Current and Emerging Biomarkers of Cell Death in Human Disease

Abstract

Cell death is a critical biological process, serving many important functions within multicellular organisms. Aberrations in cell death can contribute to the pathology of human diseases. Significant progress made in the research area enormously speeds up our understanding of the biochemical and molecular mechanisms of cell death. According to the distinct morphological and biochemical characteristics, cell death can be triggered by extrinsic or intrinsic apoptosis, regulated necrosis, autophagic cell death, and mitotic catastrophe. Nevertheless, the realization that all of these efforts seek to pursue an effective treatment and cure for the disease has spurred a significant interest in the development of promising biomarkers of cell death to early diagnose disease and accurately predict disease progression and outcome. In this review, we summarize recent knowledge about cell death, survey current and emerging biomarkers of cell death, and discuss the relationship with human diseases.

Expression of cell cycle and apoptosis regulators in thymus and thymic epithelial tumors

“…Cell cycle and death (apoptotic and non-apoptotic) regulators play crucial roles in normal tissue physiology as well as in pathological processes such as oncogenesis and inflammation [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Cell cycle regulation is achieved through a family of serine/threonine kinase holoenzyme complexes consisting of regulatory cyclin that bind to and activate catalytic cyclin-dependent kinases (CDKs) [1].…”

“…The loss of plasma membrane integrity during necrosis leads to the leakage of intracellular contents, some of which, such as high mobility group protein B1 (HMGB1) and hepatoma-derived growth factor (HDGF), evoke an inflammatory response [5,6,11,15,16]. Necrosis has been traditionally regarded as unregulated, but recent studies revealed a form of regulated necrosis which, with respect to its dependence on specific signaling pathways, was divided into necroptosis, mitochondrial permeability transition-dependent regulated necrosis and parthanatos [5,6,11,[15][16][17]. Necroptosis can be triggered in response to various factors (e.g., alkylating DNA damage, ligation of death receptors such as TNFa, FasL and TRAIL which may activate apoptosis), especially if the caspases (and in particular caspase 8) are inhibited by genetic manipulations (e.g., by gene knockout or RNA interference) or blocked by chemical inhibitors [6,11,15,16].…”

“…Necroptosis can be triggered in response to various factors (e.g., alkylating DNA damage, ligation of death receptors such as TNFa, FasL and TRAIL which may activate apoptosis), especially if the caspases (and in particular caspase 8) are inhibited by genetic manipulations (e.g., by gene knockout or RNA interference) or blocked by chemical inhibitors [6,11,15,16]. The activation of necroptosis by TNFa, FasL and TRAIL requires the kinase activity of receptor-interacting protein 1 (RIP1) which mediates the activation of RIP3 and mixed lineage kinase domain-like (MLKL); activation of MLKL promotes the activation of plasma membrane permeabilization (PMP) and then triggers the necroptosis, whereas inhibition of RIP1 kinase by necrostatins blocks necroptosis [5,6,11,[15][16][17]. Regulation of necroptosis involves apoptosis modulators (e.g., the anti-apoptotic FLIP-L prevents the assembly of FADD-dependent, caspase 8 homodimers that promote apoptosis, while the resulting FLIP-L/caspase 8 heterodimers prevent the activation of RIP3 that mediates necroptosis) [11,16].…”

“…In the MPT-dependent pathway of regulated necrosis, transition pore complex (PTPC) is involved in the regulation of mitochondrial permeability transition (MPT) which leads to the increase in ROS and Ca 2? in the cytoplasm thereby promoting the regulated necrosis; in the parthanatos pathway of the regulated necrosis, poly (ADP-ribose) polymerase 1 (PARP1) repairs the DNA damage, leading to the decrease in ATP and the activation of apoptosis-inducing factor (AIF), thereby promoting the regulated necrosis [15,17].…”

“…Autophagy is a predominantly cytoprotective process of self-digestion used for cellular adaptation to dwindling nutrient resources, but, in some cases, it has been considered as a separate modality of programmed cell death, called autophagic cell death [6,9,11,[14][15][16][17]. Three types of autophagy have been reported including macroautophagy (hereafter referred to as autophagy), microautophagy and chaperonemediated autophagy [9,11,[15][16][17]. Autophagy is characterized by the formation of a double-membrane vesicle, called autophagosome [7-9, 11, 15-17].…”