The marine compound and elongation factor 1A1 inhibitor, didemnin B, provides benefit in western diet-induced non-alcoholic fatty liver disease.

Inhibition of eukaryotic elongation factor 1A1 (EEF1A1) with the marine compound didemnin B decreases lipotoxic HepG2 cell death in vitro and improves early stage non-alcoholic fatty liver disease (NAFLD) in young genetically obese mice. However, the effects of didemnin B on NAFLD in a model of long-term diet-induced obesity are not known. We investigated the effects of didemnin B on NAFLD severity and metabolic parameters in western diet-induced obese mice, and on the cell types that contribute to liver inflammation and fibrosis in vitro. Male 129S6 mice were fed either standard chow or western diet for 26 weeks, followed by intervention with didemnin B (50 µg/kg) or vehicle by intraperitoneal (i.p.) injection once every 3 days for 14 days. Didemnin B decreased liver and plasma triglycerides, improved oral glucose tolerance, and decreased NAFLD severity. Moreover, didemnin B moderately increased hepatic expression of genes involved in ER stress response (Perk, Chop), and fatty acid oxidation (Fgf21, Cpt1a). In vitro, didemnin B decreased THP-1 monocyte proliferation, disrupted THP-1 monocyte-macrophage differentiation, decreased THP-1 macrophage IL-1ß secretion, and decreased hepatic stellate cell (HSteC) proliferation and collagen secretion under both basal and lipotoxic (high fatty acid) conditions. Thus, didemnin B improves hepatic steatosis, glucose tolerance, and blood lipids in obesity, in association with moderate, possibly hormetic, upregulation of pathways involved in cell stress response and energy balance in the liver. Furthermore, it decreases the activity of the cell types implicated in liver inflammation and fibrosis in vitro. These findings highlight the therapeutic potential of partial protein synthesis inhibition in the treatment of NAFLD.

ß1-Integrin-A Key Player in Controlling Pancreatic Beta-Cell Insulin Secretion via Interplay With SNARE Proteins.

Shortcomings in cell-based therapies for patients with diabetes have been revealed to be, in part, a result of an improper extracellular matrix (ECM) environment. In vivo, pancreatic islets are emersed in a diverse ECM that provides physical support and is crucial for healthy function. ß1-Integrin receptors have been determined to be responsible for modulation of beneficial interactions with ECM proteins influencing beta-cell development, proliferation, maturation, and function. ß1-Integrin signaling has been demonstrated to augment insulin secretion by impacting the actin cytoskeleton via activation of focal adhesion kinase and downstream signaling pathways. In other secretory cells, evidence of a bidirectional relationship between integrins and exocytotic machinery has been demonstrated, and, thus, this relationship could be present in pancreatic beta cells. In this review, we will discuss the role of ECM-ß1-integrin interplay with exocytotic proteins in controlling pancreatic beta-cell insulin secretion through their dynamic and unique signaling pathway.

Collagen IV-ß1-Integrin Influences INS-1 Cell Insulin Secretion via Enhanced SNARE Protein Expression.

ß1-integrin is a key receptor that regulates cell-ECM interactions and is important in maintaining mature beta-cell functions, including insulin secretion. However, there is little reported about the relationship between ECM-ß1-integrin interactions and exocytotic proteins involved in glucose-stimulated insulin secretion (GSIS). This study examined the effect of collagen IV-ß1-integrin on exocytotic proteins (Munc18-1, Snap25, and Vamp2) involved in insulin secretion using rat insulinoma (INS-1) cell line. Cells cultured on collagen IV (COL IV) had promoted INS-1 cell focal adhesions and GSIS. These cells also displayed changes in levels and localization of ß1-integrin associated downstream signals and exocytotic proteins involved in insulin secretion. Antibody blocking of ß1-integrin on INS-1 cells cultured on COL IV showed significantly reduced cell adhesion, spreading and insulin secretion along with reduced exocytotic protein levels. Blocking of ß1-integrin additionally influenced the cellular localization of exocytotic proteins during the time of GSIS. These results indicate that specific collagen IV-ß1-integrin interactions are critical for proper beta-cell insulin secretion.

N-acetyl-L-cysteine treatment reduces beta-cell oxidative stress and pancreatic stellate cell activity in a high fat diet-induced diabetic mouse model.

Obesity plays a major role in type II diabetes (T2DM) progression because it applies metabolic and oxidative stress resulting in dysfunctional beta-cells and activation of intra-islet pancreatic stellate cells (PaSCs) which cause islet fibrosis. Administration of antioxidant N-acetyl-L-cysteine (NAC) in vivo improves metabolic outcomes in diet-induced obese diabetic mice, and in vitro inhibits PaSCs activation. However, the effects of NAC on diabetic islets in vivo are unknown. This study examined if dosage and length of NAC treatment in HFD-induced diabetic mice effect metabolic outcomes associated with maintaining healthy beta-cells and quiescent PaSCs, in vivo. Male C57BL/6N mice were fed normal chow (ND) or high-fat (HFD) diet up to 30 weeks. NAC was administered in drinking water to HFD mice in preventative treatment (HFDpNAC) for 23 weeks or intervention treatment for 10 (HFDiNAC) or 18 (HFDiNAC+) weeks, respectively. HFDpNAC and HFDiNAC+, but not HFDiNAC, mice showed significantly improved glucose tolerance and insulin sensitivity. Hyperinsulinemia led by beta-cell overcompensation in HFD mice was significantly rescued in NAC treated mice. A reduction of beta-cell nuclear Pdx-1 localization in HFD mice was significantly improved in NAC treated islets along with significantly reduced beta-cell oxidative stress. HFD-induced intra-islet PaSCs activation, labeled by αSMA, was significantly diminished in NAC treated mice along with lesser intra-islet collagen deposition. This study determined that efficiency of NAC treatment is beneficial at maintaining healthy beta-cells and quiescent intra-islet PaSCs in HFD-induced obese T2DM mouse model. These findings highlight an adjuvant therapeutic potential in NAC for controlling T2DM progression in humans.

Early Definitive Care Is as Effective as Staged Treatment Protocols for Open Ankle Fractures Caused by Rotational Mechanisms: A Retrospective Case-Control Study.

OBJECTIVES: To compare immediate internal fixation with primary wound closure to temporary fixation/stabilization with delayed fixation and wound closure protocols for management of open ankle fractures. DESIGN: Retrospective case-control study. SETTING: Level 1 trauma center. PATIENTS: Eighty-eight consecutive patients who presented with a Gustilo-Anderson type I, II, or IIIa open ankle fracture to a single center. INTERVENTION: Patients were divided into 2 cohorts: either immediate internal fixation with primary wound closure (EARLY) or temporary fixation/stabilization with delayed fixation and wound closure (STAGED) due to practice differences of the attending surgeons. MAIN OUTCOME MEASURES: Infection, length of stay, number and type of operations, and clinical measures. We also assessed the 2 groups with regard to demographics and radiographic classification. RESULTS: Overall, incidence of infection was 6 (6.8%) with no significant difference between patients treated with EARLY versus STAGED protocols. The EARLY cohort had a significantly shorter length of hospital stay, fewer number of reoperations but similar clinical outcomes for pain, ambulation, and radiographic evidence of osteoarthritis for patients followed for >12 months. CONCLUSION: Our study showed that early definitive treatment compared with a staged protocol for Gustilo-Anderson type I, II, and IIIa open ankle fractures has similar rates of infection, shorter hospital stay, fewer surgical interventions, and similar clinical outcomes. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Effect of inherent tibial asymmetry on leg length discrepancy measurements after intramedullary nailing of comminuted femoral shaft fractures.

INTRODUCTION: Locked intramedullary nailing (IMN) is the standard treatment for femoral shaft fractures in adults with high rates of union and relatively low rates of complications. Leg length discrepancy (LLD) after IMN of femoral shaft fractures is common, and is reported in 20-43% of cases. A known surgical challenge when trying to obtain equal leg lengths is comminuted fracture, which results in a loss of bony landmarks that guide reduction. The purpose of this study was to assess the effect of inherent tibial asymmetry on LLD measurements after IMN. METHODS: Postoperative CT scanograms were performed on 79 consecutive patients after locked IMN for comminuted femoral shaft fracture. Leg lengths were determined by measurements taken from the scout view of a CT scanogram. Calculations of discrepancy were made for both femurs, tibias, and total leg length. Assessment was also made on the frequency wherein the tibial discrepancy compounded the femoral discrepancy. In situations where a limb segment was exactly symmetric to the contralateral side, the total leg was not regarded as a having compounded asymmetry. RESULTS: Notable discrepancies were found in tibial length that significantly departed from the null of symmetry (p < 0.0001). Forty-two patients (53.2%) were found to have a tibial asymmetry of 3 mm or more, and 20 patients (25.3%) were found to exhibit a difference of 6.3 mm or more. Median femoral discrepancy was 5.3 mm and median tibial discrepancy was 3.0 mm. Seven patients were found to be asymmetric in total leg length as a consequence of underlying tibial asymmetry. Conversely, 11 patients benefited from their tibial asymmetry, which compensated for femoral asymmetry after IMN. CONCLUSION: Tibial symmetry cannot be assumed. If not accounted for, inherent tibial asymmetry may influence LLD after IMN of femur fractures.