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Sirtuins as Novel Biological Targets for Pharmacological Intervention in Physiology...
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Sirtuins as Novel Biological Targets for Pharmacological Intervention in Physiology and Pathology

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 25 January 2025 | Viewed by 6921

Special Issue Editors

Dr. Michele Aventaggiato

E-Mail Website
Guest Editor
Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161 Rome, Italy
Interests: sirtuins; metabolism; extracellular vesicles; autophagy; mitophagy; apoptosis
Dr. Marco Tafani

E-Mail Website
Guest Editor
Department of Experimental Medicine, Sapienza University, 00161 Rome, ItalyDepartment of Experimental Medicine, Sapienza University, Rome, Italy
Interests: sirtuins; hypoxia inflammation; metabolism; autophagy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The sirtuin family of proteins is a class of enzymes highly conserved from yeast to humans with a high homology in sequences and in their cellular functions, underlying the fact that these proteins play important physiological roles. Seven mammalian sirtuins have been identified, which are characterized by different cellular functions, structures and localizations that can vary following different stimuli. Sirtuins were first characterized as histone deacetylases, but the presence of non-histone targets underline their involvement in many cellular processes such as the cell cycle, differentiation, senescence, stress response, inflammation, aging and metabolism. On the other hand, sirtuins are involved in several pathological conditions, such as neurodegenerative disorders, cardiovascular diseases, metabolism-related disorders, carcinogenesis and tumor development, in which they can act as disease promoters or protective factors based on their targets and functions. Nuclear sirtuins, due to their epigenetic role, and mitochondrial sirtuins, due to their involvement in several metabolic processes such as the tricarboxylic acid cycle, respiratory chain, fatty acid β-oxidation, ketogenesis, glutamine metabolism, etc., represent an important object of investigation since one of the hallmarks of carcinogenesis is represented by metabolic reprogramming and uncontrolled cell proliferation. In a broader analysis that also considers the influence of sirtuins in physiological and pathological conditions, this class of proteins represents a promising potential target of molecular and pharmacological strategies that could counteract the effects of several pathological conditions acting at various levels in molecular and cellular mechanisms. This Special Issue aims to collect and summarize the latest findings on the potential pharmacological intervention to modulate sirtuins' activity in counteracting damage and the onset of pathological states and favors the physiological homeostasis of tissues.

Dr. Michele Aventaggiato
Dr. Marco Tafani
Guest Editors

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Keywords

  • sirtuins
  • metabolism
  • cancer
  • hypoxia
  • damage recovery
  • cell death

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Published Papers (5 papers)

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Research

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24 pages, 7124 KiB  
Article
Pharmacological Activation of SIRT3 Modulates the Response of Cancer Cells to Acidic pH
by Michele Aventaggiato, Tania Arcangeli, Enza Vernucci, Federica Barreca, Luigi Sansone, Laura Pellegrini, Elena Pontemezzo, Sergio Valente, Rossella Fioravanti, Matteo Antonio Russo, Antonello Mai and Marco Tafani
Pharmaceuticals 2024, 17(6), 810; https://doi.org/10.3390/ph17060810 - 20 Jun 2024
Viewed by 1138
Abstract
Cancer cells modulate their metabolism, creating an acidic microenvironment that, in turn, can favor tumor progression and chemotherapy resistance. Tumor cells adopt strategies to survive a drop in extracellular pH (pHe). In the present manuscript, we investigated the contribution of mitochondrial sirtuin 3 [...] Read more.
Cancer cells modulate their metabolism, creating an acidic microenvironment that, in turn, can favor tumor progression and chemotherapy resistance. Tumor cells adopt strategies to survive a drop in extracellular pH (pHe). In the present manuscript, we investigated the contribution of mitochondrial sirtuin 3 (SIRT3) to the adaptation and survival of cancer cells to a low pHe. SIRT3-overexpressing and silenced breast cancer cells MDA-MB-231 and human embryonic kidney HEK293 cells were grown in buffered and unbuffered media at pH 7.4 and 6.8 for different times. mRNA expression of SIRT3 and CAVB, was measured by RT-PCR. Protein expression of SIRT3, CAVB and autophagy proteins was estimated by western blot. SIRT3-CAVB interaction was determined by immunoprecipitation and proximity ligation assays (PLA). Induction of autophagy was studied by western blot and TEM. SIRT3 overexpression increases the survival of both cell lines. Moreover, we demonstrated that SIRT3 controls intracellular pH (pHi) through the regulation of mitochondrial carbonic anhydrase VB (CAVB). Interestingly, we obtained similar results by using MC2791, a new SIRT3 activator. Our results point to the possibility of modulating SIRT3 to decrease the response and resistance of tumor cells to the acidic microenvironment and ameliorate the effectiveness of anticancer therapy. Full article
(This article belongs to the Special Issue Sirtuins as Novel Biological Targets for Pharmacological Intervention in Physiology and Pathology)
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Review

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26 pages, 1192 KiB  
Review
From Microcirculation to Aging-Related Diseases: A Focus on Endothelial SIRT1
by Martin Law, Pei-Chun Wang, Zhong-Yan Zhou and Yu Wang
Pharmaceuticals 2024, 17(11), 1495; https://doi.org/10.3390/ph17111495 - 7 Nov 2024
Viewed by 571
Abstract
Silent information regulator sirtuin 1 (SIRT1) is an NAD+-dependent deacetylase with potent anti-arterial aging activities. Its protective function in aging-related diseases has been extensively studied. In the microcirculation, SIRT1 plays a crucial role in preventing microcirculatory endothelial senescence by suppressing inflammation and oxidative [...] Read more.
Silent information regulator sirtuin 1 (SIRT1) is an NAD+-dependent deacetylase with potent anti-arterial aging activities. Its protective function in aging-related diseases has been extensively studied. In the microcirculation, SIRT1 plays a crucial role in preventing microcirculatory endothelial senescence by suppressing inflammation and oxidative stress while promoting mitochondrial function and optimizing autophagy. It suppresses hypoxia-inducible factor-1α (HIF-1α)-mediated pathological angiogenesis while promoting healthy, physiological capillarization. As a result, SIRT1 protects against microvascular dysfunction, such as diabetic microangiopathy, while enhancing exercise-induced skeletal muscle capillarization and energy metabolism. In the brain, SIRT1 upregulates tight junction proteins and strengthens their interactions, thus maintaining the integrity of the blood−brain barrier. The present review summarizes recent findings on the regulation of microvascular function by SIRT1, the underlying mechanisms, and various approaches to modulate SIRT1 activity in microcirculation. The importance of SIRT1 as a molecular target in aging-related diseases, such as diabetic retinopathy and stroke, is underscored, along with the need for more clinical evidence to support SIRT1 modulation in the microcirculation. Full article
(This article belongs to the Special Issue Sirtuins as Novel Biological Targets for Pharmacological Intervention in Physiology and Pathology)
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26 pages, 3323 KiB  
Review
Drugs Targeting Sirtuin 2 Exhibit Broad-Spectrum Anti-Infective Activity
by Thomas Shenk, John L. Kulp III and Lillian W. Chiang
Pharmaceuticals 2024, 17(10), 1298; https://doi.org/10.3390/ph17101298 - 29 Sep 2024
Viewed by 1212
Abstract
Direct-acting anti-infective drugs target pathogen-coded gene products and are a highly successful therapeutic paradigm. However, they generally target a single pathogen or family of pathogens, and the targeted organisms can readily evolve resistance. Host-targeted agents can overcome these limitations. One family of host-targeted, [...] Read more.
Direct-acting anti-infective drugs target pathogen-coded gene products and are a highly successful therapeutic paradigm. However, they generally target a single pathogen or family of pathogens, and the targeted organisms can readily evolve resistance. Host-targeted agents can overcome these limitations. One family of host-targeted, anti-infective agents modulate human sirtuin 2 (SIRT2) enzyme activity. SIRT2 is one of seven human sirtuins, a family of NAD+-dependent protein deacylases. It is the only sirtuin that is found predominantly in the cytoplasm. Multiple, structurally distinct SIRT2-targeted, small molecules have been shown to inhibit the replication of both RNA and DNA viruses, as well as intracellular bacterial pathogens, in cell culture and in animal models of disease. Biochemical and X-ray structural studies indicate that most, and probably all, of these compounds act as allosteric modulators. These compounds appear to impact the replication cycles of intracellular pathogens at multiple levels to antagonize their replication and spread. Here, we review SIRT2 modulators reported to exhibit anti-infective activity, exploring their pharmacological action as anti-infectives and identifying questions in need of additional study as this family of anti-infective agents advances to the clinic. Full article
(This article belongs to the Special Issue Sirtuins as Novel Biological Targets for Pharmacological Intervention in Physiology and Pathology)
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25 pages, 1810 KiB  
Review
Roles of Sirtuins in Hearing Protection
by Chail Koo, Claus-Peter Richter and Xiaodong Tan
Pharmaceuticals 2024, 17(8), 998; https://doi.org/10.3390/ph17080998 - 28 Jul 2024
Viewed by 1345
Abstract
Hearing loss is a health crisis that affects more than 60 million Americans. Currently, sodium thiosulfate is the only drug approved by the Food and Drug Administration (FDA) to counter hearing loss. Sirtuins were proposed as therapeutic targets in the search for new [...] Read more.
Hearing loss is a health crisis that affects more than 60 million Americans. Currently, sodium thiosulfate is the only drug approved by the Food and Drug Administration (FDA) to counter hearing loss. Sirtuins were proposed as therapeutic targets in the search for new compounds or drugs to prevent or cure age-, noise-, or drug-induced hearing loss. Sirtuins are proteins involved in metabolic regulation with the potential to ameliorate sensorineural hearing loss. The mammalian sirtuin family includes seven members, SIRT1-7. This paper is a literature review on the sirtuins and their protective roles in sensorineural hearing loss. Literature search on the NCBI PubMed database and NUsearch included the keywords ‘sirtuin’ and ‘hearing’. Studies on sirtuins without relevance to hearing and studies on hearing without relevance to sirtuins were excluded. Only primary research articles with data on sirtuin expression and physiologic auditory tests were considered. The literature review identified 183 records on sirtuins and hearing. After removing duplicates, eighty-one records remained. After screening for eligibility criteria, there were forty-eight primary research articles with statistically significant data relevant to sirtuins and hearing. Overall, SIRT1 (n = 29) was the most studied sirtuin paralog. Over the last two decades, research on sirtuins and hearing has largely focused on age-, noise-, and drug-induced hearing loss. Past and current studies highlight the role of sirtuins as a mediator of redox homeostasis. However, more studies need to be conducted on the involvement of SIRT2 and SIRT4-7 in hearing protection. Full article
(This article belongs to the Special Issue Sirtuins as Novel Biological Targets for Pharmacological Intervention in Physiology and Pathology)
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Other

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18 pages, 2118 KiB  
Systematic Review
Hydrogen Sulfide and Gut Microbiota: Their Synergistic Role in Modulating Sirtuin Activity and Potential Therapeutic Implications for Neurodegenerative Diseases
by Constantin Munteanu, Gelu Onose, Mădălina Poștaru, Marius Turnea, Mariana Rotariu and Anca Irina Galaction
Pharmaceuticals 2024, 17(11), 1480; https://doi.org/10.3390/ph17111480 - 4 Nov 2024
Viewed by 1089
Abstract
The intricate relationship between hydrogen sulfide (H2S), gut microbiota, and sirtuins (SIRTs) can be seen as a paradigm axis in maintaining cellular homeostasis, modulating oxidative stress, and promoting mitochondrial health, which together play a pivotal role in aging and neurodegenerative diseases. [...] Read more.
The intricate relationship between hydrogen sulfide (H2S), gut microbiota, and sirtuins (SIRTs) can be seen as a paradigm axis in maintaining cellular homeostasis, modulating oxidative stress, and promoting mitochondrial health, which together play a pivotal role in aging and neurodegenerative diseases. H2S, a gasotransmitter synthesized endogenously and by specific gut microbiota, acts as a potent modulator of mitochondrial function and oxidative stress, protecting against cellular damage. Through sulfate-reducing bacteria, gut microbiota influences systemic H2S levels, creating a link between gut health and metabolic processes. Dysbiosis, or an imbalance in microbial populations, can alter H2S production, impair mitochondrial function, increase oxidative stress, and heighten inflammation, all contributing factors in neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Sirtuins, particularly SIRT1 and SIRT3, are NAD+-dependent deacetylases that regulate mitochondrial biogenesis, antioxidant defense, and inflammation. H2S enhances sirtuin activity through post-translational modifications, such as sulfhydration, which activate sirtuin pathways essential for mitigating oxidative damage, reducing inflammation, and promoting cellular longevity. SIRT1, for example, deacetylates NF-κB, reducing pro-inflammatory cytokine expression, while SIRT3 modulates key mitochondrial enzymes to improve energy metabolism and detoxify reactive oxygen species (ROS). This synergy between H2S and sirtuins is profoundly influenced by the gut microbiota, which modulates systemic H2S levels and, in turn, impacts sirtuin activation. The gut microbiota–H2S–sirtuin axis is also essential in regulating neuroinflammation, which plays a central role in the pathogenesis of neurodegenerative diseases. Pharmacological interventions, including H2S donors and sirtuin-activating compounds (STACs), promise to improve these pathways synergistically, providing a novel therapeutic approach for neurodegenerative conditions. This suggests that maintaining gut microbiota diversity and promoting optimal H2S levels can have far-reaching effects on brain health. Full article
(This article belongs to the Special Issue Sirtuins as Novel Biological Targets for Pharmacological Intervention in Physiology and Pathology)
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