In this article, we review the literature regarding the role of c-Jun N-terminal kinases (JNKs) in cerebral and myocardial ischemia/reperfusion injury. Numerous studies demonstrate that JNK-mediated signaling pathways play an essential role in cerebral and myocardial ischemia/reperfusion injury. JNK-associated mechanisms are involved in preconditioning and post-conditioning of the heart and the brain. The literature and our own studies suggest that JNK inhibitors may exert cardioprotective and neuroprotective properties. The effects of modulating the JNK-depending pathways in the brain and the heart are reviewed. Cardioprotective and neuroprotective mechanisms of JNK inhibitors are discussed in detail including synthetic small molecule inhibitors (AS601245, SP600125, IQ-1S, and SR-3306), ion channel inhibitor GsMTx4, JNK-interacting proteins, inhibitors of mixed-lineage kinase (MLK) and MLK-interacting proteins, inhibitors of glutamate receptors, nitric oxide (NO) donors, and anesthetics. The role of JNKs in ischemia/reperfusion injury of the heart in diabetes mellitus is discussed in the context of comorbidities. According to reviewed literature, JNKs represent promising therapeutic targets for protection of the brain and the heart against ischemic stroke and myocardial infarction, respectively. However, different members of the JNK family exert diverse physiological properties which may not allow for systemic administration of non-specific JNK inhibitors for therapeutic purposes. Currently available candidate JNK inhibitors with high therapeutic potential are identified. The further search for selective JNK3 inhibitors remains an important task.

Senescence is a complex cellular stress response that abolishes proliferative capacity and generates a unique secretory pattern that is implicated in organismal aging and age-related disease. How a cell transitions to a senescent state is multifactorial and often requires transcriptional regulation of multiple genes. Epigenetic alterations to DNA and chromatin are powerful regulators of genome architecture and gene expression, and they play a crucial role in mediating the induction and maintenance of senescence. This review will highlight the changes in chromatin, DNA methylation, and histone alterations that establish and maintain cellular senescence, alongside the specific epigenetic regulation of the senescence-associated secretory phenotype (SASP).

How phosphate levels are detected in mammals is unknown. The bone-derived hormone fibroblast growth factor 23 (FGF23) lowers blood phosphate by reducing kidney phosphate reabsorption and 1,25(OH)2D production, but phosphate does not directly stimulate bone FGF23 expression. Using PET scanning and LC-MS, we found that phosphate increases kidney-specific glycolysis and synthesis of glycerol-3-phosphate (G-3-P), which then circulates to bone to trigger FGF23 production. Further, we found that glycerol-3-phosphate dehydrogenase 1 (Gpd1), a cytosolic enzyme that synthesizes G-3-P and oxidizes NADH to NAD+, is required for phosphate-stimulated G-3-P and FGF23 production and prevention of hyperphosphatemia. In proximal tubule cells, we found that phosphate availability is substrate-limiting for glycolysis and G-3-P production, and that increased glycolysis and Gpd1 activity are coupled through cytosolic NAD+ recycling. Finally, we show that the type II sodium-dependent phosphate cotransporter Npt2a, which is primarily expressed in the proximal tubule, conferred kidney specificity to phosphate-stimulated G-3-P production. Importantly, exogenous G-3-P stimulated FGF23 production when Npt2a or Gpd1 are absent, confirming that it is the key circulating factor downstream of glycolytic phosphate sensing in the kidney. Together, these findings place glycolysis at the nexus of mineral and energy metabolism and identify a kidney-bone feedback loop that controls phosphate homeostasis.

Summary: Society and our healthcare system are facing unprecedented challenges due to the expansion of the older population. As plastic surgeons, we can improve care of our older patients through understanding the mechanisms of aging that inevitably impact their outcomes and well-being. One of the major hallmarks of aging, cellular senescence, has recently become the focus of vigorous research in academia and industry. Senescent cells, which are metabolically active but in a state of stable cell cycle arrest, are implicated in causing aging and numerous age-related diseases. Further characterization of the biology of senescence revealed that it can be both detrimental and beneficial to organisms depending on tissue context and senescence chronicity. Here, we review the role of cellular senescence in aging, wound healing, tissue regeneration, and other domains relevant to plastic surgery. We also review the current state of research on therapeutics that modulate senescence to improve conditions of aging.