scholarly journals Aberrant paracrine signalling for bone remodelling underlies the mutant histone-driven giant cell tumour of bone.

2021 ◽  
Author(s):  
Lucia Cottone ◽  
Lorena Ligammari ◽  
Helen J Knowles ◽  
Hang-Mao Lee ◽  
Stephen Henderson ◽  
...  
Keyword(s):  
Giant Cell ◽  
Current Treatment ◽  
Causative Role ◽  
Paracrine Signalling ◽  
Contrast Gain ◽  
Giant Cell Tumours ◽  
Pathogenic Interaction ◽  
Underlying Mechanisms ◽  
Bidirectional Interactions

Oncohistones represent compelling evidence for a causative role of epigenetic perturbations in cancer. Giant cell tumours of bone (GCTs) are characterised by a mutated histone H3.3 as the sole genetic driver present in bone-forming osteoprogenitor cells but absent from abnormally large bone-resorbing osteoclasts which represent the hallmark of these neoplasms. While these striking features imply a pathogenic interaction between mesenchymal and myelomonocytic lineages during GCT development, the underlying mechanisms remain unknown. We show that the changes in the transcriptome and epigenome in the mesenchymal cells caused by the H3.3-G34W mutation contribute to increase osteoclast recruitment in part via reduced expression of the TGF-beta-like soluble factor, SCUBE3. In turn, osteoclasts secrete unregulated amounts of SEMA4D enhancing proliferation of mutated osteoprogenitors and arresting their maturation. These findings provide a mechanism by which GCTs undergo differentiation upon denosumab treatment, a drug that depletes osteoclasts. In contrast, gain of hTERT activity, commonly found in malignant GCT, makes neoplastic cells insensitive to osteoclasts, predicting the unresponsiveness to denosumab. We provide a mechanism for GCT initiation and its response to current treatment, the basis of which is dysfunctional cross-talk between bone-forming and bone-resorbing cells, emphasising the importance of tumor/microenvironment bidirectional interactions in tumorigenesis.

scholarly journals Nrf2 Deficiency Exaggerates Doxorubicin-Induced Cardiotoxicity and Cardiac Dysfunction

2014 ◽  
Vol 2014 ◽  
pp. 1-15 ◽  
Author(s):  
Siying Li ◽  
Wenjuan Wang ◽  
Ting Niu ◽  
Hui Wang ◽  
Bin Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Adverse Effects ◽  
Cardiac Dysfunction ◽  
Protein Aggregates ◽  
Autophagic Flux ◽  
Related Factor ◽  
Causative Role ◽  
Myocardial Oxidative Stress ◽  
Underlying Mechanisms

The anticancer therapy of doxorubicin (Dox) has been limited by its acute and chronic cardiotoxicity. In addition to a causative role of oxidative stress, autophagy appears to play an important role in the regulation of Dox-induced cardiotoxicity. However, the underlying mechanisms remain unclear. Accordingly, we explored a role of nuclear factor erythroid-2 related factor 2 (Nrf2) in Dox-induced cardiomyopathy with a focus on myocardial oxidative stress and autophagic activity. In wild type (WT) mice, a single intraperitoneal injection of 25 mg/kg Dox rapidly induced cardiomyocyte necrosis and cardiac dysfunction, which were associated with oxidative stress, impaired autophagy, and accumulated polyubiquitinated protein aggregates. However, these Dox-induced adverse effects were exaggerated in Nrf2 knockout (Nrf2−/−) mice. In cultured cardiomyocytes, overexpression of Nrf2 increased the steady levels of LC3-II, ameliorated Dox-induced impairment of autophagic flux and accumulation of ubiquitinated protein aggregates, and suppressed Dox-induced cytotoxicity, whereas knockdown of Nrf2 exerted opposite effects. Moreover, the exaggerated adverse effects in Dox-intoxicated Nrf2 depleted cardiomyocytes were dramatically attenuated by forced activation of autophagy via overexpression of autophagy related gene 5 (Atg5). Thus, these results suggest that Nrf2 is likely an endogenous suppressor of Dox-induced cardiotoxicity by controlling both oxidative stress and autophagy in the heart.

Response Interference as a Mechanism Underlying Implicit Measures

2008 ◽  
Vol 24 (4) ◽  
pp. 218-225 ◽  
Author(s):  
Bertram Gawronski ◽  
Roland Deutsch ◽  
Etienne P. LeBel ◽  
Kurt R. Peters
Keyword(s):  
Task Performance ◽  
Psychological Research ◽  
Implicit Measures ◽  
Mediation Model ◽  
Response Interference ◽  
Relevant Evidence ◽  
Moderated Mediation Model ◽  
Stimulus Features ◽  
Underlying Mechanisms

Over the last decade, implicit measures of mental associations (e.g., Implicit Association Test, sequential priming) have become increasingly popular in many areas of psychological research. Even though successful applications provide preliminary support for the validity of these measures, their underlying mechanisms are still controversial. The present article addresses the role of a particular mechanism that is hypothesized to mediate the influence of activated associations on task performance in many implicit measures: response interference (RI). Based on a review of relevant evidence, we argue that RI effects in implicit measures depend on participants’ attention to association-relevant stimulus features, which in turn can influence the reliability and the construct validity of these measures. Drawing on a moderated-mediation model (MMM) of task performance in RI paradigms, we provide several suggestions on how to address these problems in research using implicit measures.

The More You Say, the Less They Hear

2015 ◽  
Vol 27 (4) ◽  
pp. 159-169 ◽  
Author(s):  
Elsbeth D. Asbeek Brusse ◽  
Marieke L. Fransen ◽  
Edith G. Smit
Keyword(s):  
Hearing Protection ◽  
Entertainment Education ◽  
Mediating Role ◽  
Attitude Measures ◽  
Underlying Mechanisms

Abstract. This study examined the effects of disclosure messages in entertainment-education (E-E) on attitudes toward hearing protection and attitude toward the source. In addition, the (mediating) role of the underlying mechanisms (i.e., transportation, identification, and counterarguing) was studied. In an experiment (N = 336), three different disclosure messages were compared with a no-disclosure condition. The results show that more explicit disclosure messages negatively affect transportation and identification and stimulate the generation of counterarguments. In addition, the more explicit disclosure messages affect both attitude measures via two of these processes (i.e., transportation and counterarguing). Less explicit disclosure messages do not have this effect. Implications of the findings are discussed.

Giant Cell Tumours of the Spine

2017 ◽  
Author(s):  
Stefano Boriani ◽  
Luca Boriani
Keyword(s):  
Giant Cell ◽  
Giant Cell Tumours

Autophagy Modulators and Neuroinflammation

2020 ◽  
Vol 27 (6) ◽  
pp. 955-982 ◽  
Author(s):  
Kyoung Sang Cho ◽  
Jang Ho Lee ◽  
Jeiwon Cho ◽  
Guang-Ho Cha ◽  
Gyun Jee Song
Keyword(s):  
Neurodegenerative Disorders ◽  
Neurological Disorders ◽  
Mammalian Cells ◽  
Critical Role ◽  
Therapeutic Agents ◽  
Mechanisms Of Action ◽  
Scientific Interest ◽  
Therapeutic Tools ◽  
Underlying Mechanisms

Background: Neuroinflammation plays a critical role in the development and progression of various neurological disorders. Therefore, various studies have focused on the development of neuroinflammation inhibitors as potential therapeutic tools. Recently, the involvement of autophagy in the regulation of neuroinflammation has drawn substantial scientific interest, and a growing number of studies support the role of impaired autophagy in the pathogenesis of common neurodegenerative disorders. Objective: The purpose of this article is to review recent research on the role of autophagy in controlling neuroinflammation. We focus on studies employing both mammalian cells and animal models to evaluate the ability of different autophagic modulators to regulate neuroinflammation. Methods: We have mostly reviewed recent studies reporting anti-neuroinflammatory properties of autophagy. We also briefly discussed a few studies showing that autophagy modulators activate neuroinflammation in certain conditions. Results: Recent studies report neuroprotective as well as anti-neuroinflammatory effects of autophagic modulators. We discuss the possible underlying mechanisms of action of these drugs and their potential limitations as therapeutic agents against neurological disorders. Conclusion: Autophagy activators are promising compounds for the treatment of neurological disorders involving neuroinflammation.

Inflammatory Biomarkers in Atrial Fibrillation

2019 ◽  
Vol 26 (5) ◽  
pp. 837-854 ◽  
Author(s):  
Effimia Zacharia ◽  
Nikolaos Papageorgiou ◽  
Adam Ioannou ◽  
Gerasimos Siasos ◽  
Spyridon Papaioannou ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Plasma Levels ◽  
Large Scale ◽  
Inflammatory Biomarkers ◽  
Inflammatory Pathways ◽  
Inflammatory State ◽  
Anti Inflammatory ◽  
Underlying Mechanisms

During the last few years, a significant number of studies have attempted to clarify the underlying mechanisms that lead to the presentation of atrial fibrillation (AF). Inflammation is a key component of the pathophysiological processes that lead to the development of AF; the amplification of inflammatory pathways triggers AF, and, in tandem, AF increases the inflammatory state. Indeed, the plasma levels of several inflammatory biomarkers are elevated in patients with AF. In addition, the levels of specific inflammatory biomarkers may provide information regarding to the AF duration. Several small studies have assessed the role of anti-inflammatory treatment in atrial fibrillation but the results have been contradictory. Large-scale studies are needed to evaluate the role of inflammation in AF and whether anti-inflammatory medications should be routinely administered to patients with AF.

Inter-Tissue and Intra-Tissue Co-Expression Networks in Human Metabolism: Morphological Evaluation of the Link Between Transcription Factors ERβ and NFAT in Morbid Obesity

2020 ◽  
Vol 17 (1) ◽  
pp. 63-80
Author(s):  
Athina Chasapi ◽  
Kostas Balampanis ◽  
Eleni Kourea ◽  
Fotios Kalfaretzos ◽  
Vaia Lambadiari ◽  
...  
Keyword(s):  
Morbid Obesity ◽  
Adipose Tissue ◽  
Clinicopathological Parameters ◽  
Morbidly Obese ◽  
Human Metabolism ◽  
Activated T Cells ◽  
Alcoholic Fatty Liver ◽  
Morphological Evaluation ◽  
Underlying Mechanisms

Background: Estrogen receptor β (ERβ) plays an important role in human metabolism and some of its metabolic actions are mediated by a positive “cross-talk” with Nuclear Factor of Activated T cells (NFAT) and the key metabolic transcriptional coregulator Transcriptional Intermediary Factor 2 (TIF2). Introduction: Our study is an “in situ” morphological evaluation of the communication between ERβ, NFAT and TIF2 in morbid obesity. Potential correlations with clinicopathological parameters and with the presence of diabetes and non-alcoholic fatty liver disease (NAFLD) were also explored. The aim of the present study was to determine the role of ERβ and NFAT in the underlying pathophysiology of obesity and related comorbidities. We have investigated the expression of specific proteins using immunochemistry methodologies. Methods: Our population consists of 50 morbidly obese patients undergoing planned bariatric surgery, during which biopsies were taken from visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), skeletal muscle (SM), extramyocellular adipose tissue (EMAT) and liver and the differential protein expression was evaluated by immunohistochemistry. Results: We demonstrated an extensive intra- and inter-tissue co-expression network, which confirms the tissue-specific and integral role of each one of the investigated proteins in morbid obesity. Moreover, a beneficial role of ERβ and NFATc1 against NAFLD is implicated, whereas the distinct roles of TIF2 still remain an enigma. Conclusions: We believe that our findings will shed light on the complex underlying mechanisms and that the investigated biomarkers could represent future targets for the prevention and therapy of obesity and its comorbidities.

scholarly journals GPER-Deficient Rats Exhibit Lower Serum Corticosterone Level and Increased Anxiety-Like Behavior

2020 ◽  
Vol 2020 ◽  
pp. 1-22 ◽  
Author(s):  
Yi Zheng ◽  
Meimei Wu ◽  
Ting Gao ◽  
Li Meng ◽  
Xiaowei Ding ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Corticosterone Level ◽  
Brain Structures ◽  
Ample Evidence ◽  
Genetic Ablation ◽  
Serum Corticosterone ◽  
Underlying Mechanisms ◽  
G Protein Coupled ◽  
Prolonged Stress

Ample evidence suggests that estrogens have strong influences on the occurrence of stress-related mood disorders, but the underlying mechanisms remain poorly understood. Through multiple approaches, we demonstrate that the G protein-coupled estrogen receptor (GPER) is widely distributed along the HPA axis and in brain structures critically involved in mood control. Genetic ablation of GPER in the rat resulted in significantly lower basal serum corticosterone level but enhanced ACTH release in response to acute restraint stress, especially in the female. GPER-/- rats of either sex displayed increased anxiety-like behaviors and deficits in learning and memory. Additionally, GPER deficiency led to aggravation of anxiety-like behaviors following single-prolonged stress (SPS). SPS caused significant decreases in serum corticosterone in WT but not in GPER-deficient rats. The results highlight an important role of GPER at multiple sites in regulation of the HPA axis and mood.

scholarly journals Hypoxia and Mitochondrial Dysfunction in Pregnancy Complications

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 405 ◽  
Author(s):  
Xiang-Qun Hu ◽  
Lubo Zhang
Keyword(s):  
Pregnancy Complications ◽  
Intrauterine Growth Restriction ◽  
Animal Studies ◽  
Major Effect ◽  
Causative Role ◽  
Therapeutic Approaches ◽  
Maternal Complications ◽  
Mitochondrial Ros ◽  
Subsequent Risk

Hypoxia is a common and severe stress to an organism’s homeostatic mechanisms, and hypoxia during gestation is associated with significantly increased incidence of maternal complications of preeclampsia, adversely impacting on the fetal development and subsequent risk for cardiovascular and metabolic disease. Human and animal studies have revealed a causative role of increased uterine vascular resistance and placental hypoxia in preeclampsia and fetal/intrauterine growth restriction (FGR/IUGR) associated with gestational hypoxia. Gestational hypoxia has a major effect on mitochondria of uteroplacental cells to overproduce reactive oxygen species (ROS), leading to oxidative stress. Excess mitochondrial ROS in turn cause uteroplacental dysfunction by damaging cellular macromolecules, which underlies the pathogenesis of preeclampsia and FGR. In this article, we review the current understanding of hypoxia-induced mitochondrial ROS and their role in placental dysfunction and the pathogenesis of pregnancy complications. In addition, therapeutic approaches selectively targeting mitochondrial ROS in the placental cells are discussed.

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