Epigenetics refers to changes in gene function, not resulting from the primary DNA sequence, influenced by the environment. It provides a link between the molecular regulation of the genome and the environmental signals exposed during the life of individuals (including lifestyle, social behavior, development, and nutrition). Notably,
In the last decades, improvements in different aspects of sanitation, medical care, and nutrition, among others, have permitted an increase in the average lifespan of human population around the world. These advances have stimulated an increased interest in the study of the aging process and age-sensitive characteristics, such as the microbial community that colonizes the human body (microbiome). The human microbiome is composed of bacteria (bacteriome), archaea (archaeome), fungi (mycobiome), and viruses (virome). To date, research has mainly been centered on the composition of the bacteriome, with other members remain poorly studied. Interestingly, changes in the composition of the microbiome have been implicated in aging and age-related diseases. Therefore, in the present perspective, we suggest expanding the scope to research to include the role and the possible associations that the other members of the microbiome could have in the aging organism. An expanded view of the microbiome would increase our knowledge of the physiology of aging and may be particularly valuable for the treatment and diagnosis of age-related diseases.
Cellular senescence is a cellular condition that involves significant changes in gene expression and the arrest of cell proliferation. Recently, it has been suggested in experimental models that the elimination of senescent cells with pharmacological methods delays, prevents, and improves multiple adverse outcomes related to age. In this sense, the so-called senoylitic compounds are a class of drugs that selectively eliminates senescent cells (SCs) and that could be used in order to delay such adverse outcomes. Interestingly, the first senolytic drug (navitoclax) was discovered by using chemoinformatic and network analyses. Thus, in the present study, we searched for novel senolytic compounds through the use of chemoinformatic tools (fingerprinting and network pharmacology) over different chemical databases (InflamNat and BIOFACQUIM) coming from natural products (NPs) that have proven to be quite remarkable for drug development. As a result of screening, we obtained three molecules (hinokitiol, preussomerin C, and tanshinone I) that could be considered senolytic compound candidates since they share similarities in structure with senolytic leads (tunicamycin, ginsenoside Rb1, ABT 737, rapamycin, navitoclax, timosaponin A-III, digoxin, roxithromycin, and azithromycin) and targets involved in senescence pathways with potential use in the treatment of age-related diseases.
Background:
Preclinical studies suggest that senolytic compounds such as quercetin (a natural product) and dasatinib (a synthetic product) decrease senescent cells, reduce inflammation, and alleviate frailty in humans. This evidence has opened a new field of research for studying the effect of these compounds on age-related dysfunction and diseases.
Objective:
In the present study performed in silico, we identified new potentially senolytic candidates from an extensive database that contains natural products (NPs) and semi-synthetic products (SMSs).
Methods:
Computer programs Chemminer and rcdk packages, which compared the fingerprints of numerous molecules (40,383) with reference senolytics, and the creation of a pharmacological network built with signaling pathways and targets involved in senescence processes were used to identify compounds with potential activity.
Results:
Six drug-like candidates (3,4'-dihydroxypropiophenone, baicalein, α, β-dehydrocurvularin, lovastatin, luteolin, and phloretin) were identified.
Conclusion:
To our knowledge, this is the first time that these six natural molecules have been proposed to most likely have senolytic activity. To validate the methodology employed in the identification of new drug-like senolytics, experimental evidence is needed with models that evaluate senolytic activity.
It is known that levels of the anti-apoptotic protein survivin are reduced during Murine norovirus MNV-1 and Feline calicivirus (FCV) infection as part of the apoptosis establishment required for virus release and propagation in the host. Recently, our group has reported that overexpression of survivin causes a reduction of FCV protein synthesis and viral progeny production, suggesting that survivin may affect early steps of the replicative cycle. Using immunofluorescence assays, we observed that overexpression of survivin, resulted in the reduction of FCV infection not only in transfected but also in the neighboring nontransfected CrFK cells, thus suggesting autocrine and paracrine protective effects. Cells treated with the supernatants collected from CrFK cells overexpressing survivin showed a reduction in FCV but not MNV-1 protein production and viral yield, suggesting that FCV binding and/or entry were specifically altered. The reduced ability of FCV to bind to the surface of the cells overexpressing survivin, or treated with the supernatants collected from these cells, correlate with the reduction in the cell surface of the FCV receptor, the feline junctional adhesion molecule (fJAM) 1, while no effect was observed in the cells transfected with the pAm-Cyan vector or in cells treated with the corresponding supernatants. Moreover, the overexpression of survivin affects neither Vaccinia virus (VACV) production in CrFK cells nor MNV-1 virus production in RAW 267.4 cells, indicating that the effect is specific for FCV. All of these results taken together indicate that cells that overexpress survivin, or cell treatment with the conditioned medium from these cells, results in the reduction of the fJAM-1 molecule and, therefore, a specific reduction in FCV entry and infection.
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