955 Altered expression of SPAG17, a cilia-related gene, in scleroderma and spontaneous skin fibrosis in Spag17 knockout mice suggests that scleroderma is a unique ciliopathy

Hepatic ischemia-reperfusion (I/R) injury is an important complication of liver surgery and transplantation. Mitochondrial function is central to this injury. To examine alterations in mitochondrial function during I/R, we assessed the mitochondrial proteome in C57Bl/6 mice. Proteomic analysis of liver mitochondria revealed 234 proteins with significantly altered expression after I/R. From these, 13 proteins with the greatest expression differences were identified. One of these proteins, peroxiredoxin-6 (Prdx6), has never before been described in mitochondria. In hepatocytes from sham-operated mice, Prdx6 expression was found exclusively in the cytoplasm. After ischemia or I/R, Prdx6 expression disappeared from the cytoplasm and appeared in the mitochondria, suggesting mitochondrial trafficking. To explore the functional role of Prdx6 in hepatic I/R injury, wild-type and Prdx6-knockout mice were subjected to I/R injury. Prdx6-knockout mice had significantly more hepatocellular injury compared with wild-type mice. Interestingly, the increased injury in Prdx6-knockout mice occurred despite reduced inflammation and was associated with increased mitochondrial generation of H2O2 and dysfunction. The mitochondrial dysfunction appeared to be related to complex I of the electron transport chain. These data suggest that hepatocyte Prdx6 traffics to the mitochondria during I/R to limit mitochondrial dysfunction as a protective mechanism against hepatocellular injury.

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Coordinated alteration of hepatic gene expression in fatty acid and triglyceride synthesis in LCAT-null mice is associated with altered PUFA metabolism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00597.2004 ◽

2006 ◽

Vol 290 (1) ◽

pp. E17-E25 ◽

Cited By ~ 17

Author(s):

Hui Song ◽

Liping Zhu ◽

Clive M. Picardo ◽

Graham Maguire ◽

Vincent Leung ◽

...

Keyword(s):

Gene Expression ◽

Fatty Acid ◽

Knockout Mice ◽

Target Genes ◽

Mrna Level ◽

Triglyceride Synthesis ◽

Altered Expression ◽

Regulatory Pathways ◽

Hepatic Expression ◽

Pufa Metabolism

Complete lecithin:cholesterol acyltransferase (LCAT) deficiency is associated with fasting hypertriglyceridemia (HTG). We recently reported that, in ldlr−/−×lcat−/− mice, fasting HTG is associated with hepatic triglyceride overproduction in association with an upregulation of the hepatic srebp1 gene and altered expression of its target genes in lipogenesis and gluconeogenesis. We further investigated the role of hepatic polyunsaturated fatty acid (PUFA) metabolism in the modulation of the lipid phenotypes. In the ldlr−/−×lcat−/− mice, using the ldlr−/−×lcat+/+ littermate as controls, the hepatic level of cholesterol esters (CE) were reduced by 61.0% whereas the 20:4-CE and 22:6-CE contents were each reduced by >80%. In contrast, the hepatic levels of 20:4- and 22:6-containing phospholipid (PL) species were either unchanged or mildly elevated. Similar alterations of the hepatic PUFA in CE and in PL were also observed in the lcat−/− mice compared with their wild-type controls. In ldlr−/−×lcat−/− mice, hepatic mRNA level was markedly reduced for Δ-6 desaturase ( fads2) (70.2%) and acyl-CoA:cholesterol acyltransferase-2 ( soat2) (57.0%). A similar pattern of gene expression change was also observed in the lcat−/− single-knockout mice. In contrast, the acyl-CoA:diacylglycerol acyltransferase-2 ( dgat2) mRNA level was 1.7-fold upregulated in the double-knockout mice. In summary, we observed coordinated alterations in hepatic expression of the gene for fads2, soat2, and dgat2, resulting in a reduction in total hepatic PUFA pool and differentially in the PUFA-CE pool, in association with an increase in dgat2 gene expression for promoting triglyceride synthesis and secretion. Some of the phenotypes are not readily explained by known mechanisms and may represent novel regulatory pathways.

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Activation of liver X receptors inhibits experimental fibrosis by interfering with interleukin-6 release from macrophages

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2013-204401 ◽

2014 ◽

Vol 74 (6) ◽

pp. 1317-1324 ◽

Cited By ~ 20

Author(s):

Christian Beyer ◽

Jingang Huang ◽

Jürgen Beer ◽

Yun Zhang ◽

Katrin Palumbo-Zerr ◽

...

Keyword(s):

Knockout Mice ◽

Interleukin 6 ◽

Skin Fibrosis ◽

Target Cells ◽

Similar Response ◽

Liver X Receptors ◽

Double Knockout ◽

X Receptors ◽

And Control

ObjectivesTo investigate the role of liver X receptors (LXRs) in experimental skin fibrosis and evaluate their potential as novel antifibrotic targets.MethodsWe studied the role of LXRs in bleomycin-induced skin fibrosis, in the model of sclerodermatous graft-versus-host disease (sclGvHD) and in tight skin-1 (Tsk-1) mice, reflecting different subtypes of fibrotic disease. We examined both LXR isoforms using LXRα-, LXRβ- and LXR-α/β-double-knockout mice. Finally, we investigated the effects of LXRs on fibroblasts and macrophages to establish the antifibrotic mode of action of LXRs.ResultsLXR activation by the agonist T0901317 had antifibrotic effects in bleomycin-induced skin fibrosis, in the sclGvHD model and in Tsk-1 mice. The antifibrotic activity of LXRs was particularly prominent in the inflammation-driven bleomycin and sclGvHD models. LXRα-, LXRβ- and LXRα/β-double-knockout mice showed a similar response to bleomycin as wildtype animals. Low levels of the LXR target gene ABCA-1 in the skin of bleomycin-challenged and control mice suggested a low baseline activation of the antifibrotic LXR signalling, which, however, could be specifically activated by T0901317. Fibroblasts were not the direct target cells of LXRs agonists, but LXR activation inhibited fibrosis by interfering with infiltration of macrophages and their release of the pro-fibrotic interleukin-6.ConclusionsWe identified LXRs as novel targets for antifibrotic therapies, a yet unknown aspect of these nuclear receptors. Our data suggest that LXR activation might be particularly effective in patients with inflammatory disease subtypes. Activation of LXRs interfered with the release of interleukin-6 from macrophages and, thus, inhibited fibroblast activation and collagen release.

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Cloning, Expression Analysis, 20-Hydroxyecdysone Induction, and RNA Interference Study of Autophagy-Related Gene 8 from Heortia vitessoides Moore

Insects ◽

10.3390/insects11040245 ◽

2020 ◽

Vol 11 (4) ◽

pp. 245

Author(s):

Zhixing Li ◽

Zihao Lyu ◽

Qingya Ye ◽

Jie Cheng ◽

Chunyan Wang ◽

...

Keyword(s):

Rna Interference ◽

Molecular Mechanisms ◽

Extreme Temperature ◽

Normal Growth ◽

Related Gene ◽

Multiple Sequence ◽

Altered Expression ◽

Domain Structures ◽

Temperature Exposure ◽

Interference Study

Autophagy is a highly conserved and regulated process in eukaryotic cells and remodels cytoplasm, recovers essential nutrients, and disposes of unwanted cytoplasmic components. Autophagy-related gene (ATG) 8, identified in Heortia vitessoides Moore, which is an oligophagous pest of Aquilaria sinensis (Lour.), was characterized (HvATG8). Multiple sequence alignment showed that HvATG8 possesses highly conserved domain structures. Stage- and tissue-specific expressions indicated that HvATG8 is highly expressed in prepupal, pupal, and adult stages and in the midgut of larvae and abdomen of adults. Lack of function of HvATG8 by RNA interference resulted in a significant decrease in survival rate and an increase in abnormal or nonviable phenotypes in H. vitessoides. Transition rate from larval to pupal stages was 33.0% and from pupal to adult stages was 15.0% after injection. Reduction of ATG8 expression reduced survival of H. vitessoides. Therefore, HvATG8 possibly plays a key role in normal growth stage of H. vitessoides. HvATG8 suppression downregulates HvATG3 expression, suggesting that the two genes are interconnected. Further, HvATG8 expression increased by 20-hydroxyecdysone treatment, starvation, and extreme temperature exposure. Starvation also altered expression of other ATGs in H. vitessoide. This study may be used to guide research on molecular mechanisms of autophagy in insects.

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Modulation of the acute phase response by altered expression of the IL-1 type 1 receptor or IL-1ra

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2000.278.4.r824 ◽

2000 ◽

Vol 278 (4) ◽

pp. R824-R830 ◽

Cited By ~ 18

Author(s):

Michael D. Josephs ◽

Carmen C. Solorzano ◽

Michael Taylor ◽

Jason J. Rosenberg ◽

Daniel Topping ◽

...

Keyword(s):

Inflammatory Response ◽

Acute Phase ◽

Knockout Mice ◽

Acute Phase Response ◽

Interleukin 1 ◽

Phase Response ◽

Type I ◽

Altered Expression ◽

Factor Α ◽

Protein Response

A complete understanding of the role for endogenously produced interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and IL-1 receptor antagonist (IL-1ra) in the acute phase response to inflammation remains unknown. In the present studies, knockout mice lacking either a functional IL-1 type I receptor (IL-1RI− / −), a TNF type I receptor (TNFR-I− / −), or both IL-1 type I and TNF type I receptors (IL-1RI− / −/TNFR-I− / −) received a turpentine abscess. Additional mice deficient in IL-1ra protein (IL-1ra− / −) or overexpressing IL-1ra protein (IL-1ratg) were similarly treated. After a turpentine abscess, IL-1 receptor knockout mice exhibited an attenuated inflammatory response compared with wild-type or animals lacking a functional TNFR-I. Mice overexpressing IL-1ra also had an attenuated hepatic acute phase protein response, whereas IL-1ra knockout mice had a significantly greater hepatic acute phase response. We conclude that the inflammatory response to a turpentine abscess is the result of a balance between IL-1ra expression and IL-1 binding to its type I receptor. Endogenously produced IL-1ra plays a central role in mitigating the magnitude of the IL-1-mediated inflammatory response and, ultimately, the outcome to a turpentine abscess.

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Methamphetamine and Brain Histamine: A Study Using Histamine-Related Gene Knockout Mice

Annals of the New York Academy of Sciences ◽

10.1196/annals.1316.016 ◽

2004 ◽

Vol 1025 (1) ◽

pp. 129-134 ◽

Cited By ~ 19

Author(s):

KENTARO IWABUCHI ◽

YASUHIKO KUBOTA ◽

CHIHIRO ITO ◽

TAKESHI WATANABE ◽

TAKEHIKO WATANABE ◽

...

Keyword(s):

Knockout Mice ◽

Gene Knockout ◽

Related Gene ◽

Brain Histamine ◽

Gene Knockout Mice

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Tomato plants overexpressing cryptochrome 2 reveal altered expression of energy and stress-related gene products in response to diurnal cues

Plant Cell & Environment ◽

10.1111/j.1365-3040.2011.02467.x ◽

2011 ◽

Vol 35 (5) ◽

pp. 994-1012 ◽

Cited By ~ 31

Author(s):

LOREDANA LOPEZ ◽

FABRIZIO CARBONE ◽

LINDA BIANCO ◽

GIOVANNI GIULIANO ◽

PAOLO FACELLA ◽

...

Keyword(s):

Gene Products ◽

Related Gene ◽

Altered Expression ◽

Tomato Plants ◽

Cryptochrome 2

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Integration of Clinical and Transcriptomics Reveals Reprogramming of the Lipid Metabolism in Gastric Cancer

10.21203/rs.3.rs-936586/v1 ◽

2021 ◽

Author(s):

Yanyan Li ◽

Jungang Zhao ◽

Renpin Chen ◽

Shengwei Chen ◽

Yilun Xu ◽

...

Keyword(s):

Gastric Cancer ◽

Lipid Metabolism ◽

Cox Regression ◽

Gene Signature ◽

Cancer Cell Proliferation ◽

Related Gene ◽

Altered Expression ◽

Transcriptomic Data ◽

Cellular Processes

Abstract Background: Lipid metabolism has a profound impact on gastric cancer (GC) progression and is a newly targetable vulnerability for cancer therapy. Given the importance of lipids in cancer cellular processes, in this study we employed lipidomic clinical and transcriptomic data of GC to connect the variations of lipid metabolism changes.Method: We constructed a clinical nomogram based on the lipid factors and other clinical items. Then by using multi-omics techniques, we established a lipid-related gene signature for individualized prognosis prediction in patients with GC. Moreover, a total of 1357 GC cases were then applied to evaluate the robustness of this model. WGCNA was used to identify co-expression modules and enriched genes associated with GC lipid metabolism. The role of key genes ACLY in GC was further investigated.Results: The prognostic value of the lipidomic signature was analyzed using Cox regression model, and clinical nomogram was established. Among them, we observed overexpression of ACLY significantly increased the levels of intracellular free fatty acid and triglyceride, and activate AKT/mTOR pathway to promote cancer development.Conclusions: In conclusion, our findings delineated a GC clinical and lipidomic signature and revealed that GC exhibited a reprogramming of lipid metabolism in association with an altered expression of lipid metabolism-associated genes. Among them, ACLY significantly promoted GC lipid metabolism and increased cancer cell proliferation, suggesting that this pathway can be targetable as a metabolic vulnerability in future GC therapy.

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Altered Expression of Cadherin-8 and Cadherin-11 in Neural Circuit Development: Implications for Autism

10.1101/2020.04.24.058438 ◽

2020 ◽

Author(s):

Jeannine A. Frei ◽

Robert F. Niescier ◽

Morgan S. Bridi ◽

Madel Durens ◽

Jonathan E. Nestor ◽

...

Keyword(s):

Knockout Mice ◽

Hippocampal Neurons ◽

Neural Circuit ◽

Expression Profiles ◽

Expression Patterns ◽

Autism Spectrum ◽

Synaptic Activity ◽

Classical Type ◽

Altered Expression ◽

Expression Levels

AbstractAutism spectrum disorder (ASD) is a neurological condition characterized by difficulties in social interaction, communication, and behavior. The classical type II cadherins cadherin-8 (Cdh8, CDH8) and cadherin-11 (Cdh11, CDH11) have been implicated as autism risk gene candidates. To explore the role of cadherins in the etiology of autism, we investigated their expression patterns during mouse brain development and analyzed their functions using Cdh11 knockout mice. Expression of cadherin-8 and cadherin-11 was developmentally regulated and enriched in cortex, hippocampus, and thalamus/striatum during the peak of dendrite formation and synaptogenesis. Cadherin-8 preferentially localized to excitatory synapses where it interacted with neuroligin-1. Levels of cadherin-8, neuroligin-1, and PSD-95 were all significantly increased in Cdh11 knockout brains. Additionally, Cdh11-/- hippocampal neurons exhibited increased dendritic complexity along with altered neuronal and synaptic activity. Similar to the expression profiles in Cdh11 knockout mice, induced pluripotent stem cell (iPSC)-derived cortical neural precursor cells (NPCs) and cortical organoids generated from individuals with autism showed elevated CDH8 expression levels while CDH11 expression levels were decreased. Together, these results strongly suggest that cadherin-8 and cadherin-11 are involved in regulating the development of neuronal circuitry and that alterations in the expression levels of cadherin-8 and cadherin-11 may contribute to the etiology of autism.

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