scholarly journals A novel zebrafish intestinal tumor model reveals a role for cyp7a1-dependent tumor-liver crosstalk in tumor's adverse effects on host

2017 ◽  
Author(s):  
Sora Enya ◽  
Koichi Kawakami ◽  
Yutaka Suzuki ◽  
Shinpei Kawaoka
Keyword(s):  
Tumor Model ◽  
Host Gene ◽  
Limiting Factor ◽  
Intestinal Tumor ◽  
Liver Inflammation ◽  
Growth Defects ◽  
Rate Limiting ◽  
Important Basis ◽  
Host Genes

AbstractThe nature of host organs and genes that underlie tumor-induced physiological disruption on host remains ill-defined. Here, we establish a novel zebrafish intestinal tumor model that is optimized for addressing this issue, and find that hepatic cyp7a1, the rate-limiting factor for synthesizing bile acids (BAs), is such a host gene. Inducing krasG12D by Gal4 specifically expressed in the posterior intestine resulted in formation of an intestinal tumor classified as dysplasia. The local intestinal tumor caused systemic detrimental effects on host including liver inflammation, hepatomegaly, growth defects, and organismal death. Whole-organismal level gene expression analysis and metabolite measurements revealed that the intestinal tumor reduced total BAs levels via down-regulation of hepatic cyp7a1. Genetically rescuing cyp7a1 expression in the liver restored the BAs synthesis and ameliorated tumor-induced liver inflammation, but not other tumor-dependent phenotypes. Thus, we found a previously unknown role of cyp7a1 as the host gene that links the intestinal tumor, hepatic cholesterol-BAs metabolism, and liver inflammation in tumor-bearing fish. Our model provides an important basis to discover host genes responsible for tumor-induced phenotypes and to uncover mechanisms underlying how tumors adversely affect host organisms.

scholarly journals Glypican-1 drives unconventional secretion of Fibroblast Growth Factor 2

2021 ◽  
Author(s):  
Carola Sparn ◽  
Eleni Dimou ◽  
Annalena Meyer ◽  
Roberto Saleppico ◽  
Sabine Wegehingel ◽  
...  
Keyword(s):  
Growth Factor ◽  
Heparan Sulfate ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 2 ◽  
Structural Basis ◽  
Limiting Factor ◽  
Fibroblast Growth ◽  
Unconventional Secretion ◽  
Rate Limiting

Fibroblast Growth Factor 2 (FGF2) is a tumor cell survival factor that is transported into the extracellular space by an unconventional secretory mechanism. Cell surface heparan sulfate proteoglycans are known to play an essential role in this process. Unexpectedly, we found that among the diverse sub-classes consisting of syndecans, perlecans, glypicans and others, Glypican-1 (GPC1) is both the principle and rate-limiting factor that drives unconventional secretion of FGF2. By contrast, we demonstrate GPC1 to be dispensable for FGF2 signaling into cells. We provide first insights into the structural basis for GPC1-dependent FGF2 secretion, identifying disaccharides with N-linked sulfate groups to be enriched in the heparan sulfate chains of GPC1 to which FGF2 binds with high affinity. Our findings have broad implications for the role of GPC1 as a key molecule in tumor progression.

Why Do Children With Specific Language Impairment Name Pictures More Slowly Than Their Peers?

1996 ◽  
Vol 39 (5) ◽  
pp. 1081-1098 ◽  
Author(s):  
Margaret Lahey ◽  
Jan Edwards
Keyword(s):  
Language Impairment ◽  
Specific Language Impairment ◽  
Receptive Language ◽  
Limiting Factor ◽  
Language Performance ◽  
Specific Language ◽  
Language Problems ◽  
Different Types ◽  
Rate Limiting

To examine the role of different cognitive processes in accounting for the slower naming times of children with specific language impairment (SLI) relative to peers with no language impairment (NLI), three tasks designed to stress different types of processing were administered: naming pictures with the signal to respond presented at various delay intervals, naming following different durations of exposure to identical and unrelated primes, and vocally responding to nonlinguistic stimuli. Children with SLI, aged 4 to 9.5 years, were significantly slower than their NLI age peers on naming and on responding to nonlinguistic stimuli, but the effect of delay interval before naming and of duration of prime exposure before naming was similar for both groups. Results suggested that speed of naming is related to the slower nonlinguistic response processing of children with SLI and not to speed of their linguistic or perceptual processing. To examine differences in processing that might relate to pattern of language performance we examined responses of two subgroups of SLI. The subgroup of children whose language problems involved expressive but not receptive skills was not significantly slower than their NLI peers. The children whose problems involved both expressive and receptive language were significantly slower, but this was influenced by age. Findings are discussed in terms of language performance, age, task variables, and a generalized rate-limiting factor.

scholarly journals Role of fructose 2,6-bisphosphate in mammary gland of fed, starved and re-fed lactating rats

1985 ◽  
Vol 232 (3) ◽  
pp. 931-934 ◽  
Author(s):  
S Ward ◽  
N J Kuhn
Keyword(s):  
Mammary Gland ◽  
Intracellular Concentration ◽  
Limiting Factor ◽  
Maximal Rate ◽  
Physiological Conditions ◽  
Highly Sensitive ◽  
Lactating Mammary Gland ◽  
Rate Limiting

The fructose 2,6-bisphosphate (Fru-2,6-P2) content and intracellular concentration of lactating mammary gland was measured in fed, starved and re-fed rats. There was little or no change on starvation, and about 1.5-fold rise on re-feeding, contrasting with estimated glycolytic changes of about 10-fold. The 6-phosphofructokinase (PFK-1) activity of mammary extracts was highly sensitive to added Fru-2,6-P2 under all conditions examined, and appeared to approach saturation at physiological concentrations of this effector. The activity of mammary PFK-1 measured under optimal and ‘physiological’ conditions suggested that this enzyme operates in vivo at about 24% of maximal rate, and is likely to be an important rate-limiting factor in mammary glycolysis.

scholarly journals THE ROLE OF PNEUMATIC TUBE SYSTEM IN EFFICIENCY OF EMERGENCY LABORATORY SERVICE OF THE HOSPITAL

2018 ◽  
Vol 19 (3) ◽  
pp. 40-44
Author(s):  
V. M. Teplov ◽  
E. A. Karpova ◽  
Yu. P. Kovalchuk ◽  
I. P. Minnullin ◽  
S. S. Komedev ◽  
...  
Keyword(s):  
Blood Test ◽  
Laboratory Tests ◽  
Limiting Factor ◽  
Test Results ◽  
Tube System ◽  
Laboratory Service ◽  
Pneumatic Tube ◽  
Rate Limiting ◽  
Pneumatic Tube System

Laboratory tests are one of the most commonly ordered tests in the ED and often the rate-limiting  factor in the workup of a patient. The pneumatic tube system (PTS) can use to provide quick specimen  delivery. First aim of this study was to assess PTS by comparing routine chemistry, hematology, coagulation  blood test results and sample integrity indices between duplicate samples transported either manually or  automatically. Also we tried to assess the contribution of PTS to reduction in lab turnaround times.

scholarly journals Participation of the Ubiquitin-Conjugating Enzyme UBE2E3 in Nedd4-2-Dependent Regulation of the Epithelial Na+ Channel

2004 ◽  
Vol 24 (6) ◽  
pp. 2397-2409 ◽  
Author(s):  
Christophe Debonneville ◽  
Olivier Staub
Keyword(s):  
Binding Sites ◽  
Regulatory Mechanism ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Na Channel ◽  
Limiting Factor ◽  
Ubiquitin Conjugating Enzyme ◽  
Rate Limiting ◽  
Epithelial Na Channel

ABSTRACT The epithelial Na+ channel (ENaC) is a heteromeric protein complex playing a fundamental role in Na+ homeostasis and blood pressure regulation. Specific mutations inactivating PY motifs in ENaC C termini cause Liddle's syndrome, an inherited form of hypertension. Previously we showed that these PY motifs serve as binding sites for the E3 enzyme Nedd4-2, implying ubiquitination as a regulatory mechanism of ENaC. Ubiquitination involves the sequential action of E1, E2, and E3 enzymes. Here we identify the E2 enzyme UBE2E3, which acts in concert with Nedd4-2, and show by coimmunoprecipitation that UBE2E3 and Nedd4-2 interact together. In Xenopus laevis oocytes, UBE2E3 reduces ENaC activity marginally, consistent with Nedd4-2 being the rate-limiting factor in this process, whereas a catalytically inactive mutant of UBE2E3 (UBE2E3-CS) causes elevated ENaC activity by increasing cell surface expression. No additive effect is observed when UBE2E3-CS is coexpressed with an inactive Nedd4-2 mutant, and the stimulatory role of UBE2E3-CS depends on the integrity of the PY motifs (Nedd4-2 binding sites) and the ubiquitination sites on ENaC. In renal mpkCCDcl4 cells, displaying ENaC-dependent transepithelial Na+ transport, Nedd4-2 and UBE2E3 can be coimmunoprecipitated and overexpression of UBE2E3 affects Na+ transport, corroborating the concept of a concerted action of UBE2E3 and Nedd4-2 in ENaC regulation.

scholarly journals Gut Microbiota Has a Widespread and Modifiable Effect on Host Gene Regulation

mSystems ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Allison L. Richards ◽  
Amanda L. Muehlbauer ◽  
Adnan Alazizi ◽  
Michael B. Burns ◽  
Anthony Findley ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Gut Microbiota ◽  
Complex Traits ◽  
Chromatin Accessibility ◽  
Host Gene ◽  
Host Cells ◽  
Host Gene Expression ◽  
Host Genes

ABSTRACT Variation in gut microbiome is associated with wellness and disease in humans, and yet the molecular mechanisms by which this variation affects the host are not well understood. A likely mechanism is that of changing gene regulation in interfacing host epithelial cells. Here, we treated colonic epithelial cells with live microbiota from five healthy individuals and quantified induced changes in transcriptional regulation and chromatin accessibility in host cells. We identified over 5,000 host genes that change expression, including 588 distinct associations between specific taxa and host genes. The taxa with the strongest influence on gene expression alter the response of genes associated with complex traits. Using ATAC-seq, we showed that a subset of these changes in gene expression are associated with changes in host chromatin accessibility and transcription factor binding induced by exposure to gut microbiota. We then created a manipulated microbial community with titrated doses of Collinsella, demonstrating that manipulation of the composition of the microbiome under both natural and controlled conditions leads to distinct and predictable gene expression profiles in host cells. Taken together, our results suggest that specific microbes play an important role in regulating expression of individual host genes involved in human complex traits. The ability to fine-tune the expression of host genes by manipulating the microbiome suggests future therapeutic routes. IMPORTANCE The composition of the gut microbiome has been associated with various aspects of human health, but the mechanism of this interaction is still unclear. We utilized a cellular system to characterize the effect of the microbiome on human gene expression. We showed that some of these changes in expression may be mediated by changes in chromatin accessibility. Furthermore, we validate the role of a specific microbe and show that changes in its abundance can modify the host gene expression response. These results show an important role of gut microbiota in regulating host gene expression and suggest that manipulation of microbiome composition could be useful in future therapies.

Testing ecological release as a compensating mechanism for mass mortality in a keystone predator

2020 ◽  
Vol 637 ◽  
pp. 59-69 ◽  
Author(s):  
J Sullivan-Stack ◽  
BA Menge
Keyword(s):  
Community Dynamics ◽  
Limiting Factor ◽  
Sea Star ◽  
Top Predator ◽  
Oregon Coast ◽  
Ecological Release ◽  
Keystone Predator ◽  
Pisaster Ochraceus ◽  
Wasting Syndrome

Top predator decline has been ubiquitous across systems over the past decades and centuries, and predicting changes in resultant community dynamics is a major challenge for ecologists and managers. Ecological release predicts that loss of a limiting factor, such as a dominant competitor or predator, can release a species from control, thus allowing increases in its size, density, and/or distribution. The 2014 sea star wasting syndrome (SSWS) outbreak decimated populations of the keystone predator Pisaster ochraceus along the Oregon coast, USA. This event provided an opportunity to test the predictions of ecological release across a broad spatial scale and determine the role of competitive dynamics in top predator recovery. We hypothesized that after P. ochraceus loss, populations of the subordinate sea star Leptasterias sp. would grow larger, more abundant, and move downshore. We based these predictions on prior research in Washington State showing that Leptasterias sp. competed with P. ochraceus for food. Further, we predicted that ecological release of Leptasterias sp. could provide a bottleneck to P. ochraceus recovery. Using field surveys, we found no clear change in density or distribution in Leptasterias sp. populations post-SSWS, and decreases in body size. In a field experiment, we found no evidence of competition between similar-sized Leptasterias sp. and P. ochraceus. Thus, the mechanisms underlying our predictions were not in effect along the Oregon coast, which we attribute to differences in habitat overlap and food availability between the 2 regions. Our results suggest that response to the loss of a dominant competitor can be unpredictable even when based in theory and previous research.

scholarly journals Protective Role of Glutathione in the Hippocampus after Brain Ischemia

2021 ◽  
Vol 22 (15) ◽  
pp. 7765
Author(s):  
Youichirou Higashi ◽  
Takaaki Aratake ◽  
Takahiro Shimizu ◽  
Shogo Shimizu ◽  
Motoaki Saito
Keyword(s):  
Oxidative Stress ◽  
Neuronal Death ◽  
Excitatory Amino Acid ◽  
Ischemia Reperfusion ◽  
Thiol Group ◽  
Protective Role ◽  
Key Factor ◽  
Rate Limiting ◽  
Cysteine Uptake

Stroke is a major cause of death worldwide, leading to serious disability. Post-ischemic injury, especially in the cerebral ischemia-prone hippocampus, is a serious problem, as it contributes to vascular dementia. Many studies have shown that in the hippocampus, ischemia/reperfusion induces neuronal death through oxidative stress and neuronal zinc (Zn2+) dyshomeostasis. Glutathione (GSH) plays an important role in protecting neurons against oxidative stress as a major intracellular antioxidant. In addition, the thiol group of GSH can function as a principal Zn2+ chelator for the maintenance of Zn2+ homeostasis in neurons. These lines of evidence suggest that neuronal GSH levels could be a key factor in post-stroke neuronal survival. In neurons, excitatory amino acid carrier 1 (EAAC1) is involved in the influx of cysteine, and intracellular cysteine is the rate-limiting substrate for the synthesis of GSH. Recently, several studies have indicated that cysteine uptake through EAAC1 suppresses ischemia-induced neuronal death via the promotion of hippocampal GSH synthesis in ischemic animal models. In this article, we aimed to review and describe the role of GSH in hippocampal neuroprotection after ischemia/reperfusion, focusing on EAAC1.

Sign in / Sign up

Export Citation Format

Share Document