A Crosstalk between the Biorhythms and Gatekeepers of Longevity: Dual Role of Glycogen Synthase Kinase-3

Shilovsky, Gregory A.; Putyatina, T. S.; Моргунова, Г. В.; Селиверстов, А. В.; Ashapkin, Vasily V.; Сорокина, Е. В.; Марков, А. В.; Skulachev, Vladimir P.

doi:10.1134/s0006297921040052

Cited by 19 publications

(7 citation statements)

References 121 publications

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“…In the PPI analysis of TIMELESS, we found an association between TIMELESS, targeted miRNAs and GSK3, which was a gene screened from the autophagy related genes that could be directly associated with TIMELESS. The GSK3 system represents a “regulating valve” that modifies the core circadian clock proteins 34 . Previous studies showed that SARS-CoV-2 used the autophagy mechanism of the host cells to promote its growth and replication 35 .…”

Section: Discussionmentioning

confidence: 99%

TIMELESS is a key gene mediating thrombogenesis in COVID-19 and antiphospholipid syndrome

Zhang

Liu

et al. 2022

Sci Rep

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Abnormal coagulation and increased risk of thrombosis are some of the symptoms associated with COVID-19 severity. Anti-phospholipid antibodies (aPLs) present in critically ill COVID-19 patients contribute to systemic thrombosis. The aim of this study was to identify key common genes to characterize genetic crosstalk between COVID-19 and antiphospholipid syndrome (APS) using bioinformatics analysis and explore novel mechanisms of immune-mediated thrombosis in critically ill COVID-19 patients. The transcriptome data of mononuclear cells from severe COVID-19 patients and APS patients were evaluated to obtain the common genes. The protein–protein interaction network and cytoHubba module analysis in Cytoscape software were used to find the associated hinge genes and hub genes. Among the common differentially expressed genes, TIMELESS depletion was identified only in patients with severe COVID-19 and not in patients with mild COVID-19, and it was validated with the GSE159678 dataset. Functional analyses using gene ontology terms and the Kyoto Encyclopedia of Genes and Genomes pathway suggested that TIMELESS might contribute to the production of antiphospholipid antibody and thrombosis in both COVID-19 and APS patients. The potential role of TIMELESS and autophagy genes in momonuclear cells were further investigated, and GSK3B was found to be associated with TIMELESS. Autophagy targeting agents have a therapeutic potential against COVID-19 and thrombogenesis in APS, which may be related to the role of autophagy genes in the modification of circadian clock proteins. Interference with TIMELESS and other genes associated with it to regulate autoantibody expression may be a potential strategy for immunotherapy against thrombogenesis in severe COVID-19 patients.

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Section: Discussionmentioning

confidence: 99%

TIMELESS is a key gene mediating thrombogenesis in COVID-19 and antiphospholipid syndrome

Zhang

Liu

et al. 2022

Sci Rep

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“…Furthermore, higher GSK‐3β levels relate to cognitive symptoms of sadness. It has been proposed that inhibiting GSK‐3β may alleviate cognitive symptoms in AD (Shilovsky et al, 2021). PP2A is another protein kinase implicated in tau phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant dihydrolipolic acid protects against in vitro aluminum‐induced toxicity

Sanajou

Yirün

Demirel

et al. 2023

J of Applied Toxicology

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Dihydrolipoic acid (DHLA) is a natural antioxidant known for its ability to counteract metal toxicity and oxidative stress. It has shown the potential to safeguard cells from harmful environmental substances. It may hold therapeutic benefits in treating neurodegenerative disorders by defending against oxidative damage and chronic inflammation. Thus, this study aimed to explore the potential neuroprotective effects of DHLA against aluminum (Al)‐induced toxicity using an Alzheimer's disease (AD) model in vitro. The study focused on two important pathways: GSK‐3β and the Wnt signaling pathways. The SH‐SY5Y cell line was differentiated to establish AD, and the study group were as follows: control, Al, DHLA, Al‐DHLA, AD, AD‐Al, AD‐DHLA, and AD‐Al‐DHLA. The impact of DHLA on parameters related to oxidative stress was assessed. The activity of the GSK‐3β pathway was measured by evaluating the levels of PPP1CA, PP2A, GSK‐3β, and Akt. The Wnt signaling pathway was assessed by measuring Wnt/β‐catenin in the different study groups. Exposure to DHLA significantly reduced oxidative stress by effectively decreasing the levels of reactive oxygen species, thereby protecting against protein oxidation and limiting the production of malonaldehyde. Moreover, the DHLA‐treated groups exhibited a remarkable increase in the total antioxidant capacity. Furthermore, the study observed an upregulation of the Wnt signaling pathway and a downregulation of the GSK‐3β pathway in the groups treated with DHLA. In summary, the neuroprotective effects of DHLA, primarily achieved by reducing oxidative stress and modulating critical imbalanced pathways associated with AD, indicate its potential as a promising addition to the treatment regimens of AD patients.

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“…In some cases, aging can also have adaptive significance. Sometimes, phenoptosis is a continuation of the development programs, as for instance, the mechanism of Nrf2 inhibition by glycogen synthase kinase GSK3β, including via induction of inflammaging [ 97 , 98 ]. Some of the promising agents are antioxidant preparations targeting different metabolic processes, e.g., those preventing cytokine storm [ 99 ], both traditional (plant extracts [ 100 ] and active components of blood serum [ 101 ]) and derived, for example, from insects [ 102 ].…”

Section: Discussionmentioning

confidence: 99%

Altruism and Phenoptosis as Programs Supported by Evolution

Shilovsky

Putyatina

Марков

2021

Biochemistry Moscow

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Phenoptosis is a programmed death that has emerged in the process of evolution, sometimes taking the form of an altruistic program. In particular, it is believed to be a weapon against the spread of pandemics in the past and an obstacle in fighting pandemics in the present (COVID). However, on the evolutionary scale, deterministic death is not associated with random relationships (for example, bacteria with a particular mutation), but is a product of higher nervous activity or a consequence of established hierarchy that reaches its maximal expression in eusocial communities of Hymenoptera and highly social communities of mammals. Unlike a simple association of individuals, eusociality is characterized by the appearance of non-reproductive individuals as the highest form of altruism. In contrast to primitive programs for unicellular organisms, higher multicellular organisms are characterized by the development of behavior-based phenoptotic programs, especially in the case of reproduction-associated limitation of lifespan. Therefore, we can say that the development of altruism in the course of evolution of sociality leads in its extreme manifestation to phenoptosis. Development of mathematical models for the emergence of altruism and programmed death contributes to our understanding of mechanisms underlying these paradoxical counterproductive (harmful) programs. In theory, this model can be applied not only to insects, but also to other social animals and even to the human society. Adaptive death is an extreme form of altruism. We consider altruism and programmed death as programmed processes in the mechanistic and adaptive sense, respectively. Mechanistically, this is a program existing as a predetermined chain of certain responses, regardless of its adaptive value. As to its adaptive value (regardless of the degree of “phenoptoticity”), this is a characteristic of organisms that demonstrate high levels of kinship, social organization, and physical association typical for higher-order individuals, e.g., unicellular organisms forming colonies with some characteristics of multicellular animals or colonies of multicellular animals displaying features of supraorganisms.

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A Crosstalk between the Biorhythms and Gatekeepers of Longevity: Dual Role of Glycogen Synthase Kinase-3

Cited by 19 publications

References 121 publications

TIMELESS is a key gene mediating thrombogenesis in COVID-19 and antiphospholipid syndrome

TIMELESS is a key gene mediating thrombogenesis in COVID-19 and antiphospholipid syndrome

Antioxidant dihydrolipolic acid protects against in vitro aluminum‐induced toxicity

Altruism and Phenoptosis as Programs Supported by Evolution

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