Regulation of autophagy by mTOR-dependent and mTOR-independent pathways: autophagy dysfunction in neurodegenerative diseases and therapeutic application of autophagy enhancers

Autophagy is an intracellular degradation pathway essential for cellular and energy homoeostasis. It functions in the clearance of misfolded proteins and damaged organelles, as well as recycling of cytosolic components during starvation to compensate for nutrient deprivation. This process is regulated by mTOR (mammalian target of rapamycin)-dependent and mTOR-independent pathways that are amenable to chemical perturbations. Several small molecules modulating autophagy have been identified that have potential therapeutic application in diverse human diseases, including neurodegeneration. Neurodegeneration-associated aggregation-prone proteins are predominantly degraded by autophagy and therefore stimulating this process with chemical inducers is beneficial in a wide range of transgenic disease models. Emerging evidence indicates that compromised autophagy contributes to the aetiology of various neurodegenerative diseases related to protein conformational disorders by causing the accumulation of mutant proteins and cellular toxicity. Combining the knowledge of autophagy dysfunction and the mechanism of drug action may thus be rational for designing targeted therapy. The present review describes the cellular signalling pathways regulating mammalian autophagy and highlights the potential therapeutic application of autophagy inducers in neurodegenerative disorders.

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Combination of Cell-Penetrating Peptides with Nanoparticles for Therapeutic Application: A Review

Biomolecules ◽

10.3390/biom9010022 ◽

2019 ◽

Vol 9 (1) ◽

pp. 22 ◽

Cited By ~ 46

Author(s):

Sara Silva ◽

António Almeida ◽

Nuno Vale

Keyword(s):

Small Molecules ◽

Protein Translocation ◽

Cell Penetrating Peptides ◽

Amino Acid Residues ◽

Therapeutic Application ◽

New Class ◽

Wide Range ◽

Cell Penetrating ◽

Therapeutic Molecules ◽

Resistant Strains

Cell-penetrating peptides (CPPs), also known as protein translocation domains, membrane translocating sequences or Trojan peptides, are small molecules of 6 to 30 amino acid residues capable of penetrating biological barriers and cellular membranes. Furthermore, CPP have become an alternative strategy to overcome some of the current drug limitations and combat resistant strains since CPPs are capable of delivering different therapeutic molecules against a wide range of diseases. In this review, we address the recent conjugation of CPPs with nanoparticles, which constitutes a new class of delivery vectors with high pharmaceutical potential in a variety of diseases.

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Chemical Inducers of Autophagy That Enhance the Clearance of Mutant Proteins in Neurodegenerative Diseases

Journal of Biological Chemistry ◽

10.1074/jbc.r109.072181 ◽

2010 ◽

Vol 285 (15) ◽

pp. 11061-11067 ◽

Cited By ~ 136

Author(s):

Maurizio Renna ◽

Maria Jimenez-Sanchez ◽

Sovan Sarkar ◽

David C. Rubinsztein

Keyword(s):

Neurodegenerative Diseases ◽

Mutant Proteins ◽

Chemical Inducers

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Autophagy and ageing: implications for age-related neurodegenerative diseases

Essays in Biochemistry ◽

10.1042/bse0550119 ◽

2013 ◽

Vol 55 ◽

pp. 119-131 ◽

Cited By ~ 37

Author(s):

Bernadette Carroll ◽

Graeme Hewitt ◽

Viktor I. Korolchuk

Keyword(s):

Neurodegenerative Diseases ◽

Energy Availability ◽

Future Studies ◽

Intracellular Degradation ◽

Age Related ◽

Autophagy Induction ◽

Social Importance ◽

Cellular Dysfunction ◽

Autophagy Activity ◽

Intense Research

Autophagy is a process of lysosome-dependent intracellular degradation that participates in the liberation of resources including amino acids and energy to maintain homoeostasis. Autophagy is particularly important in stress conditions such as nutrient starvation and any perturbation in the ability of the cell to activate or regulate autophagy can lead to cellular dysfunction and disease. An area of intense research interest is the role and indeed the fate of autophagy during cellular and organismal ageing. Age-related disorders are associated with increased cellular stress and assault including DNA damage, reduced energy availability, protein aggregation and accumulation of damaged organelles. A reduction in autophagy activity has been observed in a number of ageing models and its up-regulation via pharmacological and genetic methods can alleviate age-related pathologies. In particular, autophagy induction can enhance clearance of toxic intracellular waste associated with neurodegenerative diseases and has been comprehensively demonstrated to improve lifespan in yeast, worms, flies, rodents and primates. The situation, however, has been complicated by the identification that autophagy up-regulation can also occur during ageing. Indeed, in certain situations, reduced autophagosome induction may actually provide benefits to ageing cells. Future studies will undoubtedly improve our understanding of exactly how the multiple signals that are integrated to control appropriate autophagy activity change during ageing, what affect this has on autophagy and to what extent autophagy contributes to age-associated pathologies. Identification of mechanisms that influence a healthy lifespan is of economic, medical and social importance in our ‘ageing’ world.

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Understanding Conformational Entropy in Small Molecules

10.26434/chemrxiv.12671027 ◽

2020 ◽

Author(s):

Lucian Chan ◽

Garrett Morris ◽

Geoffrey Hutchison

Keyword(s):

Small Molecules ◽

Degrees Of Freedom ◽

Absolute Error ◽

Low Energy ◽

Standard Entropy ◽

Free Energies ◽

Conformational Entropy ◽

Wide Range ◽

High Degree ◽

Empirical Corrections

The calculation of the entropy of flexible molecules can be challenging, since the number of possible conformers grows exponentially with molecule size and many low-energy conformers may be thermally accessible. Different methods have been proposed to approximate the contribution of conformational entropy to the molecular standard entropy, including performing thermochemistry calculations with all possible stable conformations, and developing empirical corrections from experimental data. We have performed conformer sampling on over 120,000 small molecules generating some 12 million conformers, to develop models to predict conformational entropy across a wide range of molecules. Using insight into the nature of conformational disorder, our cross-validated physically-motivated statistical model can outperform common machine learning and deep learning methods, with a mean absolute error ≈4.8 J/mol•K, or under 0.4 kcal/mol at 300 K. Beyond predicting molecular entropies and free energies, the model implies a high degree of correlation between torsions in most molecules, often as- sumed to be independent. While individual dihedral rotations may have low energetic barriers, the shape and chemical functionality of most molecules necessarily correlate their torsional degrees of freedom, and hence restrict the number of low-energy conformations immensely. Our simple models capture these correlations, and advance our understanding of small molecule conformational entropy.

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Targeting xanthine oxidase by natural products as a therapeutic approach for mental disorders

Current Pharmaceutical Design ◽

10.2174/1381612826666200621165839 ◽

2020 ◽

Vol 26 ◽

Author(s):

Miquel Martorell ◽

Xavier Lucas ◽

Pedro Alarcón-Zapata ◽

Xavier Capó ◽

Maria Magdalena Quetglas-Llabrés ◽

...

Keyword(s):

Mental Disorders ◽

Small Molecules ◽

Xanthine Oxidase ◽

Cell Damage ◽

Bipolar Affective Disorder ◽

Oxidative Reaction ◽

Mental Diseases ◽

Potential Therapeutic Application ◽

Increased Activity ◽

Dietary Flavonoids

: Mental disorders comprise diverse human pathologies including depression, bipolar affective disorder, schizophrenia, and dementia that affect millions of people around the world. The causes of mental disorders are unclear but growing evidence suggests that oxidative stress and the purine/adenosine system play a key role in their development and progression. Xanthine oxidase (XO) is a flavoprotein enzyme essential for the catalysis of the oxidative hydroxylation of purines -hypoxanthine and xanthine- to generate uric acid. As a consequence of the oxidative reaction of XO, reactive oxygen species (ROS) such as superoxide and hydrogen peroxide are produced and, further, contribute to the pathogenesis of mental disorders. Altered XO activity has been associated with free radical-mediated neurotoxicity inducing cell damage and inflammation. Diverse studies reported a direct association between an increased activity of XO and diverse mental diseases including depression or schizophrenia. Small-molecule inhibitors, such as the well-known allopurinol, and dietary flavonoids, can modulate the XO activity and subsequent ROS production. In the present work, we review the available literature on XO inhibition by small molecules and their potential therapeutic application in mental disorders. In addition, we discuss the chemistry and molecular mechanism of XO inhibitors, as well as the use of structure-based and computational methods to design specific inhibitors with the capability of modulating XO activity.

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AZP2006, a new promising treatment for Alzheimer’s and related diseases

Scientific Reports ◽

10.1038/s41598-021-94708-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

N. Callizot ◽

C. Estrella ◽

S. Burlet ◽

A. Henriques ◽

C. Brantis ◽

...

Keyword(s):

Therapeutic Application ◽

Neuroprotective Effects ◽

Beneficial Effects ◽

Potential Therapeutic Application ◽

Promising Treatment ◽

Central Synapses ◽

First Time ◽

Pgrn Level

AbstractProgranulin (PGRN) is a protein with multiple functions including the regulation of neuroinflammation, neuronal survival, neurite and synapsis growth. Although the mechanisms of action of PGRN are currently unknown, its potential therapeutic application in treating neurodegenerative diseases is huge. Thus, strategies to increase PGRN levels in patients could provide an effective treatment. In the present study, we investigated the effects of AZP2006, a lysotropic molecule now in phase 2a clinical trial in Progressive Supranuclear Palsy patients, for its ability to increase PGRN level and promote neuroprotection. We showed for the first time the in vitro and in vivo neuroprotective effects of AZP2006 in neurons injured with Aβ1–42 and in two different pathological animal models of Alzheimer’s disease (AD) and aging. Thus, the chronic treatment with AZP2006 was shown to reduce the loss of central synapses and neurons but also to dramatically decrease the massive neuroinflammation associated with the animal pathology. A deeper investigation showed that the beneficial effects of AZP2006 were associated with PGRN production. Also, AZP2006 binds to PSAP (the cofactor of PGRN) and inhibits TLR9 receptors normally responsible for proinflammation when activated. Altogether, these results showed the high potential of AZP2006 as a new putative treatment for AD and related diseases.

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Harnessing methylation and AdoMet-utilising enzymes for selective modification in cascade reactions

Organic & Biomolecular Chemistry ◽

10.1039/d1ob00354b ◽

2021 ◽

Author(s):

Freideriki Michailidou ◽

Andrea Rentmeister

Keyword(s):

Natural Products ◽

Small Molecules ◽

Cascade Reactions ◽

Fine Tuning ◽

Wide Range

Enzyme-mediated methylation is a very important reaction in nature, yielding a wide range of modified natural products, diversifying small molecules and fine-tuning the activity of biomacromolecules. The field has attracted...

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Mini-review: antibody therapeutics targeting G protein-coupled receptors and ion channels

Antibody Therapeutics ◽

10.1093/abt/tbaa023 ◽

2020 ◽

Vol 3 (4) ◽

pp. 257-264

Author(s):

Catherine J Hutchings

Keyword(s):

Ion Channels ◽

Research And Development ◽

Small Molecules ◽

G Protein ◽

Clinical Studies ◽

G Protein Coupled Receptors ◽

Protein Targets ◽

Antibody Therapeutics ◽

Wide Range ◽

G Protein Coupled

Abstract Antibodies are now well established as therapeutics with many additional advantages over small molecules and peptides relative to their selectivity, bioavailability, half-life and effector function. Major classes of membrane-associated protein targets include G protein-coupled receptors (GPCRs) and ion channels that are linked to a wide range of disease indications across all therapeutic areas. This mini-review summarizes the antibody target landscape for both GPCRs and ion channels as well as current progress in the respective research and development pipelines with some example case studies highlighted from clinical studies, including those being evaluated for the treatment of symptoms in COVID-19 infection.

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Non-Coding RNAs in the Transcriptional Network That Differentiates Skeletal Muscles of Sedentary from Long-Term Endurance- and Resistance-Trained Elderly

International Journal of Molecular Sciences ◽

10.3390/ijms22041539 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1539

Author(s):

Paola De Sanctis ◽

Giuseppe Filardo ◽

Provvidenza Maria Abruzzo ◽

Annalisa Astolfi ◽

Alessandra Bolotta ◽

...

Keyword(s):

Exercise Training ◽

High Intensity ◽

Vastus Lateralis ◽

Mammalian Target Of Rapamycin ◽

Differentially Expressed ◽

Transcriptional Networks ◽

Vastus Lateralis Muscle ◽

Age Related ◽

Wide Range ◽

Non Coding Rnas

In a previous study, the whole transcriptome of the vastus lateralis muscle from sedentary elderly and from age-matched athletes with an exceptional record of high-intensity, life-long exercise training was compared—the two groups representing the two extremes on a physical activity scale. Exercise training enabled the skeletal muscle to counteract age-related sarcopenia by inducing a wide range of adaptations, sustained by the expression of protein-coding genes involved in energy handling, proteostasis, cytoskeletal organization, inflammation control, and cellular senescence. Building on the previous study, we examined here the network of non-coding RNAs participating in the orchestration of gene expression and identified differentially expressed micro- and long-non-coding RNAs and some of their possible targets and roles. Unsupervised hierarchical clustering analyses of all non-coding RNAs were able to discriminate between sedentary and trained individuals, regardless of the exercise typology. Validated targets of differentially expressed miRNA were grouped by KEGG analysis, which pointed to functional areas involved in cell cycle, cytoskeletal control, longevity, and many signaling pathways, including AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), which had been shown to be pivotal in the modulation of the effects of high-intensity, life-long exercise training. The analysis of differentially expressed long-non-coding RNAs identified transcriptional networks, involving lncRNAs, miRNAs and mRNAs, affecting processes in line with the beneficial role of exercise training.

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