scholarly journals Selective Autophagy as a Potential Therapeutic Target in Age-Associated Pathologies

Metabolites ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 588
Author(s):  
Margarita-Elena Papandreou ◽  
Nektarios Tavernarakis
Keyword(s):  
Therapeutic Interventions ◽  
Autophagic Flux ◽  
Pharmacological Agents ◽  
Selective Autophagy ◽  
Age Related ◽  
Pharmacological Targets ◽  
Autophagic Process ◽  
Severe Pathology ◽  
Progressive Accumulation ◽  
Catabolic Process

Progressive accumulation of damaged cellular constituents contributes to age-related diseases. Autophagy is the main catabolic process, which recycles cellular material in a multitude of tissues and organs. Autophagy is activated upon nutrient deprivation, and oncogenic, heat or oxidative stress-induced stimuli to selectively degrade cell constituents and compartments. Specificity and accuracy of the autophagic process is maintained via the precision of interaction of autophagy receptors or adaptors and substrates by the intricate, stepwise orchestration of specialized integrating stimuli. Polymorphisms in genes regulating selective autophagy have been linked to aging and age-associated disorders. The involvement of autophagy perturbations in aging and disease indicates that pharmacological agents balancing autophagic flux may be beneficial, in these contexts. Here, we introduce the modes and mechanisms of selective autophagy, and survey recent experimental evidence of dysfunctional autophagy triggering severe pathology. We further highlight identified pharmacological targets that hold potential for developing therapeutic interventions to alleviate cellular autophagic cargo burden and associated pathologies.

Role of Autophagy in Parkinson’s Disease

2019 ◽  
Vol 26 (20) ◽  
pp. 3702-3718 ◽  
Author(s):  
Silvia Cerri ◽  
Fabio Blandini
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Therapeutic Interventions ◽  
Pharmacological Targets ◽  
Potential Efficacy ◽  
Low Toxicity ◽  
Autophagic Process ◽  
Chaperone Mediated Autophagy ◽  
Neuronal Autophagy

Autophagy is an essential catabolic mechanism that delivers misfolded proteins and damaged organelles to the lysosome for degradation. Autophagy pathways include macroautophagy, chaperone-mediated autophagy and microautophagy, each involving different mechanisms of substrate delivery to lysosome. Defects of these pathways and the resulting accumulation of protein aggregates represent a common pathobiological feature of neurodegenerative disorders such as Alzheimer, Parkinson and Huntington disease. This review provides an overview of the role of autophagy in Parkinson’s disease (PD) by summarizing the most relevant genetic and experimental evidence showing how this process can contribute to disease pathogenesis. Given lysosomes take part in the final step of the autophagic process, the role of lysosomal defects in the impairment of autophagy and their impact on disease will also be discussed. A glance on the role of non-neuronal autophagy in the pathogenesis of PD will be included. Moreover, we will examine novel pharmacological targets and therapeutic strategies that, by boosting autophagy, may be theoretically beneficial for PD. Special attention will be focused on natural products, such as phenolic compounds, that are receiving increasing consideration due to their potential efficacy associated with low toxicity. Although many efforts have been made to elucidate autophagic process, the development of new therapeutic interventions requires a deeper understanding of the mechanisms that may lead to autophagy defects in PD and should take into account the multifactorial nature of the disease as well as the phenotypic heterogeneity of PD patients.

scholarly journals SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Patricia González-Rodríguez ◽  
Pinelopi Engskog-Vlachos ◽  
Hanzhao Zhang ◽  
Adriana-Natalia Murgoci ◽  
Ioannis Zerdes ◽  
...  
Keyword(s):  
Clear Cell ◽  
Renal Clear Cell Carcinoma ◽  
Therapeutic Interventions ◽  
Autophagic Flux ◽  
Loss Of Function ◽  
Conjugation System ◽  
Gene Encoding ◽  
Molecular Feature ◽  
Autophagic Process ◽  
Gene Status

AbstractInactivating mutations in the SETD2 gene, encoding for a nonredundant histone H3 methyltransferase and regulator of transcription, is a frequent molecular feature in clear cell renal cell carcinomas (ccRCC). SETD2 deficiency is associated with recurrence of ccRCC and bears low prognostic values. Targeting autophagy, a conserved catabolic process with critical functions in maintenance of cellular homeostasis and cell conservation under stress condition, is emerging as a potential therapeutic strategy to combat ccRCC. Epigenetics-based pathways are now appreciated as key components in the regulation of autophagy. However, whether loss of function in the SETD2 histone modifying enzyme occurring in ccRCC cells may impact on their ability to undergo autophagy remained to be explored. Here, we report that SETD2 deficiency in RCC cells is associated with the aberrant accumulation of both free ATG12 and of an additional ATG12-containing complex, distinct from the ATG5–ATG12 complex. Rescue of SETD2 functions in the SETD2 deficiency in RCC cells, or reduction of SETD2 expression level in RCC cells wild type for this enzyme, demonstrates that SETD2 deficiency in RCC is directly involved in the acquisition of these alterations in the autophagic process. Furthermore, we revealed that deficiency in SETD2, known regulator of alternative splicing, is associated with increased expression of a short ATG12 spliced isoform at the depend of the canonical long ATG12 isoform in RCC cells. The defect in the ATG12-dependent conjugation system was found to be associated with a decrease autophagic flux, in accord with the role for this ubiquitin-like protein conjugation system in autophagosome formation and expansion. Finally, we report that SETD2 and ATG12 gene expression levels are associated with favorable respective unfavorable prognosis in ccRCC patients. Collectively, our findings bring further argument for considering the SETD2 gene status of ccRCC tumors, when therapeutic interventions, such as targeting the autophagic process, are considered to combat these kidney cancers.

scholarly journals Cannabidiol induces autophagy via ERK1/2 activation in neural cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Talita A. M. Vrechi ◽  
Anderson H. F. F. Leão ◽  
Ingrid B. M. Morais ◽  
Vanessa C. Abílio ◽  
Antonio W. Zuardi ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Neurodegenerative Disorders ◽  
Molecular Mechanisms ◽  
Cannabis Sativa ◽  
Autophagic Flux ◽  
Neural Cells ◽  
Human Neuroblastoma ◽  
Trpv1 Receptor ◽  
The Central Nervous System ◽  
Catabolic Process

AbstractAutophagy is a lysosomal catabolic process essential to cell homeostasis and is related to the neuroprotection of the central nervous system. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid present in Cannabis sativa. Many therapeutic actions have been linked to this compound, including autophagy activation. However, the precise underlying molecular mechanisms remain unclear, and the downstream functional significance of these actions has yet to be determined. Here, we investigated CBD-evoked effects on autophagy in human neuroblastoma SH-SY5Y and murine astrocyte cell lines. We found that CBD-induced autophagy was substantially reduced in the presence of CB1, CB2 and TRPV1 receptor antagonists, AM 251, AM 630 and capsazepine, respectively. This result strongly indicates that the activation of these receptors mediates the autophagic flux. Additionally, we demonstrated that CBD activates autophagy through ERK1/2 activation and AKT suppression. Interestingly, CBD-mediated autophagy activation is dependent on the autophagy initiator ULK1, but mTORC1 independent. Thus, it is plausible that a non-canonical pathway is involved. Our findings collectively provide evidence that CBD stimulates autophagy signal transduction via crosstalk between the ERK1/2 and AKT kinases, which represent putative regulators of cell proliferation and survival. Furthermore, our study sheds light on potential therapeutic cannabinoid targets that could be developed for treating neurodegenerative disorders.

scholarly journals Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 2. THR-687

2021 ◽  
Author(s):  
Marc Vanhove ◽  
Jean-Marc Wagner ◽  
Bernard Noppen ◽  
Bart Jonckx ◽  
Elke Vermassen ◽  
...  
Keyword(s):  
General Circulation ◽  
Pharmacokinetic Model ◽  
Systemic Exposure ◽  
Age Related Macular Degeneration ◽  
Whole Body ◽  
Pharmacological Agents ◽  
Age Related ◽  
Pharmacokinetic Properties ◽  
High Concentrations ◽  
Systemic Compartment

AbstractIntravitreal (IVT) injection remains the preferred administration route of pharmacological agents intended for the treatment of back of the eye diseases such as diabetic macular edema (DME) and neovascular age-related macular degeneration (nvAMD). The procedure enables drugs to be delivered locally at high concentrations whilst limiting whole body exposure and associated risk of systemic adverse events. Nevertheless, intravitreally-delivered drugs do enter the general circulation and achieving an accurate understanding of systemic exposure is pivotal for the evaluation and development of drugs administered in the eye. We report here the full pharmacokinetic properties of THR-687, a pan RGD integrin antagonist currently in clinical development for the treatment of DME, in both rabbit and minipig. Pharmacokinetic characterization included description of vitreal elimination, of systemic pharmacokinetics, and of systemic exposure following IVT administration. For the latter, we present a novel pharmacokinetic model that assumes clear partition between the vitreous humor compartment itself where the drug is administered and the central systemic compartment. We also propose an analytical solution to the system of differential equations that represent the pharmacokinetic model, thereby allowing data analysis with standard nonlinear regression analysis. The model accurately describes circulating levels of THR-687 following IVT administration in relevant animal models, and we suggest that this approach is relevant to a range of drugs and analysis of subsequent systemic exposure.

scholarly journals Fighting Oxidative Stress with Sulfur: Hydrogen Sulfide in the Renal and Cardiovascular Systems

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 373
Author(s):  
Joshua J. Scammahorn ◽  
Isabel T. N. Nguyen ◽  
Eelke M. Bos ◽  
Harry Van Goor ◽  
Jaap A. Joles
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Sulfide ◽  
Redox Status ◽  
The Body ◽  
Therapeutic Interventions ◽  
Oxygen Species ◽  
Enzymatic Production ◽  
Age Related ◽  
Anti Oxidant ◽  
Enzymatic Pathways

Hydrogen sulfide (H2S) is an essential gaseous signaling molecule. Research on its role in physiological and pathophysiological processes has greatly expanded. Endogenous enzymatic production through the transsulfuration and cysteine catabolism pathways can occur in the kidneys and blood vessels. Furthermore, non-enzymatic pathways are present throughout the body. In the renal and cardiovascular system, H2S plays an important role in maintaining the redox status at safe levels by promoting scavenging of reactive oxygen species (ROS). H2S also modifies cysteine residues on key signaling molecules such as keap1/Nrf2, NFκB, and HIF-1α, thereby promoting anti-oxidant mechanisms. Depletion of H2S is implicated in many age-related and cardiorenal diseases, all having oxidative stress as a major contributor. Current research suggests potential for H2S-based therapies, however, therapeutic interventions have been limited to studies in animal models. Beyond H2S use as direct treatment, it could improve procedures such as transplantation, stem cell therapy, and the safety and efficacy of drugs including NSAIDs and ACE inhibitors. All in all, H2S is a prime subject for further research with potential for clinical use.

scholarly journals Targeting Senescent Cells to Counter Aging and Aging-Related Conditions

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 818-818
Author(s):  
Nathan LeBrasseur
Keyword(s):  
Human Populations ◽  
Geriatric Syndromes ◽  
Preclinical Models ◽  
Pharmacological Agents ◽  
New Class ◽  
Age Related ◽  
Selective Elimination ◽  
Early Phase Clinical Trials ◽  
And Function ◽  
State Of The Science

Abstract In response to various forms of age-associated damage, cells can enter a state of senescence. Senescent cells can compromise the health and function of a tissue, and their accumulation with advancing age is believed to contribute to age-related diseases and geriatric syndromes. In preclinical models (i.e., mice), selective elimination of senescent cells through either genetic approaches or a new class of pharmacological agents, termed “senolytics”, has been show to effectively delay, prevent, or reverse the onset and/or progression of pulmonary disease, osteoporosis, atherosclerosis, diabetes, cognitive decline, and several other conditions. Thus, considerable efforts are underway to optimize pharmacological strategies and test their effectiveness in human populations. This seminar will highlight the state-of-the-science of senolytic drugs, and the opportunities and challenges for early phase clinical trials in humans.

scholarly journals Molecular Alterations in Sporadic and SOD1-ALS Immortalized Lymphocytes: Towards a Personalized Therapy

2021 ◽  
Vol 22 (6) ◽  
pp. 3007
Author(s):  
Isabel Lastres-Becker ◽  
Gracia Porras ◽  
Marina Arribas-Blázquez ◽  
Inés Maestro ◽  
Daniel Borrego-Hernández ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Autophagic Flux ◽  
Metabolic Disturbances ◽  
Molecular Alterations ◽  
Healthy Donors ◽  
Inflammatory Profile ◽  
Als Patients

Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition where motor neurons (MNs) degenerate. Most of the ALS cases are sporadic (sALS), whereas 10% are hereditarily transmitted (fALS), among which mutations are found in the gene that codes for the enzyme superoxide dismutase 1 (SOD1). A central question in ALS field is whether causative mutations display selective alterations not found in sALS patients, or they converge on shared molecular pathways. To identify specific and common mechanisms for designing appropriate therapeutic interventions, we focused on the SOD1-mutated (SOD1-ALS) versus sALS patients. Since ALS pathology involves different cell types other than MNs, we generated lymphoblastoid cell lines (LCLs) from sALS and SOD1-ALS patients and healthy donors and investigated whether they show changes in oxidative stress, mitochondrial dysfunction, metabolic disturbances, the antioxidant NRF2 pathway, inflammatory profile, and autophagic flux. Both oxidative phosphorylation and glycolysis appear to be upregulated in lymphoblasts from sALS and SOD1-ALS. Our results indicate significant differences in NRF2/ARE pathway between sALS and SOD1-ALS lymphoblasts. Furthermore, levels of inflammatory cytokines and autophagic flux discriminate between sALS and SOD1-ALS lymphoblasts. Overall, different molecular mechanisms are involved in sALS and SOD1-ALS patients and thus, personalized medicine should be developed for each case.

scholarly journals Genome and Epigenome Editing in Mechanistic Studies of Human Aging and Aging-Related Disease

Gerontology ◽  
2016 ◽  
Vol 63 (2) ◽  
pp. 103-117 ◽  
Author(s):  
Cia-Hin Lau ◽  
Yousin Suh
Keyword(s):  
Animal Models ◽  
Genetic Manipulation ◽  
Logic Gate ◽  
Therapeutic Interventions ◽  
Human Aging ◽  
Aging Research ◽  
Epigenome Editing ◽  
Related Disease ◽  
Age Related

The recent advent of genome and epigenome editing technologies has provided a new paradigm in which the landscape of the human genome and epigenome can be precisely manipulated in their native context. Genome and epigenome editing technologies can be applied to many aspects of aging research and offer the potential to develop novel therapeutics against age-related diseases. Here, we discuss the latest technological advances in the CRISPR-based genome and epigenome editing toolbox, and provide insight into how these synthetic biology tools could facilitate aging research by establishing in vitro cell and in vivo animal models to dissect genetic and epigenetic mechanisms underlying aging and age-related diseases. We discuss recent developments in the field with the aims to precisely modulate gene expression and dynamic epigenetic landscapes in a spatial and temporal manner in cellular and animal models, by complementing the CRISPR-based editing capability with conditional genetic manipulation tools including chemically inducible expression systems, optogenetics, logic gate genetic circuits, tissue-specific promoters, and the serotype-specific adeno-associated virus. We also discuss how the combined use of genome and epigenome editing tools permits investigators to uncover novel molecular pathways involved in the pathophysiology and etiology conferred by risk variants associated with aging and aging-related disease. A better understanding of the genetic and epigenetic regulatory mechanisms underlying human aging and age-related disease will significantly contribute to the developments of new therapeutic interventions for extending health span and life span, ultimately improving the quality of life in the elderly populations.

scholarly journals Lack of Autophagy Induction by Lithium Decreases Neuroprotective Effects in the Striatum of Aged Rats

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 135
Author(s):  
Angelica Jardim Costa ◽  
Adolfo Garcia Erustes ◽  
Rita Sinigaglia ◽  
Carlos Eduardo Neves Girardi ◽  
Gustavo José da Silva Pereira ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Ultrastructural Changes ◽  
Ros Generation ◽  
Autophagic Flux ◽  
Aged Rats ◽  
Neuroprotective Effects ◽  
Striatal Slices ◽  
Positive Effects ◽  
Age Related ◽  
Neuroprotective Strategy

The pharmacological modulation of autophagy is considered a promising neuroprotective strategy. While it has been postulated that lithium regulates this cellular process, the age-related effects have not been fully elucidated. Here, we evaluated lithium-mediated neuroprotective effects in young and aged striatum. After determining the optimal experimental conditions for inducing autophagy in loco with lithium carbonate (Li2CO3), we measured cell viability, reactive oxygen species (ROS) generation and oxygen consumption with rat brain striatal slices from young and aged animals. In the young striatum, Li2CO3 increased tissue viability and decreased ROS generation. These positive effects were accompanied by enhanced levels of LC3-II, LAMP 1, Ambra 1 and Beclin-1 expression. In the aged striatum, Li2CO3 reduced the autophagic flux and increased the basal oxygen consumption rate. Ultrastructural changes in the striatum of aged rats that consumed Li2CO3 for 30 days included electrondense mitochondria with disarranged cristae and reduced normal mitochondria and lysosomes area. Our data show that the striatum from younger animals benefits from lithium-mediated neuroprotection, while the striatum of older rats does not. These findings should be considered when developing neuroprotective strategies involving the induction of autophagy in aging.

Sign in / Sign up

Export Citation Format

Share Document