First recognized more than 30 years ago, glycine protects cells against rupture from diverse types of injury. This robust and widely observed effect has been speculated to target a late downstream process common to multiple modes of tissue injury. The molecular target of glycine that mediates cytoprotection, however, remains elusive. Here, we show that glycine works at the level of NINJ1, a newly identified executioner of plasma membrane rupture in pyroptosis, necrosis, and post-apoptosis lysis. NINJ1 is thought to cluster within the plasma membrane to cause cell rupture. We demonstrate that the execution of pyroptotic cell rupture is similar for human and mouse NINJ1, and that NINJ1 knockout functionally and morphologically phenocopies glycine cytoprotection in macrophages undergoing lytic cell death. Next, we show that glycine prevents NINJ1 clustering by either direct or indirect mechanisms. In pyroptosis, glycine preserves cellular integrity but does not affect upstream inflammasome activities or accompanying energetic cell death. By positioning NINJ1 clustering as a glycine target, our data resolve a long-standing mechanism for glycine-mediated cytoprotection. This new understanding will inform the development of cell preservation strategies to counter pathologic lytic cell death.
Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice, with a prevalence that increases alongside the ageing population worldwide. The management of AF involves restoration of sinus rhythm through antiarrhythmic drug therapy. Yet, these medications have only modest efficacy in achieving long-term success, have not shown to result in a mortality benefit, are frequently not tolerated and have associated adverse side effects. Therefore, catheter ablation has become a valuable treatment approach for AF and even a viable first-line strategy in select cases. Traditionally, the combination of radiofrequency energy and a three-dimensional electroanatomical mapping system has been used to guide catheter ablation for AF. However, single-procedural efficacy and long-term outcomes still remain suboptimal for many patients, particularly those with persistent or long-standing AF. Recent advances in ablation technology and strategy, therefore, provide new procedural approaches for catheter-based treatment with the aim of overcoming current challenges in procedural duration and overall success. The aim of this paper was to provide an updated review of the current practices and techniques relating to ablation for AF and to compare the use of these strategies for paroxysmal and persistent AF.
Chronic pain has been widely recognized as a major public health problem that impacts multiple aspects of patient quality of life. Unfortunately, chronic pain is often resistant to conventional analgesics, which are further limited by their various side effects. New therapeutic strategies and targets are needed to better serve the millions of people suffering from this devastating disease. To this end, recent clinical and preclinical studies have implicated the epidermal growth factor receptor signaling pathway in chronic pain states. EGFR is one of four members of the ErbB family of receptor tyrosine kinases that have key roles in development and the progression of many cancers. EGFR functions by activating many intracellular signaling pathways following binding of various ligands to the receptor. Several of these signaling pathways, such as phosphatidylinositol 3-kinase, are known mediators of pain. EGFR inhibitors are known for their use as cancer therapeutics but given recent evidence in pilot clinical and preclinical investigations, may have clinical use for treating chronic pain. Here, we review the clinical and preclinical evidence implicating EGFR in pathological pain states and provide an overview of EGFR signaling highlighting how EGFR and its ligands drive pain hypersensitivity and interact with important pain pathways such as the opioid system.
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