of muscarinic receptors with a pharmacologic profile correlating best to M(2) receptors.
Am J Respir Cell Mol Biol 2006 Dec
PMID:Muscarinic receptors mediate stimulation of human lung fibroblast proliferation. 1690 94

Electron crystallography determines the structure of membrane embedded proteins in the two-dimensionally crystallized state by cryo-transmission electron microscopy imaging and computer structure reconstruction. Milestones on the path to the structure are high-level expression, purification of functional protein, reconstitution into two-dimensional lipid membrane crystals, high-resolution imaging, and structure determination by computer image processing. Here we review the current state of these methods. We also created an Internet information exchange platform for electron crystallography, where guidelines for imaging and data processing method are maintained. The server (http://2dx.org) provides the electron crystallography community with a central information exchange platform, which is structured in blog and Wiki form, allowing visitors to add comments or discussions. It currently offers a detailed step-by-step introduction to image processing with the MRC software program. The server is also a repository for the 2dx software package, a user-friendly image processing system for 2D membrane protein crystals.
J Comput Aided Mol Des
PMID:Milestones in electron crystallography. 1710 18

To function in the cell, nonmuscle myosin II molecules assemble into filaments through their C-terminal tails. Because myosin II isoforms most likely assemble into homo-filaments in vivo, it seems that some self-recognition mechanisms of individual myosin II isoforms should exist. Exogenous expression of myosin IIB rod fragment is thus expected to prevent the function of myosin IIB specifically. We expected to reveal some self-recognition sites of myosin IIB from the phenotype by expressing appropriate myosin IIB rod fragments. We expressed the C-terminal 305-residue rod fragment of the myosin IIB heavy chain (BRF305) in MRC-5 SV1 TG1 cells. As a result, unstable morphology was observed like MHC-IIB(-/-) fibroblasts. This phenotype was not observed in cells expressing BRF305 mutants: 1) with a defect in assembling, 2) lacking N-terminal 57 residues (N-57), or 3) lacking C-terminal 63 residues (C-63). A myosin IIA rod fragment ARF296 corresponding to BRF305 was not effective. However, the chimeric ARF296, in which the N-57 and C-63 of BRF305 were substituted for the corresponding regions of ARF296, acquired the ability to induce unstable morphology. We propose that the N-57 and C-63 of BRF305 are involved in self-recognition when myosin IIB molecules assemble into homo-filament.
Mol Biol Cell 2007 Mar
PMID:Two regions of the tail are necessary for the isoform-specific functions of nonmuscle myosin IIB. 1720 8

We recently cloned an NHE3 orthologue from the gills of the euryhaline Atlantic stingray (Dasyatis sabina), and generated a stingray NHE3 antibody to unequivocally localize the exchanger to the apical side of epithelial cells that are rich with Na(+)/K(+)-ATPase (A MRC). We also demonstrated an increase in NHE3 expression when stingrays are in fresh water, suggesting that NHE3 is responsible for active Na(+) absorption. However, the vast majority of elasmobranchs are only found in marine environments. In the current study, immunohistochemistry with the stingray NHE3 antibody was used to localize the exchanger in the gills of the stenohaline marine spiny dogfish shark (Squalus acanthias). NHE3 immunoreactivity was confined to the apical side of cells with basolateral Na(+)/K(+)-ATPase and was excluded from cells with high levels of vacuolar H(+)-ATPase. Western blots detected a single protein of 88 kDa in dogfish gills, the same size as NHE3 in stingrays and mammals. These immunological data demonstrate that the putative cell type responsible for active Na(+) absorption in euryhaline elasmobranchs is also present in stenohaline marine elasmobranchs, and suggest that the inability of most elasmobranchs to survive in fresh water is not due to a lack of the gill ion transporters for Na(+) absorption.
Comp Biochem Physiol A Mol Integr Physiol 2007 Feb
PMID:The putative mechanism of Na(+) absorption in euryhaline elasmobranchs exists in the gills of a stenohaline marine elasmobranch, Squalus acanthias. 1720 25

Hepatocyte growth factor (HGF) has opposite biological activities in regulating apoptosis, also underlying molecular mechanisms are not clearly defined. We investigated HGF ability to inhibit cell death, which was induced by Doxorubicin, a DNA damaging agent. Also Survivin and XIAP mRNA levels were compared in HGF treated and non-treated cells. Cell proliferation and death were assessed using MTT assay and dye exclusion tests. Quantitative real-time PCR was used to evaluate Survivin and XIAP expression levels after treatment with HGF. ELISA was performed to quantify HGF secretion in the selected cancer cell lines media. HGF appeared to have inhibitory effect on Doxorubicin induced cell death in all of the studied cell lines. It had minimal effect on XAIP and Survivin expression levels in MRC-5, MOLT-4 and AGS cell lines; except for XIAP expression level in AGS cell line, which was increased substantially after treatment. Surprisingly, in KG-1 cell line, XIAP and Survivin expression levels were significantly reduced after HGF treatment. Although several members of IAP gene family are reported to play role in HGF mediated cytoprotective pathway, we showed that XIAP and Survivin do not seem to be involved.
Mol Cell Biochem 2007 Oct
PMID:Effect of hepatocyte growth factor (HGF) on the level of Survivin & XIAP expression in several human cancer cell lines, after treating with DNA damaging agent. 1753 99

Chemoresistance and side effects are considered as the major obstacles in cisplatin-based chemotherapy of various human malignant tumors. Conjugation with cancer-specific apoptotic stimuli TRAIL or typical viro-agent ONYX-015 has been extensively investigated to enhance the antitumor activity of cisplatin. In this study, we presented a novel chemo-gene-virotherapeutic strategy to further improve the toxic effects in cancer cells and reduce the damage in normal cells. Here, an oncolytic adenoviral vector (ZD55), with a deletion of E1B 55-kDa gene, was employed to express the therapeutic TRAIL gene by constructing a recombinant virus ZD55-TRAIL. Exogenous gene delivery efficacy was determined by both in vitro and in vivo experiments and enhanced cytotoxicity of combined treatment of ZD55-TRAIL with cisplatin was evaluated in several cancer cell lines. Moreover, negative effects on normal cells have been tested in both L-02 and MRC-5 cell lines by MTT assay and apoptotic cell staining. According to our observation, combination of ZD55-TRAIL with cisplatin exhibited an apparent synergistic cytotoxicity in cancer cells, yet significantly abolished the negative toxicity in normal cells by reducing the dosage. Thus, a novel chemo-gene-virotherapeutic strategy for cancer therapy was proposed.
Mol Cell Biochem 2007 Oct
PMID:Synergistic induction of tumor cell death by combining cisplatin with an oncolytic adenovirus carrying TRAIL. 1757 31

MRC-5 fibroblasts infected with human cytomegalovirus (HCMV) reference strain AD 169 were treated with different concentrations of methylated alpha-lactalbumin (Met-ALA) or methylated beta-lactoglobulin (Met-BLG), as well as with their peptic hydrolysates, and with the highly basic polypeptides such as are L-polylysines (4-15 kDa). The antiviral activity was calculated by comparing the number of infected cells in the presence and absence of the tested substances. Both Met-ALA and Met-BLG, as well as their peptic hydrolysates, decreased the infectious activity of cytomegalovirus in fibroblast cells. As expected, L-polylysines showed the highest antiviral activity. However, the tested basic proteins and polypeptides despite their lower antiviral activities might be potentially quite useful in fight of arising drug resistance activities and the persistence capacities of this virus.
J Mol Microbiol Biotechnol 2007
PMID:Anticytomegaloviral activity of esterified milk proteins and L-polylysines. 1782 77

The reasons for bacterial proliferation in the lungs of mechanically ventilated patients are poorly understood. We hypothesized that prolonged cyclic stretch of lung cells influenced bacterial growth. Human alveolar type II-like A549 cells were submitted in vitro to prolonged cyclic stretch. Bacteria were cultured in conditioned supernatants from cells submitted to stretch and from control static cells. Escherichia coli had a marked growth advantage in conditioned supernatants from stretched A549 cells, but also from stretched human bronchial BEAS-2B cells, human MRC-5 fibroblasts, and murine RAW 264.7 macrophages. Stretched cells compared with control static cells acidified the milieu by producing increased amounts of lactic acid. Alkalinization of supernatants from stretched cells blocked E. coli growth. In contrast, acidification of supernatants from control cells stimulated bacterial growth. The effect of various pharmacological inhibitors of metabolic pathways was tested in this system. Treatment of A549 cells and murine RAW 264.7 macrophages with the Na(+)/K(+)-ATPase pump inhibitor ouabain during cyclic stretch blocked both the acidification of the milieu and bacterial growth. Several pathogenic bacteria originating from lungs of patients with ventilator-associated pneumonia (VAP) also grow better in vitro at slightly acidic pH (pH 6-7.2), pH similar to those measured in the airways from ventilated patients. This novel metabolic pathway stimulated by cyclic stretch may represent an important pathogenic mechanism of VAP. Alkalinization of the airways may represent a promising preventive strategy in ventilated critically ill patients.
Am J Respir Cell Mol Biol 2008 Mar
PMID:Cyclic stretch of human lung cells induces an acidification and promotes bacterial growth. 1792 60

Myofibroblasts are metabolically and morphologically distinctive fibroblasts expressing alpha-smooth muscle actin (alpha-SMA), and their activation plays a key role in development of the fibrotic response. In an activated state, myofibroblasts cease to proliferate and start to synthesize large amounts of extracellular component proteins. The expression of alpha-SMA correlates with the activation of myofibroblasts. Decorin, a member of the small leucine-rich proteoglycan gene family, has been implicated in the negative control of cell proliferation primarily by upregulating the expression of p21, a potent inhibitor of cyclin-dependent kinase. In order to examine the effect of decorin on myofibroblast cell growth, we rendered a human lung myofibroblast cell line, MRC-5, quiescent by either cell-cell contact or serum starvation, and examined the relationship between decorin and alpha-SMA expression in these cells. The expression of decorin in cells made quiescent by serum starvation was lower than that in cells made quiescent by cell-cell contact. In contrast, the expression of alpha-SMA in cells made quiescent by cell-cell contact was lower than that in cells made quiescent by serum starvation. Furthermore, forced expression of decorin was accompanied by a suppression of alpha-SMA expression, whereas knocking down of decorin expression by RNA interference increased the expression of alpha-SMA.
Mol Cell Biochem 2008 Jan
PMID:Effects of decorin on the expression of alpha-smooth muscle actin in a human myofibroblast cell line. 1795 60


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