Showing papers in "FEBS Journal in 2022"
TL;DR: The current state of the development of senolytics and senomorphics for the treatment of age-related diseases and disorders and extension of healthy longevity is reviewed.
Abstract: The concept of geroscience is that since ageing is the greatest risk factor for many diseases and conditions, targeting the ageing process itself will have the greatest impact on human health. Of the hallmarks of ageing, cellular senescence has emerged as a druggable therapeutic target for extending healthspan in model organisms. Cellular senescence is a cell state of irreversible proliferative arrest driven by different types of stress, including oncogene‐induced stress. Many senescent cells (SnCs) develop a senescent‐associated secretory phenotype (SASP) comprising pro‐inflammatory cytokines, chemokines, proteases, bioactive lipids, inhibitory molecules, extracellular vesicles, metabolites, lipids and other factors, able to promote chronic inflammation and tissue dysfunction. SnCs up‐regulate senescent cell anti‐apoptotic pathways (SCAPs) that prevent them from dying despite the accumulation of damage to DNA and other organelles. These SCAPs and other pathways altered in SnCs represent therapeutic targets for the development of senotherapeutic drugs that induce selective cell death of SnCs, specifically termed senolytics or suppress markers of senescence, in particular the SASP, termed senomorphics. Here, we review the current state of the development of senolytics and senomorphics for the treatment of age‐related diseases and disorders and extension of healthy longevity. In addition, the challenges of documenting senolytic and senomorphic activity in pre‐clinical models and the current state of the clinical application of the different senotherapeutics will be discussed.
64 citations
TL;DR: The evidence that supports a role for mitochondria in the development of senescence is reviewed, the underlying mechanisms are described and it is proposed that a detailed road map of mitochondrial biology insenescence will be crucial to guide the future development ofsenotherapies.
Abstract: Senescence is a multi‐functional cell fate, characterized by an irreversible cell‐cycle arrest and a pro‐inflammatory phenotype, commonly known as the senescence‐associated secretory phenotype (SASP). Emerging evidence indicates that accumulation of senescent cells in multiple tissues drives tissue dysfunction and several age‐related conditions. This has spurred the academic community and industry to identify new therapeutic interventions targeting this process. Mitochondrial dysfunction is an often‐unappreciated hallmark of cellular senescence which plays important roles not only in the senescence growth arrest but also in the development of the SASP and resistance to cell‐death. Here, we review the evidence that supports a role for mitochondria in the development of senescence and describe the underlying mechanisms. Finally, we propose that a detailed road map of mitochondrial biology in senescence will be crucial to guide the future development of senotherapies.
44 citations
TL;DR: Converging evidence defining lipid dyshomeostasis in AD is summarized, followed by discussions on mechanisms by which lipid metabolism contributes to pathogenesis and modifies disease risk.
Abstract: Alzheimer’s disease (AD) is an age‐associated neurodegenerative disorder with multifactorial etiology, intersecting genetic and environmental risk factors, and a lack of disease‐modifying therapeutics. While the abnormal accumulation of lipids was described in the very first report of AD neuropathology, it was not until recent decades that lipid dyshomeostasis became a focus of AD research. Clinically, lipidomic and metabolomic studies have consistently shown alterations in the levels of various lipid classes emerging in early stages of AD brains. Mechanistically, decades of discovery research have revealed multifaceted interactions between lipid metabolism and key AD pathogenic mechanisms including amyloidogenesis, bioenergetic deficit, oxidative stress, neuroinflammation, and myelin degeneration. In the present review, converging evidence defining lipid dyshomeostasis in AD is summarized, followed by discussions on mechanisms by which lipid metabolism contributes to pathogenesis and modifies disease risk. Furthermore, lipid‐targeting therapeutic strategies, and the modification of their efficacy by disease stage, ApoE status, and metabolic and vascular profiles, are reviewed.
29 citations
TL;DR: In response to stress signal, nuclear factor-erythroid 2-related factor 2 (Nrf2) induces the expression of target genes involved in antioxidant defense and detoxification, and downstream antioxidant upregulation can act as a primary cellular defense against the cytotoxic effects of oxidative stress and help to promote hepatic recovery during Ischemia-reperfusion (IR) injury as discussed by the authors .
Abstract: In response to stress signal, nuclear factor-erythroid 2-related factor 2 (Nrf2) induces the expression of target genes involved in antioxidant defense and detoxification. Nrf2 activity is strictly regulated through a variety of mechanisms, including regulation of Keap1-Nrf2 stability, transcriptional regulation (NF-ĸB, ATF3, ATF4), and post-transcriptional regulation (miRNA), evidencing that transcriptional responses of Nrf2 are critical for the maintenance of homeostasis. Ischemia-reperfusion (IR) injury is a major cause of graft loss and dysfunction in clinical transplantation and organ resection. During the IR process, the generation of reactive oxygen species (ROS) leads to damage from oxidative stress, oxidation of biomolecules, and mitochondrial dysfunction. Oxidative stress can trigger apoptotic and necrotic cell death. Stress factors also result in the assembly of the inflammasome protein complex and the subsequent activation and secretion of proinflammatory cytokines. After Nrf2 activation, the downstream antioxidant upregulation can act as a primary cellular defense against the cytotoxic effects of oxidative stress and help to promote hepatic recovery during IR. The complex crosstalk between Nrf2 and cellular pathways in liver IR injury and the potential therapeutic target of the Nrf2 inducers will be discussed in the present review.
26 citations
TL;DR: It has been revealed that ferroptosis has the property of propagating to surrounding cells along with lipid peroxidation and the propagation phenomenon could be used to realize anticancer cell therapy in the future.
Abstract: Ferroptosis is triggered by a chain of intracellular labile iron‐dependent peroxidation of cell membrane phospholipids. Ferroptosis is important not only as a cause of ischaemic and neurodegenerative diseases but also as a mechanism of cancer suppression, and a better understanding of its regulatory mechanism is required. It has become clear that ferroptosis is finely controlled by two oxidative stress‐responsive transcription factors, NRF2 (NF‐E2‐related factor 2) and BACH1 (BTB and CNC homology 1). NRF2 and BACH1 inhibit and promote ferroptosis, respectively, by activating or suppressing the expression of genes in the major regulatory pathways of ferroptosis: intracellular labile iron metabolism, the GSH (glutathione) ‐GPX4 (glutathione peroxidase 4) pathway and the FSP1 (ferroptosis suppressor protein 1)‐CoQ (coenzyme Q) pathway. In addition to this, NRF2 and BACH1 control ferroptosis through the regulation of lipid metabolism and cell differentiation. This multifaceted regulation of ferroptosis by NRF2 and BACH1 is considered to have been acquired during the evolution of multicellular organisms, allowing the utilization of ferroptosis for maintaining homeostasis, including cancer suppression. In terms of cell–cell interaction, it has been revealed that ferroptosis has the property of propagating to surrounding cells along with lipid peroxidation. The regulation of ferroptosis by NRF2 and BACH1 and the propagation phenomenon could be used to realize anticancer cell therapy in the future. In this review, these points will be summarized and discussed.
24 citations
TL;DR: The current knowledge on cellularsenescence and the senescence-associated secretory phenotype is discussed to develop a structural understanding of their roles in the tumor microenvironment and provide perspectives for future research, including the possibility of senotherapy for the treatment of cancer.
Abstract: Cellular senescence refers to a state of irreversible cell cycle arrest that can be induced by various cellular stresses and is known to play a pivotal role in tumour suppression. While senescence‐associated growth arrest can inhibit the proliferation of cancer‐prone cells, the altered secretory profile of senescent cells, termed the senescence‐associated secretory phenotype, can contribute to the microenvironment that promotes tumour development. Although the senescence‐associated secretory phenotype and its effects on tumorigenesis are both highly context dependent, mechanisms underlying such diversity are becoming better understood, thereby allowing the creation of new strategies to effectively target the senescence‐associated secretory phenotype and senescent cells for cancer therapy. In this review, we discuss the current knowledge on cellular senescence and the senescence‐associated secretory phenotype to develop a structural understanding of their roles in the tumour microenvironment and provide perspectives for future research, including the possibility of senotherapy for the treatment of cancer.
20 citations
TL;DR: Overall, this suggests the presence of variable regions on S1 and N protein surfaces, which confer sequence and antigenic flexibility to the virus without altering its protein functions.
Abstract: The SARS‐CoV‐2 pandemic is maintained by the emergence of successive variants, highlighting the flexibility of the protein sequences of the virus. We show that experimentally determined intrinsically disordered regions (IDRs) are abundant in the SARS‐CoV‐2 viral proteins, making up to 28% of disorder content for the S1 subunit of spike and up to 51% for the nucleoprotein, with the vast majority of mutations occurring in the 13 major variants mapped to these IDRs. Strikingly, antigenic sites are enriched in IDRs, in the receptor‐binding domain (RBD) and in the N‐terminal domain (NTD), suggesting a key role of structural flexibility in the antigenicity of the SARS‐CoV‐2 protein surface. Mutations occurring in the S1 subunit and nucleoprotein (N) IDRs are critical for immune evasion and antibody escape, suggesting potential additional implications for vaccines and monoclonal therapeutic strategies. Overall, this suggests the presence of variable regions on S1 and N protein surfaces, which confer sequence and antigenic flexibility to the virus without altering its protein functions.
19 citations
TL;DR: The IUBMB enzyme classification system, available at the ExplorEnz website, uses a four-component number (the EC number) that identifies an enzyme in terms of reaction catalysed as discussed by the authors .
Abstract: The IUBMB enzyme classification system, available at the IUBMB ExplorEnz website, uses a four-component number (the EC number) that identifies an enzyme in terms of reaction catalysed. There were originally six recognized groups of enzymes: Oxidoreductases (EC 1), Transferases (EC 2), Hydrolases (EC 3), Lyases (EC 4), Isomerases (EC 5) and Ligases (EC 6). Of these, the lyases, which are defined as ‘enzymes that cleave C-C, C-O, C-N and other bonds by means other than by hydrolysis or oxidation’, present particular recognition and classification problems. Recently, a new class, the Translocases (EC 7), has been added, which incorporates enzymes that catalyse the movement of ions or molecules across membranes or their separation within membranes. A new subclass of the isomerases has also been included for those enzymes that alter the conformations of proteins and nucleic acids. Newly reported enzymes are being regularly added to the list after validation and where new information affects the classification of an existing entry, a new EC number is created, but the old one is not reused.
17 citations
TL;DR: Recent findings that illustrate the cellular machinery that contributes to miRNA-induced silencing are reviewed, with a focus on the factors that could influence translational repression vs. decay.
Abstract: Post‐transcriptional regulation of messenger RNAs (mRNAs) (i.e., mechanisms that control translation, stability and localization) is a critical focal point in spatiotemporal regulation of gene expression in response to changes in environmental conditions. The human genome encodes ~ 2000 microRNAs (miRNAs), each of which could control the expression of hundreds of protein‐coding mRNAs by inducing translational repression and/or promoting mRNA decay. While mRNA degradation is a terminal event, translational repression is reversible and can be employed for rapid response to internal or external cues. Recent years have seen significant progress in our understanding of how miRNAs induce degradation or translational repression of the target mRNAs. Here, we review the recent findings that illustrate the cellular machinery that contributes to miRNA‐induced silencing, with a focus on the factors that could influence translational repression vs. decay.
14 citations
TL;DR:
Abstract: A‐to‐I RNA editing by ADARs is an abundant epitranscriptomic RNA‐modification in metazoa. In mammals, Flna pre‐mRNA harbours a single conserved A‐to‐I RNA editing site that introduces a Q‐to‐R amino acid change in Ig repeat 22 of the encoded protein. Previously, we showed that FLNA editing regulates smooth muscle contraction in the cardiovascular system and affects cardiac health. The present study investigates how ADAR2‐mediated A‐to‐I RNA editing of Flna affects actin crosslinking, cell mechanics, cellular adhesion and cell migration. Cellular assays and AFM measurements demonstrate that the edited version of FLNA increases cellular stiffness and adhesion but impairs cell migration in both, mouse fibroblasts and human tumour cells. In vitro, edited FLNA leads to increased actin crosslinking, forming actin gels of higher stress resistance. Our study shows that Flna RNA editing is a novel regulator of cytoskeletal organisation, affecting the mechanical property and mechanotransduction of cells.
14 citations
TL;DR: A perspective of how the regulatory mechanisms for the two proteins could be entwined at multiple points in a BRD4-MYC nexus that leads to the modulation of their functions and disease upon dysregulation is presented.
Abstract: The MYC proto-oncogene and BRD4, a BET family protein, are two cardinal proteins that have a broad influence in cell biology and disease. Both proteins are expressed ubiquitously in mammalian cells and play central roles in controlling growth, development, stress responses and metabolic function. As chromatin and transcriptional regulators, they play a critical role in regulating the expression of a burgeoning array of genes, maintaining chromatin architecture and genome stability. Consequently, impairment of their function or regulation leads to many diseases, with cancer being the most predominant. Interestingly, accumulating evidence indicates that regulation of the expression and functions of MYC are tightly intertwined with BRD4 at both transcriptional and post transcriptional levels. Here, we review the mechanisms by which MYC and BRD4 are regulated, their functions in governing various molecular mechanisms and the consequences of their dysregulation that lead to disease. We present a perspective of how the regulatory mechanisms for the two proteins could be entwined at multiple points in a BRD4-MYC nexus that leads to the modulation of their functions and disease upon dysregulation.
TL;DR: Astroglial sleep mechanisms are evolutionarily conserved and dynamically change their activity across the sleep-wake cycle and may encode sleep need via changes in intracellular signaling pathways, according to recent findings.
Abstract: Astrocytes mediate many important aspects of neural homeostasis, but until recently, their role in sleep was largely unknown. The situation has dramatically changed in the last decade. The use of transgenic animals, optogenetics, chemogenetics, brain imaging and sophisticated molecular assays has led to exciting discoveries. Astrocytes dynamically change their activity across the sleep–wake cycle and may encode sleep need via changes in intracellular signalling pathways. Astrocytes also exocytose/secrete sleep‐inducing molecules which modulate brain activity, sleep architecture and sleep regulation. Many of these observations have been made in mice and Drosophila melanogaster, indicating that astroglial sleep mechanisms are evolutionarily conserved. We review recent findings and discuss future directions.
TL;DR: A close look is taken at astrocyte-synapse interactions involved in the coordination of synaptogenesis and astroCyte maturation in the developing brain through to the contribution ofAstrocytes in synaptic plasticity in the adult brain, and end with a perspective on astracyte function in behaviours and diseases.
Abstract: Astrocytes are increasingly gaining attention as a major player in regulating brain functions. Not only are astrocytes important for their supporting roles in maintaining optimal neuronal activity, they also dynamically interact with synapses through their highly ramified morphology to directly influence information processing by the neural circuits and the behaviours that depend on it. Here, we take a close look at astrocyte–synapse interactions involved in the coordination of synaptogenesis and astrocyte maturation in the developing brain through to the contribution of astrocytes in synaptic plasticity in the adult brain, and end with a perspective on astrocyte function in behaviours and diseases. In particular, we focus on the roles of synapse adhesion proteins. While cell adhesion proteins that form a bridge between the presynaptic and the postsynaptic compartments have been extensively studied, recent reports highlighting the striking participation of astrocytic cell adhesion proteins in synapse formation and function underscores the importance of reconsidering the conventional neurocentric view of synaptic adhesive interactions and the underlying logic.
TL;DR:
Abstract: Most chloroplast proteins are nucleus‐encoded, translated on cytoplasmic ribosomes as precursor proteins, and imported into chloroplasts through TOC and TIC, the translocons of the outer and inner chloroplast envelope membranes. While the composition of the TOC complex is well established, there is still some controversy about the importance of a recently identified TIC complex consisting of Tic20, Tic214, Tic100, and Tic56. TOC and TIC form a supercomplex with a protein channel at the junction of the outer and inner envelope membranes through which preproteins are pulled into the stroma by the ATP‐powered Ycf2 complex consisting of several FtsH‐like ATPases and/or by chloroplast Hsp proteins. Several components of the TOC/TIC system are moonlighting proteins with additional roles in chloroplast gene expression and metabolism. Chaperones and co‐chaperones, associated with TOC and TIC on the cytoplasmic and stromal side of the chloroplast envelope, participate in the unfolding and folding of the precursor proteins and act together with the ubiquitin–proteasome system in protein quality control. Chloroplast protein import is also intimately linked with retrograde signaling, revealing altogether an unsuspected complexity in the regulation of this process.
TL;DR: An overview of the role of kinases in carcinogenesis is provided and the current progress with small-molecule kinase inhibitors that have been approved for clinical use are described, and the application of mass spectrometry (MS)-based proteomics strategies to help in the design of kinase inhibitor strategies are discussed.
Abstract: Kinases are key regulatory signalling proteins governing numerous essential biological processes and cellular functions. Dysregulation of many protein kinases is associated with cancer initiation and progression. Given their crucial roles, there has been increasing interest in harnessing kinases as prospective drug targets for cancer. In recent decades, numerous small‐molecule kinase inhibitors have been developed and revolutionized the cancer treatment landscape. Despite their great potential, challenges remain in developing highly selective and effective kinase inhibitors, with toxicity and resistance issues frequently arising. In this review, we first provide an overview of the role of kinases in carcinogenesis and describe the current progress with small‐molecule kinase inhibitors that have been approved for clinical use. We then discuss the application of mass spectrometry (MS)‐based proteomics strategies to help in the design of kinase inhibitors. Finally, we discuss the challenges and outlook concerning MS‐based proteomics techniques for kinase drug research.
TL;DR: In this article , the euchromatin histone lysine methyltransferase 1 (EHMT1) and Euchromaten histone leysine 9 di-methylation (H3K9me2) were reviewed for their role in cancer metastasis, stemness and drug resistance.
Abstract: Metastasis, therapy failure and tumour recurrence are major clinical challenges in cancer. The interplay between tumour-initiating cells (TICs) and epithelial-mesenchymal transition (EMT) drives tumour progression and spread. Recent advances have highlighted the involvement of epigenetic deregulation in these processes. The euchromatin histone lysine methyltransferase 1 (EHMT1) and euchromatin histone lysine methyltransferase 2 (EHMT2) that primarily mediate histone 3 lysine 9 di-methylation (H3K9me2), as well as methylation of non-histone proteins, are now recognised to be aberrantly expressed in many cancers. Their deregulated expression is associated with EMT, cellular plasticity and therapy resistance. In this review, we summarise evidence of their myriad roles in cancer metastasis, stemness and drug resistance. We discuss cancer-type specific molecular targets, context-dependent mechanisms and future directions of research in targeting EHMT1/EHMT2 for the treatment of cancer.
TL;DR: The secretion systems, the functions of various secretory proteins of M. tuberculosis and their roles in modulating immune responses of the host are discussed and the feasibility of their use as possible therapeutic targets is discussed.
Abstract: Mycobacterium tuberculosis, the bacterium responsible for tuberculosis, is one of the most successful pathogens in human history. An extremely resilient cell wall and highly evolved and coordinated strategies for immune evasion have made it a very formidable pathogen. The secretory proteins of M. tuberculosis play a crucial role in its virulence and immune evasion. The secretory proteins are secreted through tightly regulated secretion systems and modulate the host immune responses through a plethora of strategies, including epigenetic reprogramming of infected cells, targeting antigen presentation, inhibition of phagosomal maturation, modulation of cytokine production, apoptosis and redox regulation, etc. Upon infection, the secretory proteins become localized into various cellular organelles, such as nucleus, cytoplasm, phagosomes and Golgi, bodies and hijack the host machineries through their wide gamut of functions, including kinase, phosphatase, methyl transferase activities and interaction with several host partners. In this review, we discuss the secretion systems, the functions of various secretory proteins of M. tuberculosis and their roles in modulating immune responses of the host. We also discuss the feasibility of their use as possible therapeutic targets. This information is likely to improve our understanding of the host–pathogen interaction and help in the design of effective anti‐tuberculosis therapeutics.
TL;DR: This Special Issue of The FEBS Journal, Cancer Epigenetics, features an exciting collection of review articles that focus on the functions of a broad spectrum of epigenetic modulators in cancer.
Abstract: Over the past few decades, epigenetic regulators have emerged as major players in cellular processes that drive cancer initiation and progression, and subsequently modulate the responsiveness of cancers to therapeutic agents. This Special Issue of The FEBS Journal, Cancer Epigenetics, features an exciting collection of review articles that focus on the functions of a broad spectrum of epigenetic modulators in cancer. The diverse topics explored herein range from the roles of transposable elements and chromatin architecture in cancer and the most recent research advances on cancer‐associated histone variants (oncohistones), to the effects of altered epigenetics on transcription and advanced cancer cell phenotypes. Moreover, the prospective key function of cancer metabolism in linking epigenetics and transcriptional regulation, and the potential of epigenetics for targeted cancer therapeutics is discussed. We hope that this collection of articles will give readers an enlightening overview of the most recent advances in the fast‐moving field of cancer epigenetics.
TL;DR: The role of senescent cells within the cardiovascular system and the contribution of senescence cells to common cardiovascular diseases is discussed in this paper , where the emerging role for senolytics in cardiovascular disease management is discussed.
Abstract: Cellular senescence within the cardiovascular system has, until recently, been understudied and unappreciated as a factor in the development of age‐related cardiovascular diseases such as heart failure, myocardial infarction and atherosclerosis. This is in part due to challenges with defining senescence within post‐mitotic cells such as cardiomyocytes. However, recent evidence has demonstrated senescent‐like changes, including a senescence‐associated secretory phenotype (SASP), in cardiomyocytes in response to ageing and cell stress. Other replicating cells, including fibroblasts and vascular smooth muscle cells, within the cardiovascular system have also been shown to undergo senescence and contribute to disease pathogenesis. These findings coupled with the emergence of senolytic therapies, to target and eliminate senescent cells, have provided fascinating new avenues for management of several age‐related cardiovascular diseases with high prevalence. In this review, we discuss the role of senescent cells within the cardiovascular system and highlight the contribution of senescence cells to common cardiovascular diseases. We discuss the emerging role for senolytics in cardiovascular disease management while highlighting important aspects of senescence biology which must be clarified before the potential of senolytics can be fully realized.
TL;DR: Upregulation of autophagy represents a cellular adaptation to NGLY1 inhibition or KD, and ATG13‐deficient mouse embryonic fibroblasts (MEFs) show reduced viability under these conditions, and Q‐VD‐OPh represents an alternative caspase inhibitor free from this limitation.
Abstract: The polycaspase inhibitor Z‐VAD‐fmk acts as an inhibitor of peptide: N‐glycanase (NGLY1), an endoglycosidase which cleaves N‐linked glycans from glycoproteins exported from the endoplasmic reticulum (ER) during ER‐associated degradation (ERAD). Both pharmacological N‐glycanase inhibition by Z‐VAD‐fmk and siRNA‐mediated knockdown (KD) of NGLY1 induce GFP‐LC3‐positive puncta in HEK 293 cells. The activation of ER stress markers or induction of reactive oxygen species (ROS) is not observed under either condition. Moreover, Ca2+ handling is unaffected when observing release from intracellular stores. Under conditions of pharmacological NGLY1 inhibition or NGLY1 KD, upregulation of autophagosome formation without impairment of autophagic flux is observed. Enrichment of autophagosomes by immunoprecipitation (IP) and mass spectrometry‐based proteomic analysis reveals comparable autophagosomal protein content. Gene ontology analysis of proteins enriched in autophagosome IPs shows overrepresentation of factors involved in protein translation, localization and targeting, RNA degradation and protein complex disassembly. Upregulation of autophagy represents a cellular adaptation to NGLY1 inhibition or KD, and ATG13‐deficient mouse embryonic fibroblasts (MEFs) show reduced viability under these conditions. In contrast, treatment with pan‐caspase inhibitor, Q‐VD‐OPh, does not induce cellular autophagy. Therefore, experiments with Z‐VAD‐fmk are complicated by the effects of NGLY1 inhibition, including induction of autophagy, and Q‐VD‐OPh represents an alternative caspase inhibitor free from this limitation.
TL;DR: Recent advances in the understanding of the structure and catalytic activity of DPP3 are reviewed, with a focus on attributing its molecular architecture and catalysttic mechanism to its wide-ranging biological functions.
Abstract: Dipeptidyl peptidase 3 (DPP3), a zinc‐dependent aminopeptidase, is a highly conserved enzyme among higher animals. The enzyme cleaves dipeptides from the N‐terminus of tetra‐ to decapeptides, thereby taking part in activation as well as degradation of signalling peptides critical in physiological and pathological processes such as blood pressure regulation, nociception, inflammation and cancer. Besides its catalytic activity, DPP3 moonlights as a regulator of the cellular oxidative stress response pathway, e.g., the Keap1‐Nrf2 mediated antioxidative response. The enzyme is also recognized as a key modulator of the renin‐angiotensin system. Recently, DPP3 has been attracting growing attention within the scientific community, which has significantly augmented our knowledge of its physiological relevance. Herein, we review recent advances in our understanding of the structure and catalytic activity of DPP3, with a focus on attributing its molecular architecture and catalytic mechanism to its wide‐ranging biological functions. We further highlight recent intriguing reports that implicate a broader role for DPP3 as a valuable biomarker in cardiovascular and renal pathologies and furthermore discuss its potential as a promising drug target.
TL;DR: The impact of dysregulated mRNA processing and metabolism on senescence and ageing at the level of molecules, cells and systems is outlined, and the mechanisms by which progressive deterioration in these processes may impact senescences and organismal ageing are described.
Abstract: The human genome is capable of producing hundreds of thousands of different proteins and non‐coding RNAs from <20 000 genes, in a co‐ordinated and regulated fashion. This is achieved by a collection of phenomena known as mRNA processing and metabolism, and encompasses events in the life cycle of an RNA from synthesis to degradation. These factors are critical determinants of cellular adaptability and plasticity, which allows the cell to adjust its transcriptomic output in response to its internal and external environment. Evidence is building that dysfunctional RNA processing and metabolism may be a key contributor to the development of cellular senescence. Senescent cells by definition have exited cell cycle, but have gained functional features such as the secretion of the senescence‐associated secretory phenotype (SASP), a known driver of chronic disease and perhaps even ageing itself. In this review, I will outline the impact of dysregulated mRNA processing and metabolism on senescence and ageing at the level of genes, cells and systems, and describe the mechanisms by which progressive deterioration in these processes may impact senescence and organismal ageing. Finally, I will present the evidence implicating this important process as a new hallmark of ageing, which could be harnessed in the future to develop new senotherapeutic interventions for chronic disease.
TL;DR: In this article , the authors revisited the seven pillars of aging from the perspective of exercise and discussed how regular physical exercise can modulate these pillars to stave off age-related chronic diseases and maintain functional capacity.
Abstract: Biological aging is the main driver of age-associated chronic diseases. In 2014, the United States National Institute of Aging (NIA) sponsored a meeting between several investigators in the field of aging biology, who identified seven biological pillars of aging and a consensus review, “Geroscience: Linking Aging to Chronic Disease,” was published. The pillars of aging demonstrated the conservation of aging pathways in diverse model organisms and thus represent a useful framework with which to study human aging. In this present review, we revisit the seven pillars of aging from the perspective of exercise and discuss how regular physical exercise can modulate these pillars to stave off age-related chronic diseases and maintain functional capacity.
TL;DR: This review surveys cytokines that meet two criteria: evidence of expression by muscle cells; and evidence demonstrating a myogenic function, and concludes that dozens of cytokines representing several major classes regulate all steps of the myogenic process.
Abstract: Regeneration of the mammalian adult skeletal muscle is a well‐orchestrated process regulated by multiple proteins and signalling pathways. Cytokines constitute a major class of regulators of skeletal myogenesis. It is well established that infiltrating immune cells at the site of muscle injury secrete cytokines, which play critical roles in the myofibre repair and regeneration process. In the past 10–15 years, skeletal muscle itself has emerged as a prolific producer of cytokines. Much attention in the field has been focused on the endocrine effects of muscle‐secreted cytokines (myokines) on metabolic regulation. However, ample evidence suggests that muscle‐derived cytokines also regulate myogenic differentiation and muscle regeneration in an autocrine manner. In this review, we survey cytokines that meet two criteria: (a) evidence of expression by muscle cells; (b) evidence demonstrating a myogenic function. Dozens of cytokines representing several major classes make up this group, and together they regulate all steps of the myogenic process. How such a large array of cytokines coordinate their signalling to form a regulatory network is a fascinating, pressing question. Functional studies that can distinguish the source of the cytokines in vivo are also much needed in order to facilitate exploration of their full therapeutic potential.
TL;DR: The impact of obesity and aging on the intestinal immune system and its downstream consequences on gut barrier function are reviewed, which is strongly implicated in the pathogenesis of Obesity and age-related diseases.
Abstract: Obesity and aging predispose to numerous, yet overlapping chronic diseases. For example, metabolic abnormalities, including insulin resistance (IR) and type 2 diabetes (T2D) are important causes of morbidity and mortality. Low-grade chronic inflammation of tissues, such as the liver, visceral adipose tissue and neurological tissues, is considered a significant contributor to these chronic diseases. Thus, it is becoming increasingly important to understand what drives this inflammation in affected tissues. Recent evidence, especially in the context of obesity, suggests that the intestine plays an important role as the gatekeeper of inflammatory stimuli that ultimately fuel low-grade chronic tissue inflammation. In addition to metabolic diseases, abnormalities in the intestinal mucosal barrier have been linked to a range of other chronic inflammatory conditions, such as neurodegeneration and aging. The flow of inflammatory stimuli from the gut is in part controlled by local immunological inputs impacting the intestinal barrier. Here, we will review the impact of obesity and aging on the intestinal immune system and its downstream consequences on gut barrier function, which is strongly implicated in the pathogenesis of obesity and age-related diseases. In particular, we will discuss the effects of age-related intestinal dysfunction on neurodegenerative diseases.
TL;DR: In this paper , the authors identified indolyl-ethyl amine and serotonin small molecules using a reverse chemical genomics approach, with these acting as potent inhibitors of ABA biosynthesis through transient regulation of bZIP23 transcription factor activity.
Abstract: Drought‐induced abscisic acid (ABA) accumulation plays a key role in plant water relations by regulating stomatal movements. Although ABA helps in the survival of the plants, reduced carbon gain affects plant productivity. To improve crop productivity under mild drought stress conditions, it is necessary to manipulate ABA responses. Other research groups have used forward chemical genomics for the identification of ABA agonists and antagonists aiming to manipulate ABA biosynthesis and signalling. In the present study, we identified indolyl‐ethyl amine and serotonin small molecules using a reverse chemical genomics approach, with these acting as potent inhibitors of ABA biosynthesis through transient regulation of bZIP23 transcription factor activity. In rice, wheat and soybean, each of the small molecules enhanced the germination of seeds, even in the presence of ABA. These molecules nullified the effect of ABA on intact and detached leaves, resulting in higher photosynthesis. Furthermore, these small molecules effectively reduced the transcription levels of bZIP23 targeting NCED4, PP2C49 and CO3 genes. Rice plants treated with the small molecules were found to have improved stomatal conductance, spikelet fertility and yield compared to untreated plants under mild drought stress conditions. Our results suggest that indolyl‐ethyl amine and serotonin small molecules could be utilized to improve yield under mild drought conditions.
TL;DR: The role of heterotypic interactions between amyloids and other proteins and macromolecules and how this contributes to disease is discussed in this article , with a focus on neurodegenerative amyloid-associated diseases.
Abstract: Amyloid aggregation results from the self-assembly of identical aggregation-prone sequences into cross-beta-sheet structures. The process is best known for its association with a wide range of human pathologies but also as a functional mechanism in all kingdoms of life. Less well elucidated is the role of heterotypic interactions between amyloids and other proteins and macromolecules and how this contributes to disease. We here review current data with a focus on neurodegenerative amyloid-associated diseases. Evidence indicates that heterotypic interactions occur in a wide range of amyloid processes and that these interactions modify fundamental aspects of amyloid aggregation including seeding, aggregation rates and toxicity. More work is required to understand the mechanistic origin of these interactions, but current understanding suggests that both supersaturation and sequence-specific binding can contribute to heterotypic amyloid interactions. Further unravelling these mechanisms may help to answer outstanding questions in the field including the selective vulnerability of cells types and tissues and the stereotypical spreading patterns of amyloids in disease.
TL;DR: Recent evidence that modulation of the early secretory pathway has great impact on the biogenesis and release of WPBs is summarized, suggesting that rare, as yet unidentified quantitative trait loci influencing intracellular VWF transport contribute to highly variable VWF levels in the population.
Abstract: Von Willebrand factor (VWF) is a glycoprotein that is secreted into the circulation and controls bleeding by promoting adhesion and aggregation of blood platelets at sites of vascular injury. Substantial inter‐individual variation in VWF plasma levels exists among the healthy population. Prior to secretion, VWF polymers are assembled and condensed into helical tubules, which are packaged into Weibel‐Palade bodies (WPBs), a highly specialized post‐Golgi storage compartment in vascular endothelial cells. In the inherited bleeding disorder Von Willebrand disease (VWD), mutations in the VWF gene can cause qualitative or quantitative defects, limiting protein function, secretion, or plasma survival. However, pathogenic VWF mutations cannot be found in all VWD cases. Although an increasing number of genetic modifiers have been identified, even more rare genetic variants that impact VWF plasma levels likely remain to be discovered. Here, we summarize recent evidence that modulation of the early secretory pathway has great impact on the biogenesis and release of WPBs. Based on these findings, we propose that rare, as yet unidentified quantitative trait loci influencing intracellular VWF transport contribute to highly variable VWF levels in the population. These may underlie the thrombotic complications linked to high VWF levels, as well as the bleeding tendency in individuals with low VWF levels.
TL;DR: PTPs have been showing many possibilities to auto‐protect from irreversible oxidation, which is important for cell signalling regulation, and possible mechanisms that may account for this apparent contradiction between biological and chemical redox aspects of PTPs are discussed.
Abstract: Protein phosphorylation is a major post‐translational modification involved in cell signalling that regulates many physiological and pathological processes. Despite their biological importance, protein phosphatases are less studied than protein kinases. Importantly, the activity of Cys‐based protein tyrosine phosphatases (PTPs) can be regulated by reversible oxidation. The initial two‐electron oxidation product of the active site Cys is a sulfenic acid (Cys‐SOH) that can then undergo distinct outcomes, such as the disulfide bond or a sulfenyl amide formation. Here, we review the biochemical and structural features of PTPs to find patterns that might specify their oxidation products, aiming to get insights into redox regulatory mechanisms. Initially, the structure and biochemistry of PTP1B is presented. Then, we describe structural aspects that are relevant for substrate recognition and catalysis. Notably, all PTPs contain critical Cys residues for the catalysis of dephosphorylation that is prone to oxidative inactivation, which are frequently found oxidized in cells under physiological conditions, such as upon growth factor stimuli. However, direct oxidations of Cys residues in PTPs by H2O2 are rather slow. Therefore, we discuss possible mechanisms that may account for this apparent contradiction between biological and chemical redox aspects of PTPs. Furthermore, we performed a systematic analysis of the distance between active site cysteine and its backdoor cysteine with the attempt to analyse the preference between disulfide bond formation or sulfenyl amide interaction upon oxidation. In summary, PTPs have been showing many possibilities to auto‐protect from irreversible oxidation, which is important for cell signalling regulation.
TL;DR: This review focuses on summarizing the current knowledge on early cerebellar development with a particular emphasis on the molecular determinants that secure neuron specification and contribute to the diversity of cerebellary neurons.
Abstract: The study of cerebellar development has been at the forefront of neuroscience since the pioneering work of Wilhelm His Sr., Santiago Ramón y Cajal and many others since the 19th century. They laid the foundation to identify the circuitry of the cerebellum, already revealing its stereotypic three‐layered cortex and discerning several of its neuronal components. Their work was fundamental in the acceptance of the neuron doctrine, which acknowledges the key role of individual neurons in forming the basic units of the nervous system. Increasing evidence shows that the cerebellum performs a variety of homeostatic and higher order neuronal functions beyond the mere control of motor behaviour. Over the last three decades, many studies have revealed the molecular machinery that regulates distinct aspects of cerebellar development, from the establishment of a cerebellar anlage in the posterior brain to the identification of cerebellar neuron diversity at the single cell level. In this review, we focus on summarizing our current knowledge on early cerebellar development with a particular emphasis on the molecular determinants that secure neuron specification and contribute to the diversity of cerebellar neurons.