Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

https://biblio.ugent.be/publication/8555786/file/8555788.pdf

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

■ Abstract Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli. Studies performed over the past 10 years have demonstrated that proteases play critical roles in initiation and execution of this process. The caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases. Caspases are synthesized as relatively inactive zymogens that become activated by scaffold-mediated transactivation or by cleavage via upstream proteases in an intracellular cascade. Regulation of caspase activation and activity occurs at several different levels: ( a) Zymogen gene transcription is regulated; ( b) antiapoptotic members of the Bcl-2 family and other cellular polypeptides block proximity-induced activation of certain procaspases; and ( c) certain cellular inhibitor of apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair machinery, and a number of protein kinases. Collectively, these scissions disrupt survival pathways and disassemble important architectural components of the cell, contributing to the stereotypic morphological and biochemical changes that characterize apoptotic cell death.

Mammalian caspases: structure ,a ctivation ,s ubstrates, and functions during apoptosis

In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.

/pdf/molecular-definitions-of-cell-death-subroutines-q5g428rlyi.pdf

Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

mTOR Signaling in Growth, Metabolism, and Disease

Autophagy is a mechanism by which cellular material is delivered to lysosomes for degradation, leading to the basal turnover of cell components and providing energy and macromolecular precursors. Autophagy has opposing, context-dependent roles in cancer, and interventions to both stimulate and inhibit autophagy have been proposed as cancer therapies. This has led to the therapeutic targeting of autophagy in cancer to be sometimes viewed as controversial. In this Review, we suggest a way forwards for the effective targeting of autophagy by understanding the context-dependent roles of autophagy and by capitalizing on modern approaches to clinical trial design.

/pdf/targeting-autophagy-in-cancer-2pjcn0h04a.pdf

Targeting autophagy in cancer

Antiglioma action of Sideritis scardica extracts

This study investigated the transport of tiazofurin (2-beta-D-ribofuranosyl thiazole-4-carboxamide) across the blood-aqueous humor barrier, using the vascular perfusion method in the guinea pig. Volume of distribution (Vd) of [3H] tiazofurin increased almost linearly in time, from 4% of its plasma concentration at 3 min to 10% after 12 min of perfusion. Unidirectional transport constant, K(in) was 7.01 +/- 1.06 x 10(-3) ml/min/g. These results indicate that tiazofurin penetrates the aqueous humor to a considerable extent. Addition of unlabelled tiazofurin to the perfusing medium caused a significant decrease in the uptake of [3H] labelled tiazofurin (K(in) = 2.60 +/- 0.91 x 10(-3) ml/min/g). Therefore, penetration of tiazofurin from blood into aqueous humor seems to be a saturable process with a diffusional component that cannot be disregarded. Such findings could be of considerable importance since this molecule is known to affect tissue metabolism.

Penetration of [3H] tiazofurin into guinea pig eye by a saturable mechanism.

Tiazofurin is a nucleoside analog with potent antitumor activity. The objective of this study was to define the kinetic parameters of tiazofurin transport from blood into the guinea pig brain. The second aim was to define kinetic parameters of tiazofurin transport inhibition by adenosine (K i and K d a ), as well as whether tiazofurin blood-to-brain transport was performed in countertransport with Na + . In order to determine these parameters, the in situ method of perfusion of guinea pig brain was used. Addition ofincreasing concentrations of unlabelled tiazofurin to perfusing medium (0.05-2.7 mmol/l) caused progressive decrease of [ 3 H]-tiazofurin brain clearance with K m values ranging from 119.57 ± 40.12 to 150.17 ± 51.68 x 10 -6 mol/l. Maximal transport capacity ranged from 325.03 ± 113.93 to 417.50 ± 151.53 pmol/min/g. Introduction of adenosine into the perfusing medium (0.005-0.2 mmol/l) caused similar but more rapid decrease of [ 3 H]-tiazofurin brain clearance (K i = 6.36 ± 3.14 x 10 -6 mol/l for nucleus caudate and 11.74 ± 4.85 x 10 -6 mol/l for cerebral cortex). Therefore, it seems that transport system for adenosine plays the main role in tiazofurin brain uptake, but another transport mechanism is also involved in this process. Depletion ofperfusing medium from sodium ions did not cause significant change in volume of distribution values for [ 3 H]-tiazofurin in guinea pig cerebral cortex.

Kinetics and sodium independence of [3H]-tiazofurin blood to brain transport in the guinea pig.

Background/Aim. Introduction of acetylcholine esterase inhibitors as a symptomatic treatment of Alzheimer's disease (AD) has additionally highlighted the importance of diagnostic markers in cerebrospinal fluid (CSF) for early AD diagnosis: low level of 42 amino acid form of amyloid-β peptide (Aβ42), and levels of tau protein (T-tau) and phosphorylated tau protein (P-tau). The aim of this study was to diagnostic potential of CSF biomarkers T-tau, P-tau and Aβ42 as biochemical markers for AD. Methods. Lumbar puncture was performed in 63 patients with AD and 26 control subjects who passed orthopedic surgery. The Innotest, ELISA sandwich test (Innogenetics - Belgium) was used for measuring the levels of T-tau, P-tau and Aβ42. Results. The patients and the control group did not differ in age, education and sex. Mean levels of CSF T-tau and P-tau were significantly higher in the patients with AD (p < 0.001) compared to the control group, in contrast to significantely lower CSF Aβ42 in AD group (p < 0.001). A significant progressive decrease of Aβ42, as well as significant progressive increase of T-tau and P-tau was found among AD subgroups (according to MMSE staging) and controls. Conclusion. The obtained results suggest that these biomarkers may be supportive in the diagnosis of AD, especially in the early course of the disease and could be used in the routine clinical practice considering the approaching target therapeutics.

/pdf/cerebrospinal-fluid-amyloid-beta-and-tau-protein-biomarkers-1ykts666e1.pdf

[Cerebrospinal fluid amyloid beta and tau protein: biomarkers for Alzheimer's disease].

Parkinson’s disease (PD) is defined as a chronic neurodegenerative disorder with a gradual demise of dopaminergic (DA) neurons in substantia nigra pars compacta. Although molecular mechanisms of DA neurons’ degeneration are still insufficiently understood, different studies based on animal, toxic and genetic models, as well as post-mortem brain tissue analyses revealed several common features of neuronal death in SN: mitochondrial dysfunction, increased ROS production and impaired proteostasis. Each of these mechanisms might be, at least in part, related to adenosine monophosphate-activated protein kinase (AMPK). The AMPK is a major intracellular energy sensor. It can be activated by different types of metabolic stress, mediated by at least three different kinases LKB1, CAMKKβ, and TAK1, in conditions of decreased cellular ATP and/or increased Ca2+ level. Once activated, AMPK promotes catabolic pathways, inhibits mTORC1, and stimulates autophagy, mitochondrial biogenesis, and turnover. Different studies revealed a growing body of evidence suggesting an important role of AMPK in PD. Many of them have documented the protective effect of AMPK activation in different PD models by facilitating mitochondrial quality control, enhancing autophagic clearance of defective mitochondria and protein aggregates. However, some studies have shown the detrimental effect of AMPK activation in DA neurons in advanced stages of neuronal damage, where prolonged activation could inhibit protein synthesis and impair synaptic integrity and plasticity. In this review, we will try to summarize the literature data regarding the role of AMPK in PD pathogenesis.

/pdf/the-role-of-adenosine-monophosphate-activated-protein-kinase-1rtrhpb35l.pdf

Ivanka Markovic

Papers

Antiglioma action of Sideritis scardica extracts

Penetration of [3H] tiazofurin into guinea pig eye by a saturable mechanism.

Kinetics and sodium independence of [3H]-tiazofurin blood to brain transport in the guinea pig.

[Cerebrospinal fluid amyloid beta and tau protein: biomarkers for Alzheimer's disease].

The role of adenosine monophosphate-activated protein kinase in neurodegeneration in Parkinson's disease