18 alpha-Glycyrrhetinic Acid Proteasome Activator Decelerates Aging and Alzheimer's Disease Progression in Caenorhabditis elegans and Neuronal Cultures

Aims: Proteasomes are constituents of the cellular proteolytic networks that maintain protein homeostasis through regulated proteolysis of normal and abnormal (in any way) proteins. Genetically mediated proteasome activation in multicellular organisms has been shown to promote longevity and to exert protein antiaggregation activity. In this study, we investigate whether compound-mediated proteasome activation is feasible in a multicellular organism and we dissect the effects of such approach in aging and Alzheimer's disease (AD) progression. Results: Feeding of wild-type Caenorhabditis elegans with 18 alpha-glycyrrhetinic acid (18 alpha-GA; a previously shown proteasome activator in cell culture) results in enhanced levels of proteasome activities that lead to a skinhead-1- and proteasomeactivation-dependent life span extension. The elevated proteasome function confers lower paralysis rates in various AD nematode models accompanied by decreased A beta deposits, thus ultimately decelerating the progression of AD phenotype. More importantly, similar positive results are also delivered when human and murine cells of nervous origin are subjected to 18 alpha-GA treatment. Innovation: This is the first report of the use of 18 alpha-GA, a diet-derived compound as prolongevity and antiaggregation factor in the context of a multicellular organism. Conclusion: Our results suggest that proteasome activation with downstream positive outcomes on aging and AD, an aggregation-related disease, is feasible in a nongenetic manipulation manner in a multicellular organism. Moreover, they unveil the need for identification of antiaging and antiamyloidogenic compounds among the nutrients found in our normal diet.Peer reviewe

The dietary triterpenoid 18α-Glycyrrhetinic acid protects from MMC-induced genotoxicity through the ERK/Nrf2 pathway.

18α-Glycyrrhetinic acid (18α-GA) is a bioactive triterpenoid that has been shown to activate the nuclear factor (erythroid-derived-2)-like 2 (Nrf2), the main transcription factor that orchestrates the cellular antioxidant response, in both cellular and organismal context. Although various beneficial properties of 18α-GA have been revealed, including its anti-oxidation and anti-aging activity, its possible protective effect against DNA damage has never been addressed. In this study, we investigated the potential beneficial properties of 18α-GA against DNA damage induced by mitomycin C (MMC) treatment. Using human primary fibroblasts exposed to MMC following pre-treatment with 18α-GA, we reveal an Nrf2-mediated protective effect against MMC-induced cell death that depends on extracellular signal-regulated kinase (ERK) signaling. In total, our results reveal an additional beneficial effect of the Nrf2 activator 18α-GA, suggesting that this important phytochemical compound is a potential candidate in preventive and/or therapeutic schemes against conditions (such as aging) or diseases that are characterized by both oxidative stress and DNA damage

Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation.

A progressive loss of protein homeostasis is characteristic of aging and a driver of neurodegeneration. To investigate this process quantitatively, we characterized proteome dynamics during brain aging in the short-lived vertebrate Nothobranchius furzeri combining transcriptomics and proteomics. We detected a progressive reduction in the correlation between protein and mRNA, mainly due to post-transcriptional mechanisms that account for over 40% of the age-regulated proteins. These changes cause a progressive loss of stoichiometry in several protein complexes, including ribosomes, which show impaired assembly/disassembly and are enriched in protein aggregates in old brains. Mechanistically, we show that reduction of proteasome activity is an early event during brain aging and is sufficient to induce proteomic signatures of aging and loss of stoichiometry in vivo. Using longitudinal transcriptomic data, we show that the magnitude of early life decline in proteasome levels is a major risk factor for mortality. Our work defines causative events in the aging process that can be targeted to prevent loss of protein homeostasis and delay the onset of age-related neurodegeneration

Bacterial production and direct functional screening of expanded molecular libraries for discovering inhibitors of protein aggregation.

Protein misfolding and aggregation are associated with a many human disorders, including Alzheimer's and Parkinson's diseases. Toward increasing the effectiveness of early-stage drug discovery for these conditions, we report a bacterial platform that enables the biosynthesis of molecular libraries with expanded diversities and their direct functional screening for discovering protein aggregation inhibitors. We illustrate this approach by performing, what is to our knowledge, the largest functional screen of small-size molecular entities described to date. We generated a combinatorial library of ~200 million drug-like, cyclic peptides and rapidly screened it for aggregation inhibitors against the amyloid-β peptide (Aβ42), linked to Alzheimer's disease. Through this procedure, we identified more than 400 macrocyclic compounds that efficiently reduce Aβ42 aggregation and toxicity in vitro and in vivo. Finally, we applied a combination of deep sequencing and mutagenesis analyses to demonstrate how this system can rapidly determine structure-activity relationships and define consensus motifs required for bioactivity

Corrigendum to "European contribution to the study of ROS:A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)" [Redox Biol. 13 (2017) 94-162]

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed

European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS).

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed.The EU-ROS consortium (COST Action BM1203) was supported by the European Cooperation in Science and Technology (COST). The present overview represents the final Action dissemination summarizing the major achievements of COST Action BM1203 (EU-ROS) as well as research news and personal views of its members. Some authors were also supported by COST Actions BM1005 (ENOG) and BM1307 (PROTEOSTASIS), as well as funding from the European Commission FP7 and H2020 programmes, and several national funding agencies

Redox regulation of proteasome function

Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) were initially regarded mainly as metabolic by-products with damaging properties. Over the last decade, our understanding of their role in metabolism was drastically changed and they were recognized as essential mediators in cellular signaling cascades, as well as modulators of biochemical pathways. Proteostasis is highly affected by the various levels of intracellular and extracellular free radicals with either mild or severe outcomes. As part of the proteostatic network, the proteasome system is equally affected by redox alterations. This short review summarizes the effects of oxidative stress on proteasome status while it also recapitulates conditions and processes where redox alterations signal changes to proteasome expression, assembly and function

The Error Reporting in the ATLAS TDAQ System

The ATLAS Error Reporting feature, which is used in the TDAQ environment, provides a service that allows experts and shift crew to track and address errors relating to the data taking components and applications. This service, called the Error Reporting Service(ERS), gives software applications the opportunity to collect and send comprehensive data about errors, happening at run-time, to a place where it can be intercepted in real-time by any other system component. Other ATLAS online control and monitoring tools use the Error Reporting service as one of their main inputs to address system problems in a timely manner and to improve the quality of acquired data. The actual destination of the error messages depends solely on the run-time environment, in which the online applications are operating. When applications send information to ERS, depending on the actual configuration the information may end up in a local file, in a database, in distributed middle-ware, which can transport it to an expert system or display it to a users, who can work around a problem. Thanks to the open framework design of ERS, new information destinations can be added at any moment without touching the reporting and receiving applications. The ERS API is provided in three programming languages used in the ATLAS online environment: C++, Java and Python. All APIs use exceptions for error reporting but each of them exploits advanced features of a given language to simplify program writing experience. For the example, as C++ lacks language support for exceptions, a special macro have been designed to generate hierarchies of C++ exception classes at compile time. Using this approach a software developer can write a single line of code to generate a boilerplate code for a fully qualified C++ exception class declaration with arbitrary number of parameters and multiple constructors, which encapsulates all relevant static information about the given type of issues. When corresponding error occurs at run time, a program just need to create an instance of that class passing relevant values to one of the available class constructors and send this instance to ERS. This paper presents the original design solutions exploited for the ERS implementation and describes the experience of using ERS for the first ATLAS run period, where the cross-system error reporting standardization, introduced by ERS, was one of the key points for successful launching and utilization of automated problem-solving solutions in the TDAQ online environment

Quest for Bioactive Compounds in Our Diet with Anti-Ageing and Anti-Aggregation Properties

Ageing is a complex process affected by both genetic and environmental factors, characterized by a gradual failure of functionality, reduced stress response and resistance, leading to enhanced probability for age-related diseases and mortality. During the last decades, natural compounds have attracted the attention of researchers in the quest of bioactive phytochemicals with anti-ageing properties. For a few of these compounds an extra advantage appears; many of them have been shown to decelerate the progression of age-related diseases with emphasis on aggregation-related diseases. Using the nematode Caenorhabditis elegans along with the replicative senescence model of human primary fibroblasts, we have identified compounds that are part of our diet with anti-oxidation, anti-ageing and anti-aggregation activities. Some of the identified compounds promote their anti-ageing activity through activation of the proteasome, others through the activation of Nrf2 transcription factor, while others through inhibition of glucose transporters (GLUTs). Our work identifies new bioactive compounds with anti-ageing and/or anti-aggregation properties or reveals additional beneficial properties on already known bioactive compounds

Network analysis in aged C. elegans reveals candidate regulatory genes of ageing

Ageing is a biological process guided by genetic and environmental factors that ultimately lead to adverse outcomes for organismal lifespan and healthspan. Determination of molecular pathways that are affected with age and increase disease susceptibility is crucial. The gene expression profile of the ideal ageing model, namely the nematode Caenorhabditis elegans mapped with the microarray technology initially led to the identification of age-dependent gene expression alterations that characterize the nematode's ageing process. The list of differentially expressed genes was then utilized to construct a network of molecular interactions with their first neighbors/interactors using the interactions listed in the WormBase database. The subsequent network analysis resulted in the unbiased selection of 110 candidate genes, among which well-known ageing regulators appeared. More importantly, our approach revealed candidates that have never been linked to ageing before, thus suggesting promising potential targets/ageing regulators. © 2021, The Author(s), under exclusive licence to Springer Nature B.V