Ischemic preconditioning is a process which serves to mitigate reperfusion injury. Preconditioning of the heart can be achieved through natural, pharmacological, and mechanical means. Mechanical preconditioning appears to have the greatest chance of good outcomes while methods employing pharmacologic preconditioning have been largely unsuccessful. Remote ischemic preconditioning achieves a cardioprotective effect by applying cycles of ischemia and reperfusion in a distal limb, stimulating the release of a neurohumoral cardioprotective factor incited by stimulation of afferent neurons. The cardioprotective factor stimulates the reperfusion injury salvage kinase (RISK) and survivor activator factor enhancement (SAFE) signaling cascades in cardiomyocytes which promote cell survival by the expression of anti-apoptotic genes and inhibition of the opening of mitochondrial permeability transition pores. Clinical application of ischemic preconditioning involving targets in the RISK and SAFE signaling appears promising in the treatment of acute myocardial infarction; however, clinical trials have yet to demonstrate additional benefit to current therapy.

Wear debris-induced osteolysis is a common cause of arthroplasty failure in several joints including the knee, hip and intervertebral disc. Debris from the prosthesis can trigger an inflammatory response that leads to aseptic loosening and prosthesis failure. In the spine, periprosthetic pain also occurs following accumulation of wear debris through neovascularization of the disc. The role of the immune system in the pathobiology of periprosthetic osteolysis of joint replacements is debatable. Areas covered: We discussed the stimulation of pro-inflammatory and pro-protective and pro-regenerative pathways due to debris from the prosthetics. The balance between the two pathways may determine the outcome results. Also, the role of cytokines and immune cells in periprosthetic inflammation in the etiology of osteolysis is critically reviewed. Expert commentary: Therapies targeting the inflammatory process associated with ultra-high-molecular-weight polyethylene wear debris could reduce implant failure. Additionally, therapies targeting neovascularization of discs following arthroplasty could mitigate periprosthetic pain.

Introduction: Recurrent atrial fibrillation (RAF) following ablation therapy occurs in about 50% of patients. The pathogenesis of RAF is unknown, but is believed to be driven by atrial remodeling in the setting of background inflammation. Structural, electrophysiological and mechanical remodeling has been associated with atrial fibrillation (AF). Inflammation and fibrotic remodeling are the major factors perpetuating AF, as mediators released from the atrial tissues and cardiomyocytes due to mechanical and surgical injury could initiate the inflammatory process. In this article, we have critically reviewed the key mediators that may serve as potential biomarkers to predict RAF. Areas covered: Damage associated molecular patterns, heat shock proteins, inflammatory cytokines, non-inflammatory markers, markers of inflammatory cell activity, and markers of collagen deposition and metabolism are evaluated as potential biomarkers with molecular treatment options in RAF. Expert commentary: Establishing biomarkers to predict RAF could be useful in reducing morbidity and mortality. Investigations into the role of DAMPs participating in a sterile immune response may provide greater insight into the pathogenesis of RAF. Markers evaluating immune cell activity, collagen deposition, and levels of heat shock proteins show the greatest promise as potential biomarkers to predict RAF and develop novel therapies.

Chronic alcohol consumption contributes to fatty liver disease. Our studies revealed that the hepatic circadian clock is disturbed in alcohol-induced hepatic steatosis, and effects of chronic alcohol administration upon the clock itself may contribute to steatosis. We extended these findings to explore the effects of chronic alcohol treatment on daily feeding and locomotor activity patterns. Mice were chronically pair-fed ad libitum for 4 weeks using the Lieber-DeCarli liquid diet, with calorie-controlled liquid and standard chow diets as control groups. Locomotor activity, feeding activity, and real-time bioluminescence recording of PERIOD2::LUCIFERASE expression in tissue explants were measured. Mice on liquid control and chow diets exhibited normal profiles of locomotor activity, with a ratio of 22:78% day/night activity and a peak during early night. This pattern was dramatically altered in alcohol-fed mice, marked by a 49:51% ratio and the absence of a distinct peak. While chow-diet fed mice had a normal 24:76% ratio of feeding activity, with a peak in the early night, this pattern was dramatically altered in both liquid-diet groups: mice had a 43:57% ratio, and an absence of a distinct peak. Temporal differences were also observed between the two liquid-diet groups during late day. Cosinor analysis revealed a ~4-h and ~6-h shift in the alcohol-fed group feeding and locomotor activity rhythms, respectively. Analysis of hepatic PER2 expression revealed that the molecular clock in alcohol-fed and control liquid-diet mice was shifted by ~11 h and ~6 h, respectively. No differences were observed in suprachiasmatic nucleus explants, suggesting that changes in circadian phase in the liver were generated independently from the central clock. These results suggest that chronic alcohol consumption and a liquid diet can differentially modulate the daily rhythmicity of locomotor and feeding behaviors, aspects that might contribute to disturbances in the circadian timing system and development of hepatic steatosis.

Cardiac tissue has minimal endogenous regenerative capacity in response to injury. Treatment options are limited following tissue damage after events such as myocardial infarction. Current strategies are aimed primarily at injury prevention, but attention has been increasingly targeted toward the development of regenerative therapies. This review focuses on recent developments in the field of cardiac fibroblast reprogramming into induced cardiomyocytes. Early efforts to produce cardiac regeneration centered around induced pluripotent stem cells, but clinical translation has proved elusive. Currently, techniques are being developed to directly transdifferentiate cardiac fibroblasts into induced cardiomyocytes. Viral vector-driven expression of a combination of transcription factors including Gata4, Mef2c, and Tbx5 induced cardiomyocyte development in mice. Subsequent combinational modifications have extended these results to human cell lines and increased efficacy. The miRNAs including combinations of miR-1, miR-133, miR-208, and miR-499 can improve or independently drive regeneration of cardiomyocytes. Similar results could be obtained by combinations of small molecules with or without transcription factor or miRNA expression. The local tissue environment greatly impacts favorability for reprogramming. Modulation of signaling pathways, especially those mediated by VEGF and TGF-β, enhance differentiation to cardiomyocytes. Current reprogramming strategies are not ready for clinical application, but recent breakthroughs promise regenerative cardiac therapies in the near future.