Tristetraprolin (TTP) is a mRNA-destabilizing protein that binds to AU-rich elements in labile transcripts, such as the mRNA encoding TNF, and promotes their deadenylation and degradation. ...TTP-deficient (knockout KO) mice exhibit an early-onset, severe inflammatory phenotype, with cachexia, erosive arthritis, left-sided cardiac valvulitis, myeloid hyperplasia, and autoimmunity, which can be prevented by injections of anti-TNF Abs, or interbreeding with TNF receptor-deficient mice. To determine whether the excess TNF that causes the TTP KO phenotype is produced by myeloid cells, we performed myeloid-specific disruption of Zfp36, the gene encoding TTP. We documented the lack of TTP expression in LPS-stimulated bone marrow-derived macrophages from the mice, whereas fibroblasts expressed TTP mRNA and protein normally in response to serum. The mice exhibited a minimal phenotype, characterized by slight slowing of weight gain late in the first year of life, compared with the early-onset, severe weight loss and inflammation seen in the TTP KO mice. Instead, the myeloid-specific TTP KO mice were highly and abnormally susceptible to a low-dose LPS challenge, with rapid development of typical endotoxemia signs and extensive organ damage, and elevations of serum TNF levels to 110-fold greater than control. We conclude that myeloid-specific TTP deficiency does not phenocopy complete TTP deficiency in C57BL/6 mice under normal laboratory conditions, implying contributions from other cell types to the complete phenotype. However, myeloid cell TTP plays a critical role in protecting mice against LPS-induced septic shock, primarily through its posttranscriptional regulation of TNF mRNA stability.
Background and Purpose
Neurodegenerative diseases present progressive neurological disorder induced by cell death or apoptosis. Catalpol, an iridoid glucoside isolated from the root of Rehmannia ...glutinosa Libosch, is present in a wide range of plant families. Although catalpol is an effective anti‐apoptotic agent in LPS‐induced neurodegeneration, the underlying mechanism has not been established. Here we have identified some of the mechanisms involved the prevention by catalpol of apoptosis induced by LPS in an experimental model of neurodegeneration in vitro.
Experimental Approach
Apoptosis was induced by adding LPS (80 ng·mL−1) to pheochromocytoma (PC12) cells, pretreated with catalpol for 12 h. We measured intracellular reactive oxygen species (ROS), apoptosis and intracellular calcium concentration ( Ca2+i) by flow cytometry or laser confocal scanning microscopy. We also analysed the protein expression of Bcl‐2, Bax and Ca2+‐calmodulin‐dependent protein kinase II (CaMKII)‐dependent apoptosis signal‐regulating kinase‐1 (ASK‐1)/JNK/p38 signalling pathway in PC12 cells by Western blot.
Key Results
Catalpol stimulated expression of Bcl‐2 and inhibited the expression of Bax. Catalpol also attenuated the increase in Ca2+ concentration induced by LPS in PC12 cells and down‐regulated CaMK phosphorylation. The CaMKII‐dependent ASK‐1/JNK/p38 signalling cascade was blocked by catalpol. All these changes were accompanied by a decrease of apoptosis induced by LPS in PC12 cells.
Conclusions and Implications
The data presented here provide new mechanistic insights into the links between the CaMKII‐dependent ASK‐1/JNK/p38 signalling pathway and the protective effect of catalpol on apoptosis induced by LPS in PC12 cells.
TTP‐promoted decay of transcripts is a critical post‐transcriptional regulatory mechanism in the response of fibroblasts to TNF released from primary immune cells.
TTP is an anti‐inflammatory protein ...that acts by binding to AREs in its target mRNAs, such as Tnf mRNA, and promoting their deadenylation and decay. TNF released from inflammatory cells can then stimulate gene expression in tissue cells, such as fibroblasts. To determine whether TTP could affect the decay of TNF‐induced transcripts in fibroblasts, we exposed primary embryonic fibroblasts and stable fibroblast cell lines, derived from WT and TTP KO mice, to TNF. The decay rates of transcripts encoded by several early‐response genes, including Cxcl1, Cxcl2, Ier3, Ptgs2, and Lif, were significantly slowed in TTP‐deficient fibroblasts after TNF stimulation. These changes were associated with TTP‐dependent increases in CXCL1, CXCL2, and IER3 protein levels. The TTP‐susceptible transcripts contained multiple, conserved, closely spaced, potential TTP binding sites in their 3′‐UTRs. WT TTP, but not a nonbinding TTP zinc finger mutant, bound to RNA probes that were based on the mRNA sequences of Cxcl1, Cxcl2, Ptgs2, and Lif. TTP‐promoted decay of transcripts encoding chemokines and other proinflammatory mediators is thus a critical post‐transcriptional regulatory mechanism in the response of secondary cells, such as fibroblasts, to TNF released from primary immune cells.
Diabetes, characterized as a well-known chronic metabolic syndrome, with its associated complications pose a substantial and escalating health and healthcare challenge on a global scale. Current ...strategies addressing diabetes are mainly symptomatic and there are fewer available curative pharmaceuticals for diabetic complications. Thus, there is an urgent need to identify novel pharmacological targets and agents. The impaired mitochondria have been associated with the etiology of diabetes and its complications, and the intervention of mitochondrial dysfunction represents an attractive breakthrough point for the treatments of diabetes and its complications. Natural products (NPs), with multicenter characteristics, multi-pharmacological activities and lower toxicity, have been caught attentions as the modulators of mitochondrial functions in the therapeutical filed of diabetes and its complications. This review mainly summarizes the recent progresses on the potential of 39 NPs and 2 plant-extracted mixtures to improve mitochondrial dysfunction against diabetes and its complications. It is expected that this work may be useful to accelerate the development of innovative drugs originated from NPs and improve upcoming therapeutics in diabetes and its complications.
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The effect of grape polyphenols on blood pressure remains unclear, which we aimed to address via a meta-analysis study.
We conducted study trial searches in PubMed, Embase, and the Cochrane Library ...databases. Summary estimates of weighted mean differences and 95% confidence intervals were obtained by using fixed-effects models. Subgroup analyses were performed to identify the source of heterogeneity. The protocol details of our meta-analysis have been submitted to the international database of prospectively registered systematic reviews (registration number CRD42015019196).
Ten studies were included in the present meta-analysis. Our results showed daily grape polyphenol intake could significantly reduce systolic blood pressure by 1.48 mmHg when compared to control subjects (12 comparisons; -1.48 -2.79 to -0.16 mmHg; P = 0.03). Subgroup analyses indicated larger reduction was identified in the intake of low-dose of grape polyphenols (< 733 mg/day, median level of the included studies) or patients with metabolic syndrome. Contrarily, diastolic blood pressure was not significantly decreased in the grape polyphenols group as compared to controls. No significant heterogeneity or publication bias was detected in the meta-analysis of either systolic or diastolic blood pressure.
Daily grape polyphenol intake can significantly reduce the systolic blood pressure in humans, although the reduction is modest when compared with anti-hypertensive medications. Larger, better designed trials, that specifically include hypertensive subjects, are required to verify our results in the future.
PurposeThe aim of this study is to evaluate the expression of osteopontin (OPN) and its relationship with relative cytokines in patients with Graves' ophthalmopathy (GO), and to observe the effect of ...OPN on orbital fibroblasts (OFs) proliferation, migration, and the expression of relative cytokines, as well as the signaling pathways involved in its effect. MethodsThe orbital adipose connective tissue was obtained from 24 patients with GO (12 cases of active GO, and 12 cases of inactive GO) and 12 healthy controls. OFs were isolated from orbital tissues obtained from patients with active GO who were undergoing orbital decompression surgery. Quantitative PCR and Western blot were performed to detect RNA and protein expression. The proliferation and cell migration rates of OFs were measured by methylthiazol tetrazolium (MTT) and the cell scratch test. Signaling pathway inhibitors, such as OPN monoclonal antibody 1A12, ERK1/2 inhibitor PD98059, and PI3K inhibitor LY294002, were applied to determine the involved pathways. ResultsThe mRNA and protein levels of OPN were increased in orbital adipose connective tissue from patients with active GO than those from patients with inactive GO (2.83-fold increase, P < 0.001; 1.91-fold increase, P < 0.05). The OPN mRNA level was positively correlated with CD40 ligand (CD40L) and hyaluronan synthases 2 (HAS2) mRNA in patients with GO. OPN promoted proliferation and migration rate of OFs and induced vascular endothelial growth factor (VEGF) and collagen I mRNA expression, and the effects were inhibited by 1A12 or LY294002. ConclusionsOPN in orbital adipose connective tissues were significantly increase in active GO, and there were significant correlations of OPN with CD40L and HAS2 mRNA levels in patients with GO. OPN promoted proliferation and migration of OFs and induced VEGF and collagen I mRNA expression in OFs through PI3K/Akt signaling pathway. This suggested a role for OPN in the pathogenesis of GO through the activation of OFs.
Titanium alloy has been widely applied in industrial fields because of its excellent material properties. Electrical discharge machining (EDM) is commonly technology for processing titanium alloy. ...When titanium alloy was processed by EDM, a recast layer was inevitably be produced on its surface, which can adversely affect the surface quality and working life. Focus on the above problem, this paper proposed to add B4C powders into the spark oil and cooperate with the tool electrode sloshing for powder mixed electrical discharge machining (PMEDM) of titanium alloy, which can reduce the thickness of the recast layer and thereby improve the quality of the machined surface. Firstly, B4C powders were mixed in the spark oil and the PMEDM of the titanium alloy was carried out. In this step, the thickness of recast layer was preliminarily reduced and the quality of machined surface was improved. Secondly, when the PMEDM of the titanium alloy was nearly completed, the tool electrode sloshed along the machine tool spindle within the EDM gap. Combining PMEDM with the tool electrode sloshing, the recast layer on the machined surface was further eliminated and the quality of machined surface was further improved. By adding 3000 mesh B4C powders into the spark oil, the paper carried out the PMEDM of titanium alloy combining with the tool electrode sloshing. Under the action of appropriate process parameters, the micro-groove structure with surface roughness Ra of 0.205 μm was obtained in the titanium alloy and the recast layer on the machined surface was almost invisible.
Okur-Chung neurodevelopmental syndrome (OCNDS) and tricho-rhino-phalangeal syndrome type I (TRPSI) are rare Mendelian diseases. OCNDS is caused by CSNK2A1 gene variants and TRPSI is caused by the ...TRPS1gene. However, to have two Mendelian diseases in one patient is even rarer. This is the first reported case of a dual molecular diagnosis of tricho-rhino-phalangeal syndrome type I and Okur-Chung neurodevelopmental syndrome in the same patient. This patient is the first published example of vertical transmission of this recurrent CSN2A1 variant from parent to child. A novel variant in the TRPS1 gene that is pathogenic was also identified. In conclusion, identification of the variants in this patient expands the phenotypes and molecular basis of dual Mendelian diseases.
History of Superior Oblique Muscle Surgery Wu, Lian-Qun; Zhao, Chen
Sichuan da xue xue bao. Journal of Sichuan University. Yi xue ban,
11/2021, Letnik:
52, Številka:
6
Journal Article
is a harmful pathogen causing head blight in cereals such as wheat and barley, and thymol has been proven to inhibit the growth of many pathogens. This study aims to explore the fungistatic effect of ...thymol on
and its mechanism. Different concentrations of thymol were used to treat
. The results showed that the EC
concentration of thymol against
was 40 μg/mL. Compared with the control group, 40 μg/mL of thymol reduced the production of Deoxynivalenol (DON) and 3-Ac-DON by 70.1% and 78.2%, respectively. Our results indicate that thymol can effectively inhibit the growth and toxin production of
and cause an extensive transcriptome response. Transcriptome identified 16,727 non-redundant unigenes and 1653 unigenes that COG did not annotate. The correlation coefficients between samples were all >0.941. When FC was 2.0 times, a total of 3230 differential unigenes were identified, of which 1223 were up-regulated, and 2007 were down-regulated. Through the transcriptome, we confirmed that the expression of many genes involved in
growth and synthesis of DON and other secondary metabolites were also changed. The gluconeogenesis/glycolysis pathway may be a potential and important way for thymol to affect the growth of
hyphae and the production of DON simultaneously.
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