Salubrinal acts as a Dusp2 inhibitor and suppresses inflammation in anti-collagen antibody-induced arthritis

Dual-specificity phosphatase 2 (Dusp2; also called phosphatase of activated cells 1, PAC1) is highly expressed in activated immune cells. We examined whether a potential inhibitor of Dusp2, salubrinal, prevents inflammatory cytokine expression in immune cells and arthritic responses in a mouse model of anti-collagen antibody-induced arthritis (CAIA). Salubrinal is a synthetic chemical that inhibits de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). In this study, we examined the effects of salubrinal on expression of inflammation linked genes as well as a family of DUSP genes using genome-wide microarrays, qPCR, and RNA interference. We also evaluated the effects of salubrinal on arthritic responses in CAIA mice using clinical and histological scores. The results revealed that salubrinal decreased inflammatory gene expression in macrophages, T lymphocytes, and mast cells. Dusp2 was suppressed by salubrinal in LPS-activated macrophages as well as PMA/ionomycin-activated T lymphocytes and mast cells. Furthermore, a partial silencing of Dusp2 downregulated IL1β and Cox2, and the inflammatory signs of CAIA mice were significantly suppressed by salubrinal. Collectively, this study presents a novel therapeutic possibility of salubrinal for inflammatory arthritis such as RA through inhibition of Dusp2

Predicting and validating the pathway of Wnt3a-driven suppression of osteoclastogenesis

Wnt signaling plays a major role in bone homeostasis and mechanotransduction, but its role and regulatory mechanism in osteoclast development are not fully understood. Through genome-wide in silico analysis, we examined Wnt3a-driven regulation of osteoclast development. Mouse bone marrow-derived cells were incubated with RANKL in the presence and absence of Wnt3a. Using microarray mRNA expression data, we conducted principal component analysis and predicted transcription factor binding sites (TFBSs) that were potentially involved in the responses to RANKL and Wnt3a. The principal component analysis predicted potential Wnt3a responsive regulators that would reverse osteoclast development, and a TFBS prediction algorithm indicated that the AP1 binding site would be linked to Wnt3a-driven suppression. Since c-Fos was upregulated by RANKL and downregulated by Wnt3a in a dose-dependent manner, we examined its role using RNA interference. The partial silencing of c-Fos suppressed RANKL-driven osteoclastogenesis by downregulating NFATc1, a master transcription factor of osteoclast development. Although the involvement of c-Myc was predicted and partially silencing c-Myc slightly reduced the level of TRAP, c-Myc silencing did not alter the expression of NFATc1. Collectively, the presented systems-biology approach demonstrates that Wnt3a attenuates RANKL-driven osteoclastogenesis by blocking c-Fos expression and suggests that mechanotransduction of bone alters the development of not only osteoblasts but also osteoclasts through Wnt signaling

Failure analysis of sandwich-type ceramic-on-ceramic hip joints: A spectroscopic investigation into the role of the polyethylene shell component

The mechanisms leading to systematic failure in modular acetabular components with a sandwich insertion (alumina/polyethylene/titanium) have been reconsidered in light of the newly collected Raman spectroscopic results. Raman assessments were conducted on the polyethylene shells, which belonged to a series of six failed sandwich implants with in vivo lifetimes ranging between 2 and 9 yr. With only one exception, all implants commonly showed dislodgment of the polyethylene shell during radiographic analyses prior to revision surgery. The polyethylene shell slipped out of the backing titanium shell, while always remaining integer to the ceramic liner. Four implants fractured at the ceramic liners, but their fractures occurred according to distinctly different patterns, which could be rationalized and classified. The insertion of the polyethylene layer, originally conceived to reduce the rigidity of the ceramic-on-ceramic bearing and to prevent impingement between the ceramic liner rim and the femoral neck, played a role in implant failure with its initial (asymmetric) thickness reduction due to creep deformation (eventually followed by cup rotation and backside wear). The results of the present spectroscopic investigation suggest that a simplistic failure classification of the sandwich-type implant as a "ceramic fracture failure" could be misleading and might represent a confounding factor in judging about the reliability of modern ceramic implants. (C) 2013 Elsevier Ltd. All rights reserved

Clinical efficacy of intermittent pressure augmented–retrograde cerebral perfusion

ObjectiveDuring aortic surgery under hypothermic circulatory arrest, retrograde cerebral perfusion (RCP) is commonly used as a cerebroprotective method to extend the duration of circulatory arrest safely. Kitahori and colleagues described a novel protocol of RCP using intermittent pressure augmented (IPA)–RCP in 2005. The aim of the present study was to determine the clinical effectiveness of this novel protocol.MethodsA total of 20 consecutive patients undergoing total replacement of the aortic arch were assigned to a conventional RCP (n = 10) or an IPA-RCP group (n = 10). Cerebral perfusion was provided at a continuous venous pressure of 25 mm Hg in the conventional RCP, and venous pressure was intermittently provided at 20 mm Hg for 120 seconds and at 45 mm Hg for 30 seconds in the IPA-RCP group. The clinical outcomes were compared between the 2 groups. Regional cerebral oxygen saturation (rSO2) was measured using near infrared spectroscopy every 10 minutes from the beginning of RCP initiation. To represent the brain oxygen consumption, the decline ratio of rSO2 was calculated.ResultsThere was no surgical mortality or major neurologic complications in either group. The interval from the end of surgery to full wakefulness was significantly shorter in the IPA-RCP group (85 ± 64 minutes) than in the conventional RCP group (310 ± 282 minutes; P < .05). Although the initial rSO2 value did not show significant difference in both groups, the rSO2 with IPA-RCP was greater than that with conventional RCP from 10 to 70 minutes (P < .05). The decline ratio of rSO2 was lower in the IPA-RCP group than in the RCP perfusion group at all points (P < .05).ConclusionsIPA-RCP might provide more homogenous cerebral perfusion and a more effective oxygen supply to the brain with better clinical results than conventional RCP

Guanabenz Downregulates Inflammatory Responses via eIF2α Dependent and Independent Signaling

Integrated stress responses (ISR) may lead to cell death and tissue degeneration via eukaryotic translation initiation factor 2 α (eIF2α)-mediated signaling. Alleviating ISR by modulating eIF2α phosphorylation can reduce the symptoms associated with various diseases. Guanabenz is known to elevate the phosphorylation level of eIF2α and reduce pro-inflammatory responses. However, the mechanism of its action is not well understood. In this study, we investigated the signaling pathway through which guanabenz induces anti-inflammatory effects in immune cells, in particular macrophages. Genome-wide mRNA profiling followed by principal component analysis predicted that colony stimulating factor 2 (Csf2, or GM-CSF as granulocyte macrophage colony stimulating factor) is involved in the responses to guanabenz. A partial silencing of Csf2 or eIF2α by RNA interference revealed that Interleukin-6 (IL6), Csf2, and Cyclooxygenase-2 (Cox2) are downregulated by guanabenz-driven phosphorylation of eIF2α. Although expression of IL1β and Tumor Necrosis Factor-α (TNFα) was suppressed by guanabenz, their downregulation was not directly mediated by eIF2α signaling. Collectively, the result herein indicates that anti-inflammatory effects by guanabenz are mediated by not only eIF2α-dependent but also eIF2α-independent signaling

The adverse effect of an unplanned surgical excision of foot soft tissue sarcoma

<p>Abstract</p> <p>Background</p> <p>Malignant soft tissue tumors of the foot are extremely rare and thus can be prematurely excised without appropriate preoperative evaluation. The present study compares adverse effects between unplanned and planned surgical excisions.</p> <p>Methods</p> <p>We retrospectively reviewed the clinical records, radiographs, pathology reports and pathological specimens of 14 consecutive patients with soft tissue sarcoma of the foot among 592 with sarcomas between 1973 and 2009. We then compared the incidence and clinical outcomes after unplanned (UT; n = 5) and planned (PT; n = 9) surgical excisions of foot sarcomas.</p> <p>Results</p> <p>The most frequent diagnosis was synovial sarcoma (n = 4; 28.6%). The overall 5-year survival rates of the PT and UT groups were 65.6% and 60.0%, respectively, and the event-free 5-year survival rates were 63.5% and 40.0%, respectively. Event-free and overall survival rates did not significantly differ between the two groups. However, tumors were significantly larger in the PT group than in the UT group (p < 0.05).</p> <p>Conclusions</p> <p>Unplanned resection lead to a relatively worse prognosis and a likelihood of recurrence despite additional resections. We recommend that soft tumors of the foot should only be excised after appropriate preoperative evaluation regardless of the size of the tumor.</p

Salubrinal improves mechanical properties of the femur in osteogenesis imperfecta mic

Salubrinal is an agent that reduces the stress to the endoplasmic reticulum by inhibiting de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). We and others have previously shown that the elevated phosphorylation of eIF2α stimulates bone formation and attenuates bone resorption. In this study, we applied salubrinal to a mouse model of osteogenesis imperfecta (Oim), and examined whether it would improve Oim's mechanical property. We conducted in vitro experiments using RAW264.7 pre-osteoclasts and bone marrow derived cells (BMDCs), and performed in vivo administration of salubrinal to Oim (+/−) mice. The animal study included two control groups (wildtype and Oim placebo). The result revealed that salubrinal decreased expression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1) and suppressed osteoclast maturation, and it stimulated mineralization of mesenchymal stem cells from BMDCs. Furthermore, daily injection of salubrinal at 2 mg/kg for 2 months made stiffness (N/mm) and elastic module (GPa) of the femur undistinguishable to those of the wildtype control. Collectively, this study supported salubrinal's beneficial role to Oim's femora. Unlike bisphosphonates, salubrinal stimulates bone formation. For juvenile OI patients who may favor strengthening bone without inactivating bone remodeling, salubrinal may present a novel therapeutic option