PROTACs – A Novel and Rapidly Developing Field of Targeted Protein Degradation

There is a continued need for new technology and strategies for tackling cancer and other diseases, and within the current century a novel therapeutic strategy has emerged in the realm of targeted protein degradation called Proteolysis-Targeting Chimeras (PROTACs). This technology specifically targets and degrades disease-causing proteins via the ubiquitin-proteasome system, and has seen an explosion of research and intrigue in both academia and industry over the past two decades. The diversity of PROTAC classes based on the E3 ligase recruiting ligand and the target protein allows for a universal molecular structure that can be customized for a specific target and disease. While it is primarily heavily focused in the realm of cancer therapeutics, PROTACs have expanded into other diseases such as cardiovascular, neurodegenerative, and virus-caused diseases. The discovery of novel PROTAC designs also allows for the field to overcome its own shortcomings and develop into new directions. Overall, the intrigue of PROTAC technology’s ability to degrade ‘undruggable’ targets has driven the field of research to expand rapidly in the short time since its initial discovery and continued intense efforts will help further shape the field to transition into the clinical setting to benefit the world

Redox inhibition of protein phosphatase PP2A: Potential implications in oncogenesis and its progression

Cellular processes are dictated by the active signaling of proteins relaying messages to regulate cell proliferation, apoptosis, signal transduction and cell communications. An intricate web of protein kinases and phosphatases are critical to the proper transmission of signals across such cascades. By governing 30–50% of all protein dephosphorylation in the cell, with prominent substrate proteins being key regulators of signaling cascades, the phosphatase PP2A has emerged as a celebrated player in various developmental and tumorigenic pathways, thereby posing as an attractive target for therapeutic intervention in various pathologies wherein its activity is deregulated. This review is mainly focused on refreshing our understanding of the structural and functional complexity that cocoons the PP2A phosphatase, and its expression in cancers. Additionally, we focus on its physiological regulation as well as into recent advents and strategies that have shown promise in countering the deregulation of the phosphatase through its targeted reactivation. Finally, we dwell upon one of the key regulators of PP2A in cancer cells-cellular redox status-its multifarious nature, and its integration into the reactome of PP2A, highlighting some of the significant impacts that ROS can inflict on the structural modifications and functional aspect of PP2A

Peroxisome Proliferator-Activated Receptors and Caloric Restriction-Common Pathways Affecting Metabolism, Health, and Longevity.

Caloric restriction (CR) is a traditional but scientifically verified approach to promoting health and increasing lifespan. CR exerts its effects through multiple molecular pathways that trigger major metabolic adaptations. It influences key nutrient and energy-sensing pathways including mammalian target of rapamycin, Sirtuin 1, AMP-activated protein kinase, and insulin signaling, ultimately resulting in reductions in basic metabolic rate, inflammation, and oxidative stress, as well as increased autophagy and mitochondrial efficiency. CR shares multiple overlapping pathways with peroxisome proliferator-activated receptors (PPARs), particularly in energy metabolism and inflammation. Consequently, several lines of evidence suggest that PPARs might be indispensable for beneficial outcomes related to CR. In this review, we present the available evidence for the interconnection between CR and PPARs, highlighting their shared pathways and analyzing their interaction. We also discuss the possible contributions of PPARs to the effects of CR on whole organism outcomes

Modulating mitophagy in mitochondrial disease

Mitochondrial diseases may result from mutations in the maternally-inherited mitochondrial DNA (mtDNA) or from mutations in nuclear genes encoding mitochondrial proteins. Their bi-genomic nature makes mitochondrial diseases a very heterogeneous group of disorders that can present at any age and can affect any type of tissue. The autophagic-lysosomal degradation pathway plays an important role in clearing dysfunctional and redundant mitochondria through a specific quality control mechanism termed mitophagy. Mitochondria could be targeted for autophagic degradation for a variety of reasons including basal turnover for recycling, starvation induced degradation, and degradation due to damage. While the core autophagic machinery is highly conserved and common to most pathways, the signaling pathways leading to the selective degradation of damaged mitochondria are still not completely understood. Type 1 mitophagy due to nutrient starvation is dependent on PI3K (phosphoinositide 3-kinase) for autophagosome formation but independent of mitophagy proteins, PINK1 (PTEN-induced putative kinase 1) and Parkin. Whereas type 2 mitophagy that occurs due to damage is dependent on PINK1 and Parkin but does not require PI3K. Autophagy and mitophagy play an important role in human disease and hence could serve as therapeutic targets for the treatment of mitochondrial as well as neurodegenerative disorders. Therefore, we reviewed drugs that are known modulators of autophagy (AICAR and metformin) and may effect this by activating the AMP-activated protein kinase signaling pathways. Furthermore, we reviewed data available on supplements, such as Coenzyme Q and the quinone idebenone, that we assert rescue increased mitophagy in mitochondrial disease by benefiting mitochondrial function

The role of TET-mediated DNA hydroxymethylation in prostate cancer

Massie C. is funded by an ERC grant (337905) and acknowledges support of the University of Cambridge, the Cancer Research UK Cambridge Centre and Hutchison Whampoa Limited. Claessens F. and Joniau S. hold grants from Fonds Wetenschappelijk Onderzoek-Vlaanderen (GOA9816N, G.0684.12N, G.0830.13N). Van den Broeck T. is supported by a PhD fellowship from Fonds Wetenschappelijk Onderzoek-Vlaanderen (11ZO616N). This work was also supported by the KU Leuven (GOA/15/017) and Kom op tegen Kanker.Ten-eleven translocation (TET) proteins are recently characterized dioxygenases that regulate demethylation by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine and further derivatives. The recent finding that 5hmC is also a stable and independent epigenetic modification indicates that these proteins play an important role in diverse physiological and pathological processes such as neural and tumor development. Both the genomic distribution of (hydroxy)methylation and the expression and activity of TET proteins are dysregulated in a wide range of cancers including prostate cancer. Up to now it is still unknown how changes in TET and 5(h)mC profiles are related to the pathogenesis of prostate cancer. In this review, we explore recent advances in the current understanding of how TET expression and function are regulated in development and cancer. Furthermore, we look at the impact on 5hmC in prostate cancer and the potential underlying mechanisms. Finally, we tried to summarize the latest techniques for detecting and quantifying global and locus-specific 5hmC levels of genomic DNA.PostprintPeer reviewe

Cell clearing systems as targets of polyphenols in viral infections: Potential implications for COVID-19 pathogenesis

The novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has generated the ongoing coronavirus disease-2019 (COVID-19) pandemic, still with an uncertain outcome. Besides pneumonia and acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), other features became evident in the context of COVID-19. These includes endothelial and coagulation dysfunction with disseminated intravascular coagulation (DIC), and multiple organ dysfunction syndrome (MODS), along with the occurrence of neurological alterations. The multi-system nature of such viral infection is a witness to the exploitation and impairment of ubiquitous subcellular and metabolic pathways for the sake of its life-cycle, ranging from host cell invasion, replication, transmission, up to a cytopathic effect and overt systemic inflammation. In this frame, alterations in cell-clearing systems of the host are emerging as a hallmark in the pathogenesis of various respiratory viruses, including SARS-CoV-2. Indeed, exploitation of the autophagy and proteasome pathways might contribute not only to the replication of the virus at the site of infection but also to the spreading of either mature virions or inflammatory mediators at both cellular and multisystem levels. In this frame, besides a pharmacological therapy, many researchers are wondering if some non-pharmacological substances might counteract or positively modulate the course of the infection. The pharmacological properties of natural compounds have gained increasing attention in the field of alternative and adjunct therapeutic approaches to several diseases. In particular, several naturally-occurring herbal compounds (mostly polyphenols) are reported to produce widespread antiviral, anti-inflammatory, and anti-oxidant effects while acting as autophagy and (immuno)-proteasome modulators. This article attempts to bridge the perturbation of autophagy and proteasome pathways with the potentially beneficial effects of specific phytochemicals and flavonoids in viral infections, with a focus on the multisystem SARS-CoV-2 infection

The impact of frequent wildfires during the Permian-Triassic transition: Floral change and terrestrial crisis in southwestern China

Wildfires are considered to have played an important role in the land plants crisis during the Permian–Triassic (P–T) transition. However, the nature and impact of wildfires in the P–T terrestrial crisis remains unclear. Organic petrology data from a terrestrial sequence from southwestern China show that the inertinite content ranges from 21.3% to 80.9% (mean 44.5%), suggesting that wildfires were a frequent phenomenon in low-latitude tropical rainforests during the P–T transition. Abundant inertinite and Hg/TOC peaks in earliest Triassic strata support the co-existence of wildfires and volcanism at that time. Volcanic emissions were potentially lethal for plants and adjacent arc volcanism represents a possible source of ignition. Inertinite reflectance values are used to estimate wildfire combustion temperatures, which themselves are a function of wildfire type. Inertinite with reflectances higher than 4.5% have concentrations between 47% and 65% in the P–T transitional strata. Crown fires with high combustion temperatures were prevalent in wetland settings in the latest Permian. However, surface fires with lower combustion temperatures became dominant during the major terrestrial extinction phase as a result of the sparse, scrubby vegetation that dominated at that time. The subsequent spread of gymnosperms in the earliest Triassic resulted in the re-establishment of high-temperature crown fires. Wildfires associated with the onset of volcanism in the late Permian likely contributed to ecological disturbance in terrestrial settings, which occurred notably earlier than that seen in marine environments. Thus, enhanced wildfire activity destabilised wetlands and increased ecological stress in the late Permian. Wildfire activity on land potentially had devastating consequences for late Permian marine environments via a complex cascade of terrestrial denudation, runoff, and nutrient flux