Repeated social defeat selectively increases ΔFosB expression and histone H3 acetylation in the infralimbic medial prefrontal cortex

Exposure to social stress has been linked to the development and maintenance of mood-related psychopathology; however, the underlying neurobiological changes remain uncertain. In this study, we examined numbers of ΔFosB-immunoreactive cells in the forebrains of rats subjected to 12 episodes of social defeat. This was achieved using the social conflict model whereby animals are introduced into the home cage of older males (“residents”) trained to attack and defeat all such “intruders”; importantly, controls were treated identically except that the resident was absent. Our results indicated that the only region in which ΔFosB-positive cells were found in significantly higher numbers in intruders than in controls was the infralimbic medial prefrontal cortex (mPFC). This same effect was not apparent using another psychological stressor, noise stress. Cells of the infralimbic mPFC also displayed evidence of chromatin remodeling. We found that exposure to repeated episodes of social defeat increased numbers of cells immunoreactive for histone H3 acetylation, but not for histone H3 phosphoacetylation, in the infralimbic mPFC. Collectively, these findings highlight the importance of the infralimbic mPFC in responding to social stress—a finding that provides insight into the possible neurobiological alterations associated with stress-induced psychiatric illness.

Low-dose histone deacetylase inhibitor treatment leads to tumor growth arrest and multi-lineage differentiation of malignant rhabdoid tumors

PURPOSE: Malignant rhabdoid tumor (MRT) and atypical teratoid rhabdoid tumors (ATRT) are rare aggressive undifferentiated tumors primarily affecting the kidney and CNS of infants and young children. MRT are almost exclusively characterized by homozygous deletion or inactivation of the chromatin remodeling gene SMARCB1 SMARCB1 protein loss leads to direct impairment of chromatin remodeling and we have previously reported a role for this protein in histone acetylation. This provided the rationale for investigating the therapeutic potential of histone deactylase inhibitors (HDACi) in MRT. EXPERIMENTAL DESIGN: Whereas previously HDACis have been used at doses and schedules that induce cytotoxicity, in the current studies we have tested the hypothesis, both in vitro and in vivo, that sustained treatment of human MRT with low-dose HDACi can lead to sustained cell growth arrest and differentiation. RESULTS: Sustained low-dose panobinostat (LBH589) treatment led to changes in cellular morphology associated with a marked increase in the induction of neural, renal, and osteoblast differentiation pathways. Genome-wide transcriptional profiling highlighted differential gene expression supporting multilineage differentiation. Using mouse xenograft models, sustained low-dose LBH589 treatment caused tumor growth arrest associated with tumor calcification detectable by X-ray imaging. Histological analysis of LBH589-treated tumors revealed significant regions of ossification, confirmed by Alizarin Red staining. Immunohistochemical analysis showed increased TUJ1 and PAX2 staining suggestive of neuronal and renal differentiation, respectively. CONCLUSIONS: Low-dose HDACi treatment can terminally differentiate MRT tumor cells and reduce their ability to self-renew. The use of low-dose HDACi as a novel therapeutic approach warrants further investigation.

ANXA2 enhances the progression of hepatocellular carcinoma via remodeling the cell motility associated structures

Hepatocellular carcinoma (HCC) ranks as the fifth most common malignancy worldwide. The detailed mechanism of signal regulation for HCC progression is still not known, and the high motility of cancer cells is known as a core property for cancer progression maintenance. Annexin A2 (ANXA2), a calcium-dependent phospholipids binding protein is highly expressed in HCC. To study the roles the excessively expressed ANXA2 during the progression of HCC, we inhibited the ANXA2 expression in SMMC-7721 cells using RNAi, followed by the analysis of cell growth, apoptosis and cell motility. To explore the relationship between the cell behaviors and its structures, the microstructure changes were observed under fluorescence microscopy, laser scanning confocal microscopy and electron microscopy. Our findings demonstrated that down-regulation of ANXA2 results in decreased the cell proliferation and motility, enhanced apoptosis, suppressed cell pseudopodia/filopodia, inhibited expression of F-actin and β-tubulin, and inhibited or depolymerized Lamin B. The cell contact inhibition was also analyzed in the paper. Take together, our results indicate that ANXA2 plays an important role to enhance the malignant behaviors of HCC cells, and the enhancement is closely based on its remodeling to cell structures.

MMP2 and MMP9 plasma levels as markers of bone remodeling : a study on young male tennis players

Introduction
Our goal is to study the effects of tennis practice in pre-pubescent boys on bone remodeling, by means of enzyme activity involved in balance of matrix remodeling (MMP2 and MMP9).
Results
Mineral bone density has been found higher in the dominant arm (P < 0.0001) as well as MMP2 and MMP9 levels in plasma (P < 0.05).
Conclusion
Tennis practice in children increases bone remodeling, which can be assessed by MMP dosage, in addition of densitometry technique.

Changes in zinc ligation promote remodeling of the active site in the zinc hydrolase superfamily

The zinc hydrolase superfamily is a group of divergently related proteins that are predominantly enzymes with a zinc-based catalytic mechanism. The common structural scaffold of the superfamily consists of an eight-stranded β-sheet flanked by six α-helices. Previous analyses, while acknowledging the likely divergent origins of leucine aminopeptidase, carboxypeptidase A and the co-catalytic enzymes of the metallopeptidase H clan based on their structural scaffolds, have failed to find any homology between the active sites in leucine aminopeptidase and the metallopeptidase H clan enzymes. Here we show that these two groups of co-catalytic enzymes have overlapping dizinc centers where one of the two zinc atoms is conserved in each group. Carboxypeptidase A and leucine aminopeptidase, on the other hand, no longer share any homologous zinc-binding sites. At least three catalytic zinc-binding sites have existed in the structural scaffold over the period of history defined by available structures. Comparison of enzyme-inhibitor complexes show that major remodeling of the substrate-binding site has occurred in association with each change in zinc ligation in the binding site. These changes involve re-registration and re-orientation of the substrate. Some residues important to the catalytic mechanism are not conserved amongst members. We discuss how molecules acting in trans may have facilitated the mutation of catalytically important residues in the active site in this group.

Effect of exercise training on left ventricular remodeling in diabetic patients with diastolic dysfunction: rationale and design

This study will examine the effects of combined aerobic and resistance training on left ventricular remodeling in diabetic patients with diastolic dysfunction. This is the first randomized controlled trial to look for effects of combined strength training and aerobic exercise on myocardial function as well as other clinical, functional, or psychological parameters in diabetic patients with isolated diastolic dysfunction, and will provide important insights into the potential management strategies for heart failure with preserved ejection fraction.

Impact of bed rest on conduit artery remodeling: effect of exercise countermeasures

Physical inactivity is a potent stimulus for vascular remodeling, leading to a marked decrease in conduit artery diameter. However, little is known about the impact of physical inactivity on artery wall thickness or wall:lumen ratio or the potential of exercise countermeasures to modify artery wall thickness. The purpose of the study was to examine the impact of 60 days of bed rest, with or without exercise countermeasures, on carotid and superficial femoral artery wall thickness. Eighteen men were assigned to bed rest (second Berlin Bed Rest Study) and randomly allocated to control, resistive exercise, or resistive vibration exercise. Both exercise countermeasures were applied 3 times per week while the subjects were in the supine position on the bed. Sonography was used to examine baseline diameter and wall thickness of the carotid and femoral arteries. Bed rest decreased diameter of the superficial femoral artery (P=0.001) but not the carotid artery (P=0.29). Bed rest induced a significant increase in carotid and superficial femoral artery wall thickness (P=0.007 and 0.03) and wall:lumen ratio (P=0.009 and 0.001). Exercise prevented the increase in wall thickness of the carotid artery. In addition, exercise partly prevented the increased wall:lumen ratio in the superficial femoral artery. In conclusion, 8 weeks of bed rest resulted in approximately 20% increase in conduit artery wall thickness. Exercise countermeasures completely (carotid artery) or partly (superficial femoral artery) abolished the increase in wall thickness. These findings suggest that conduit artery wall thickness, a vascular characteristic associated previously with atherosclerosis, can rapidly adapt to physical inactivity and exercise in humans.