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1.
Yan-Fung Wong Qing Sheng Janet WL Chung Jacky KF Chan King L Chow 《BMC developmental biology》2010,10(1):82
Background
C. elegans TGF-β-like Sma/Mab signaling pathway regulates both body size and sensory ray patterning. Most of the components in this pathway were initially identified by genetic screens based on the small body phenotype, and many of these mutants display sensory ray patterning defect. At the cellular level, little is known about how and where these components work although ray structural cell has been implicated as one of the targets. Based on the specific ray patterning abnormality, we aim to identify by RNAi approach additional components that function specifically in the ray lineage to elucidate the regulatory role of TGF-β signaling in ray differentiation. 相似文献2.
3.
Gautier JC Holzhaeuser D Markovic J Gremaud E Schilter B Turesky RJ 《Free radical biology & medicine》2001,30(10):1089-1098
Ochratoxin A (OTA) is a mycotoxin found in some cereal and grain products.It is a potent renal carcinogen in male rats, although its mode of carcinogenic action is not known. Oxidative stress may play a role in OTA-induced toxicity and carcinogenicity.In this study, we measured several chemical and biological markers that are associated with oxidative stress response to determine if this process is involved in OTA-mediated toxicity in rats. Treatment of male rats with OTA (up to 2 mg/ 24 h exposure) did not increase the formation of biomarkers of oxidative damage such as the lipid peroxidation marker malondialdehyde in rat plasma, kidney, and liver, or the DNA damage marker 8-oxo-7,8-dihydro-2' deoxyguanosine in kidney DNA. However, OTA treatment (1 mg/kg) did result in a 22% decrease in alpha-tocopherol plasma levels and a 5-fold increase in the expression of the oxidative stress responsive protein haem oxygenase-1, specifically in the kidney. The selective alteration of these latter two markers indicates that OTA does evoke oxidative stress, which may contribute at least in part to OTA renal toxicity and carcinogenicity in rats during long-term exposure. 相似文献
4.
MR Starkey RY Kim EL Beckett HC Schilter D Shim AT Essilfie DH Nguyen KW Beagley J Mattes CR Mackay JC Horvat PM Hansbro 《PloS one》2012,7(8):e42588
Background
Viral and bacterial respiratory tract infections in early-life are linked to the development of allergic airway inflammation and asthma. However, the mechanisms involved are not well understood. We have previously shown that neonatal and infant, but not adult, chlamydial lung infections in mice permanently alter inflammatory phenotype and physiology to increase the severity of allergic airway disease by increasing lung interleukin (IL)-13 expression, mucus hyper-secretion and airway hyper-responsiveness. This occurred through different mechanisms with infection at different ages. Neonatal infection suppressed inflammatory responses but enhanced systemic dendritic cell:T-cell IL-13 release and induced permanent alterations in lung structure (i.e., increased the size of alveoli). Infant infection enhanced inflammatory responses but had no effect on lung structure. Here we investigated the role of hematopoietic cells in these processes using bone marrow chimera studies.Methodology/Principal Findings
Neonatal (<24-hours-old), infant (3-weeks-old) and adult (6-weeks-old) mice were infected with C. muridarum. Nine weeks after infection bone marrow was collected and transferred into recipient age-matched irradiated naïve mice. Allergic airway disease was induced (8 weeks after adoptive transfer) by sensitization and challenge with ovalbumin. Reconstitution of irradiated naïve mice with bone marrow from mice infected as neonates resulted in the suppression of the hallmark features of allergic airway disease including mucus hyper-secretion and airway hyper-responsiveness, which was associated with decreased IL-13 levels in the lung. In stark contrast, reconstitution with bone marrow from mice infected as infants increased the severity of allergic airway disease by increasing T helper type-2 cell cytokine release (IL-5 and IL-13), mucus hyper-secretion, airway hyper-responsiveness and IL-13 levels in the lung. Reconstitution with bone marrow from infected adult mice had no effects.Conclusions
These results suggest that an infant chlamydial lung infection results in long lasting alterations in hematopoietic cells that increases the severity of allergic airway disease in later-life. 相似文献5.
Cavin C Delannoy M Malnoe A Debefve E Touché A Courtois D Schilter B 《Biochemical and biophysical research communications》2005,327(3):742-749
Chicory is a major source of fructans with reported prebiotic-bifidogenic properties. In the present study, the potential anti-inflammatory activities of chicory were investigated. Ethyl acetate chicory root extract produced a marked inhibition of prostaglandin E(2) (PGE(2)) production in human colon carcinoma HT29 cells treated with the pro-inflammatory agent TNF-alpha. Two independent mechanisms of action were identified: (1) a drastic inhibition of the induction by TNF-alpha of cyclooxygenase 2 (COX-2) protein expression and (2) a direct inhibition of COX enzyme activities with a significantly higher selectivity for COX-2 activity. The inhibition of TNF-alpha-dependent induction of COX-2 expression was mediated by an inhibition of NF-kappaB activation. A major sesquiterpene lactone of chicory root, the guaianolide 8-deoxylactucin, was identified as the key inhibitor of COX-2 protein expression present in chicory extract. Altogether, the data presented strongly support chicory root as a promising source of functional food ingredient, combining prebiotic and anti-inflammatory properties. 相似文献
6.
The lysyl oxidase like 2/3 enzymatic inhibitor,PXS‐5153A,reduces crosslinks and ameliorates fibrosis
Heidi Schilter Alison D. Findlay Lara Perryman Tin T. Yow Joshua Moses Amna Zahoor Craig I. Turner Mandar Deodhar Jonathan S. Foot Wenbin Zhou Angelique Greco Amar Joshi Benjamin Rayner Sarah Townsend Alberto Buson Wolfgang Jarolimek 《Journal of cellular and molecular medicine》2019,23(3):1759-1770
Fibrosis is characterized by the excessive deposition of extracellular matrix and crosslinked proteins, in particular collagen and elastin, leading to tissue stiffening and disrupted organ function. Lysyl oxidases are key players during this process, as they initiate collagen crosslinking through the oxidation of the ε‐amino group of lysine or hydroxylysine on collagen side‐chains, which subsequently dimerize to form immature, or trimerize to form mature, collagen crosslinks. The role of LOXL2 in fibrosis and cancer is well documented, however the specific enzymatic function of LOXL2 and LOXL3 during disease is less clear. Herein, we describe the development of PXS‐5153A, a novel mechanism based, fast‐acting, dual LOXL2/LOXL3 inhibitor, which was used to interrogate the role of these enzymes in models of collagen crosslinking and fibrosis. PXS‐5153A dose‐dependently reduced LOXL2‐mediated collagen oxidation and collagen crosslinking in vitro. In two liver fibrosis models, carbon tetrachloride or streptozotocin/high fat diet‐induced, PXS‐5153A reduced disease severity and improved liver function by diminishing collagen content and collagen crosslinks. In myocardial infarction, PXS‐5153A improved cardiac output. Taken together these results demonstrate that, due to their crucial role in collagen crosslinking, inhibition of the enzymatic activities of LOXL2/LOXL3 represents an innovative therapeutic approach for the treatment of fibrosis. 相似文献
7.
Shim DS Schilter HC Knott ML Almeida RA Short RP Mackay CR Dent LA Sewell WA 《Immunology and cell biology》2012,90(5):553-558
Granulocyte macrophage-colony stimulating factor (GM-CSF) is a cytokine with the capacity to promote inflammation in a wide variety of infectious and inflammatory diseases. These conditions include allergic airway inflammation, which is driven by T-helper 2 (Th2) cells. Because of the importance of Th2 cells in parasite infections, we have investigated the role of GM-CSF in mice infected with the nematode Nippostrongylus brasiliensis. The effect of primary and secondary infection was investigated in mice lacking functional genes for GM-CSF (CSF2 genes) (ΔGM-CSF mice), and in mice lacking the cytokine receptor common β chain (Δβ mice), the latter being unable to signal in response to GM-CSF and interleukin (IL)-5. ΔGM-CSF mice showed no significant defect in parasite immunity, measured by larval numbers in the lungs, worm numbers in the intestine or egg numbers in the faeces, in either primary or secondary infection. By contrast, the Δβ mice showed increased parasite burden, with higher numbers of lung larvae after secondary infection and higher numbers of intestinal worms and faecal eggs after both primary and secondary infection. Unexpectedly, there were increased numbers of circulating eosinophils in the ΔGM-CSF mice, associated with significantly reduced larval numbers in the lungs. These results indicate that GM-CSF is redundant in protection against N. brasiliensis infection, and that the increased susceptibility of Δβ mice to infection is likely to be attributed to the lack of IL-5 signalling in these mice. The results suggest that clinical use of agents that neutralise GM-CSF may not be associated with increased risk of parasite infection. 相似文献
8.
Reis LM Tyler RC Schilter KF Abdul-Rahman O Innis JW Kozel BA Schneider AS Bardakjian TM Lose EJ Martin DM Broeckel U Semina EV 《Human genetics》2011,130(4):495-504
BMP4 loss-of-function mutations and deletions have been shown to be associated with ocular, digital, and brain anomalies, but due to the paucity of these reports, the full phenotypic spectrum of human BMP4 mutations is not clear. We screened 133 patients with a variety of ocular disorders for BMP4 coding region mutations or genomic deletions. BMP4 deletions were detected in two patients: a patient affected with SHORT syndrome and a patient with anterior segment anomalies along with craniofacial dysmorphism and cognitive impairment. In addition to this, three intragenic BMP4 mutations were identified. A patient with anophthalmia, microphthalmia with sclerocornea, right-sided diaphragmatic hernia, and hydrocephalus was found to have a c.592C>T (p.R198X) nonsense mutation in BMP4. A frameshift mutation, c.171dupC (p.E58RfsX17), was identified in two half-siblings with anophthalmia/microphthalmia, discordant developmental delay/postaxial polydactyly, and poor growth as well as their unaffected mother; one affected sibling carried an additional BMP4 mutation in the second allele, c.362A>G (p.H121R). This is the first report indicating a role for BMP4 in SHORT syndrome, Axenfeld?CRieger malformation, growth delay, macrocephaly, and diaphragmatic hernia. These results significantly expand the number of reported loss-of-function mutations, further support the critical role of BMP4 in ocular development, and provide additional evidence of variable expression/non-penetrance of BMP4 mutations. 相似文献
9.
Stem cells in vivo are housed within a functional microenvironment termed the “stem cell niche.” As the niche components can modulate stem cell behaviors like proliferation, migration and differentiation, evaluating these components would be important to determine the most optimal platform for their maintenance or differentiation. In this review, we have discussed methods and technologies that have aided in the development of high throughput screening assays for stem cell research, including enabling technologies such as the well-established multiwell/microwell plates and robotic spotting, and emerging technologies like microfluidics, micro-contact printing and lithography. We also discuss the studies that utilized high throughput screening platform to investigate stem cell response to extracellular matrix, topography, biomaterials and stiffness gradients in the stem cell niche. The combination of the aforementioned techniques could lay the foundation for new perspectives in further development of high throughput technology and stem cell research. 相似文献
10.
Heidi C Schilter Adam Collison Remo C Russo Jonathan S Foot Tin T Yow Angelica T Vieira Livia D Tavares Joerg Mattes Mauro M Teixeira Wolfgang Jarolimek 《Respiratory research》2015,16(1)