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CpG-ODN, in addition to stimulation of osteoclastogenic signals in early osteoclast precursors, also induces phosphatase, shifting the pattern of ERK phosphorylation from sustained to transient. This shift results in the degradation of c-fos, an essential molecule for osteoclast differentiation. Therefore, CpG-ODN blocks osteoclast differentiation. INTRODUCTION: Activation of either Toll-like receptor 9 (TLR9) or RANK induces similar responses in osteoclast precursors. Paradoxically, activation of TLR9 results in inhibition of RANKL-induced osteoclastogenesis. MATERIALS AND METHODS: We used bone marrow-derived osteoclast precursors. Analyses of signaling molecules phosphorylation were performed using Western blotting. Different levels of gene expression analyses were performed using RT-PCR, Northern, and run-on analyses (for RNA), and EMSA, Western, and pulse-chase experiments (for protein). Phosphatase activity was measured spectrophotometrically. RESULTS: We found that RANKL and TLR9 ligand, oligodeoxynucleotides containing unmethylated CpG dinucleotides (CpG-ODN), induce sustained and transient extracellular signal-regulated kinase (ERK) phosphorylation, respectively. Furthermore, together they induce a transient phosphorylation of ERK. The duration of ERK phosphorylation is a key factor in determining induction of c-fos, a protein critical for osteoclastogenesis. Indeed, we found that CpG-ODN does not induce c-fos and inhibits its induction by RANKL by enhancing c-fos mRNA and protein degradation. Our observation that CpG-ODN, but not RANKL, induces the expression of the phosphatase PP2A suggests that CpG-ODN exerts its inhibitory activity by induction of ERK dephosphorylation. Moreover, together with the phosphatase inhibitor okadaic acid, CpG-ODN induces sustained ERK phosphorylation and c-fos expression. CONCLUSIONS: Our findings suggest that the increased rate of c-fos degradation by the TLR9 ligand mediates the inhibition of RANKL-induced osteoclast differentiation. The TLR9 ligand, through induction of dephosphorylation, prevents the sustained ERK phosphorylation needed for maintaining high c-fos levels that are essential for osteoclast differentiation. 相似文献
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Murielle Jacquet‐Smailovic Cyril Tarquinio Franois Alla Ilona Denis Amanda Kirche Camille Tarquinio Marie‐Jo Brennstuhl 《Journal of traumatic stress》2021,34(1):190-199
The objective of the present review is to provide an overview of existing research that has reported on the association between posttraumatic stress disorder (PTSD) and ischemic heart disease. Specific focus is given to the incidence of PTSD following myocardial infarction (MI). A systematic review using Preferred Reporting Items for Systematic reviews and Meta‐Analysis (PRISMA) guidelines was performed by searching four bibliographic databases: PubMed, PsychINFO, ScienceDirect, and ProQuest Dissertations and Theses. A total of 39 articles were included in this literature review. The results of these studies suggest that the occurrence of an acute cardiac event is likely to contribute to the development of PTSD. Not only is this type of psychiatric disorder associated with significant suffering and impaired quality of life, but it is also a predictor of an increased risk of recurrent adverse cardiovascular events and mortality. Screening, assessment, and treatment of PTSD and posttraumatic stress symptoms following a major cardiac event are critical for offsetting potential deleterious psychological and physical consequences. 相似文献
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Melman Alla Maher Chris G. Needs Chris Machado Gustavo C. 《Clinical rheumatology》2022,41(6):1867-1871
Clinical Rheumatology - To determine the proportion of patients admitted to the hospital for back pain who have nonserious back pain, serious spinal, or serious other pathology as their final... 相似文献
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Victor A. Aniol Aleksandra Y. Ivanova-Dyatlova Ora Keren Alla B. Guekht Yosef Sarne Natalia V. Gulyaeva 《Epilepsy & behavior : E&B》2013,26(2):196-202
According to different studies, between 5% and 10% of people suffer a single isolated seizure episode at some time in their life. However, little is known about the effects of a single seizure episode on cognitive function, and clinical investigations of this issue are not easy to perform. In this situation, animal models may be a reasonable choice. The aim of our study was to follow the time course of delayed effects of generalized clonic-tonic convulsions on learning and memory functions in rats. A clonic-tonic seizure episode was induced by a single i.p. injection of pentylenetetrazole (70 mg/kg). Different behavioral tests were performed between days 10 and 100 after the convulsant administration. A single seizure episode resulted in a gradual decline in short-term memory function as assessed by novel object recognition and social recognition tests. The seizure episode induced a quick increase in hippocampal cell proliferation; however, the excessive newly generated cells seemed to be eliminated by the time of obvious cognitive impairment. These observations are indicative of a slowly developing and long-lasting influence of a single seizure episode on cognitive function. A rather long time period between the seizure episode and the manifestations of cognitive decline provides a window for a possible therapeutic intervention, and an elaboration of such “post-conditioning” treatments may be a promising opportunity to prevent subsequent mental impairments in patients. 相似文献