[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
You seem to have javascript disabled. Please note that many of the page functionalities won't work as expected without javascript enabled.
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
6.1
4.3
Journals
Pharmaceuticals
Special Issues
Sirtuins as Novel Biological Targets for Pharmacological Intervention in Physiology...
share announcement

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: closed (25 January 2025) | Viewed by 13152

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
Special Issues, Collections and Topics in MDPI journals
Dr. Marco Tafani

E-Mail Website
Guest Editor
Department of Experimental Medicine, Sapienza University, 00161 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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

Benefits of Publishing in a Special Issue

  • Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue policies can be found here.

Published Papers (7 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review, Other

22 pages, 2878 KiB  
Article
Protective Role and Enhanced Intracellular Uptake of Curcumin in Retinal Cells Using Self-Emulsifying Drug Delivery Systems (SNEDDS)
by Elide Zingale, Sebastiano Masuzzo, Tatu Lajunen, Mika Reinisalo, Jarkko Rautio, Valeria Consoli, Agata Grazia D’Amico, Luca Vanella and Rosario Pignatello
Pharmaceuticals 2025, 18(2), 265; https://doi.org/10.3390/ph18020265 - 17 Feb 2025
Viewed by 407
Abstract
Background: Sirtuin-1 (SIRT1), a histone deacetylase enzyme expressed in ocular tissues with intracellular localization, plays a critical protective role against various degenerative ocular diseases. The link between reduced SIRT1 levels and diabetic retinopathy (DR) has prompted the exploration of natural therapeutic compounds that [...] Read more.
Background: Sirtuin-1 (SIRT1), a histone deacetylase enzyme expressed in ocular tissues with intracellular localization, plays a critical protective role against various degenerative ocular diseases. The link between reduced SIRT1 levels and diabetic retinopathy (DR) has prompted the exploration of natural therapeutic compounds that act as SIRT1 agonists. Curcumin (CUR), which has been shown to upregulate SIRT1 expression, is one such promising compound. However, effective delivery of CUR to the deeper ocular tissues, particularly the retina, remains a challenge due to its poor solubility and limited ocular penetration following topical administration. Within this context, the development of self-nanoemulsifying drug delivery systems (SNEDDS) for CUR topical ocular delivery represents a novel approach. Methods: In accordance with our prior research, optimized SNEDDS loaded with CUR were developed and characterized post-reconstitution with simulated tear fluid (STF) at a 1:10 ratio, showing suitable physicochemical and technological parameters for ocular delivery. Results: An entrapment efficiency (EE%) of approximately 99% and an absence of drug precipitation were noticed upon resuspension with STF. CUR-SNEDDS resulted in a better stability and release profile than free CUR under simulated ocular conditions. In vitro analysis of mucoadhesive properties revealed that CUR-SNEDDS, modified with a cationic lipid, demonstrated enhanced interactions with mucin, indicating the potential for improved ocular retention. Cytotoxicity tests demonstrated that CUR-SNEDDS did not affect the viability of human corneal epithelial (HCE) cells up to concentrations of 3 μM and displayed superior antioxidant activity compared to free CUR in an oxidative stress model using retinal pigment epithelial (ARPE-19) cells exposed to hydroquinone (HQ). Cell uptake studies confirmed an enhanced accumulation of CUR within the retinal cells following exposure to CUR-SNEDDS compared to neat CUR. CUR-SNEDDS, at lower concentrations, were found to effectively induce SIRT1 expression. Conclusions: The cytocompatibility, antioxidant properties, and enhanced cellular uptake suggest that these developed systems hold promise as formulations for the delivery of CUR to the retina. Full article
(This article belongs to the Special Issue Sirtuins as Novel Biological Targets for Pharmacological Intervention in Physiology and Pathology)
►▼ Show Figures

Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Solubility (mg/mL) of CUR in different vehicles (oils and surfactants).</p> Full article ">Figure 2
<p>(<b>A</b>) Macroscopic visualization of AC and AC after reconstitution 1:10 in STF and (<b>B</b>) microscopic morphological analysis of AC after reconstitution (1:100,000 with PBS) by Zeta view analysis.</p> Full article ">Figure 3
<p>Mucoadhesion strength of A+ in contact with mucin dispersion in terms of (<b>A</b>) absorbance and (<b>B</b>) zeta potential. Each bar represents the mean value ±SD; <span class="html-italic">n</span> = 3. Statistical analysis was performed by 2-way ANOVA (**** <span class="html-italic">p</span> &lt; 0.0001 vs. A+ at different time points).</p> Full article ">Figure 4
<p>In vitro CUR release from CUR-SNEDDS (AC) compared to free CUR investigated for 48 h.</p> Full article ">Figure 5
<p>Stability investigation of native CUR(C) in PBS and CURC-loaded SNEDDS (AC) at different conditions of exposition: 4 °C, 25 °C light and dark, and 40 °C. (Statistical analysis was made with Tukey’s multiple comparisons test **** <span class="html-italic">p</span> &lt; 0.0001 vs. C at different exposition conditions).</p> Full article ">Figure 6
<p>Evaluation of cytotoxicity of CUR-SNEDDS loaded with different concentrations of CUR (0.1–5 μM), respectively, on the (<b>A</b>) HCE and (<b>B</b>) ARPE-19 cell lines (**** <span class="html-italic">p</span> &lt; 0.0001 vs. control, *** <span class="html-italic">p</span> &lt; 0.0005 vs. control).</p> Full article ">Figure 7
<p>The (<b>A</b>) internalization and uptake of CUR (central column): 0.1 µM; 0.5 µM; 1 µM; 2 µM and CUR-loaded SNEDDS (right column): AC 0.1 µM; AC 0.5 µM; AC 1 µM; AC 2 µM into ARPE-19. White arrows point out CUR nanocarriers poutside cells. (<b>B</b>) Quantitative evaluation of recovered CUR in medium and not internalized after uptake test (**** <span class="html-italic">p</span> &lt; 0.0001 vs. C). (<b>C</b>) Assessment of SIRT1 protein expression levels following AC treatment for 24 h at selected concentrations of 0.1 and 0.5 µM (** <span class="html-italic">p</span> &lt; 0.005 vs. CTRL).</p> Full article ">Figure 8
<p>Evaluation of HQ (600 μM) effect on ARPE-19 cell viability and recovery with co-treatment of HQ and SNEDDS loaded with different concentrations of CUR (0.1–2 μM) (**** <span class="html-italic">p</span> &lt; 0.0001 vs. HQ; *** <span class="html-italic">p</span> &lt; 0.0005 vs. HQ).</p> Full article ">
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 1463
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)
►▼ Show Figures

Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>SIRT3 overexpression increases cell survival of MDA-MB-231 in buffered and unbuffered medium. (<b>A</b>) MDA-MB-231 proliferation at different time points in buffered media at a pHe of 7.4. (<b>B</b>) MDA-MB-231 proliferation at different time points in buffered media at a pHe of 6.8. (<b>C</b>) Proliferation rate of MDA-MB-231 clones in unbuffered media at a pHe of 7.4 at different time points. (<b>D</b>) Proliferation rate of MDA-MB-231 clones in unbuffered media at a pHe of 6.8 at different time points. (<b>E</b>) Cell viability of MDA-MB-231 scramble, o/e SIRT3, and sh SIRT3 after 2 h, 4 h, 6 h, 8 h, 17 h, 24 h, 48 h, and 72 h in unbuffered media at a pHe of 7.4 and 6.8. Data are represented as mean ± SD. * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, and *** <span class="html-italic">p</span> &lt; 0.001. (<b>F</b>) Images of MDA-MB-231 cells and clones after 2 and 24 h in unbuffered media, pH 6.8 taken at 20× magnification.</p> Full article ">Figure 2
<p>SIRT3 overexpression increases cell survival of HEK293 in buffered and unbuffered medium. (<b>A</b>) HEK293 proliferation at different time points in buffered media at a pHe of 7.4. (<b>B</b>) HEK293 proliferation at different time points in buffered media at a pHe of 6.8. (<b>C</b>) Proliferation rate of HEK293 clones in unbuffered media at a pHe of 7.4 at different time points. (<b>D</b>) Proliferation rate of HEK293 clones in unbuffered media at a pHe of 6.8 at different time points. (<b>E</b>) Cell viability of HEK293 scramble, o/e SIRT3, and sh SIRT3 after 4 h, 8 h, 17 h, 24 h, 48 h, and 72 h in unbuffered media at a pHe of 7.4 and 6.8. Data are represented as mean ± SD. * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, and *** <span class="html-italic">p</span> &lt; 0.001. (<b>F</b>) Images of HEK293 cells and clones after 2 and 24 h in unbuffered media, pH 6.8 taken at 10× magnification.</p> Full article ">Figure 3
<p>Modulation of SIRT3 and CAVB in MDA-MB-231 during treatment with acidic medium. (<b>A</b>) Relative mRNA levels of SIRT3 in MDA-MB-231 clones after different time points of treatments in unbuffered medium at a pHe of 7.4 and 6.8. (<b>B</b>) Western blot showing SIRT3 expression in MDA-MB-231 clones after 2 h in unbuffered media at a pHe of 7.4 and 6.8. Prohibitin (PHB) was used as a mitochondrial loading control. Densitometric analysis of SIRT3 protein expression obtained by Western blot after treating MDA-MB-231 clones for 2 h with unbuffered medium at a pHe of 7.4 and 6.8. (<b>C</b>) Western blot showing SIRT3 expression in MDA-MB-231 clones after 24 h of treatment with unbuffered media at a pHe of 7.4 and 6.8. Prohibitin was used as a mitochondrial loading control. Densitometric analysis of SIRT3 protein expression obtained by Western blot after treating MDA-MB-231 clones for 24 h with unbuffered medium at a pHe of 7.4 and 6.8. (<b>D</b>) Western blot showing SIRT3 expression in MDA-MB-231 clones after 48 h of treatment with unbuffered media at a pHe of 7.4 and 6.8. Prohibitin was used as a mitochondrial loading control. Densitometric analysis of SIRT3 protein expression obtained by Western blot after treating MDA-MB-231 clones for 48 h with unbuffered medium at a pHe of 7.4 and 6.8. (<b>E</b>) Western blot showing SIRT3 expression in MDA-MB-231 clones after 72 h of treatment with unbuffered media at a pHe of 7.4 and 6.8. Prohibitin was used as a mitochondrial loading control. Densitometric analysis of SIRT3 protein expression obtained by Western blot after treating MDA-MB-231 clones for 72 h with unbuffered medium at a pHe of 7.4 and 6.8. (<b>F</b>) Relative mRNA levels of CAVB in MDA-MB-231 clones after 2, 24, 48, and 72 h of unbuffered medium at a pHe of 7.4 and 6.8. (<b>G</b>) Western blot showing CAVB expression in MDA-MB-231 clones after 2 h of treatment with unbuffered media at a pHe of 7.4 and 6.8. Prohibitin (PHB) was used as a mitochondrial loading control. Densitometric analysis of CAVB protein expression obtained by Western blot after treating MDA-MB-231 clones for 2 h with unbuffered medium at a pHe of 7.4 and 6.8. (<b>H</b>) Western blot showing CAVB expression in MDA-MB-231 clones after 24 h of treatment with unbuffered media at a pHe of 7.4 and 6.8. Prohibitin was used as a mitochondrial loading control. Densitometric analysis of CAVB protein expression obtained by Western blot after treating MDA-MB-231 clones for 24 h with unbuffered medium at a pHe of 7.4 and 6.8. (<b>I</b>) Western blot showing CAVB expression in MDA-MB-231 clones after 48 h of treatment with unbuffered media at a pHe of 7.4 and 6.8. Prohibitin (PHB) was used as a mitochondrial loading control. Densitometric analysis of CAVB protein expression obtained by Western blot after treating MDA-MB-231 clones for 48 h with unbuffered medium at a pHe of 7.4 and 6.8. (<b>J</b>) Western blot showing CAVB expression in MDA-MB-231 clones after 72 h of treatment with unbuffered media at a pHe of 7.4 and 6.8. Prohibitin (PHB) was used as mitochondrial loading control. Densitometric analysis of CAVB protein expression obtained by Western blot after treating MDA-MB-231 clones for 72 h with unbuffered medium at a pHe of 7.4 and 6.8. Data are represented as mean ± SD. * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, and *** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 4
<p>Modulation of SIRT3 and CAVB in HEK293 during treatment with acidic medium. (<b>A</b>) Relative mRNA levels of SIRT3 in HEK293 clones after 6, 24, and 48 h of unbuffered medium at a pHe of 7.4 and 6.8. (<b>B</b>) Western blot showing SIRT3 expression in HEK293 clones after 6 h of treatment with unbuffered media at a pHe of 7.4 and 6.8. Prohibitin (PHB) was used as a mitochondrial loading control. Densitometric analysis of SIRT3 protein expression obtained by Western blot after treating HEK293 clones for 6 h with unbuffered medium at a pHe of 7.4 and 6.8. (<b>C</b>) Western blot showing SIRT3 expression in HEK293 clones after 24 h of treatment with unbuffered media at a pHe of 7.4 and 6.8. Prohibitin (PHB) was used as a mitochondrial loading control. Densitometric analysis of SIRT3 protein expression obtained by Western blot after treating HEK293 clones for 24 h with unbuffered medium at a pHe of 7.4 and 6.8. (<b>D</b>) Western blot showing SIRT3 expression in HEK293 clones after 48 h of treatment with unbuffered media at a pHe of 7.4 and 6.8. Prohibitin (PHB) was used as a mitochondrial loading control. Densitometric analysis of SIRT3 protein expression obtained by Western blot after treating HEK293 clones for 48 h with unbuffered medium at a pHe of 7.4 and 6.8. (<b>E</b>) Relative mRNA levels of CAVB in HEK293 clones after 6, 24, and 48 h of unbuffered medium at a pHe of 7.4 and 6.8. (<b>F</b>) Western blot showing CAVB expression in HEK293 clones after 6 h of treatment with unbuffered media at a pHe of 7.4 and 6.8. Prohibitin (PHB) was used as a mitochondrial loading control. Densitometric analysis of CAVB protein expression obtained by Western blot after treating HEK293 clones for 6 h with unbuffered medium at a pHe of 7.4 and 6.8. (<b>G</b>) Western blot showing CAVB expression in HEK293 clones after 24 h of treatment with unbuffered media at a pHe of 7.4 and 6.8. Prohibitin (PHB) was used as a mitochondrial loading control. Densitometric analysis of CAVB protein expression obtained by Western blot after treating HEK293 clones for 24 h with unbuffered medium at a pHe of 7.4 and 6.8. (<b>H</b>) Western blot showing CAVB expression in HEK293 clones after 48 h of treatment with unbuffered media at a pHe of 7.4 and 6.8. Prohibitin (PHB) was used as a mitochondrial loading control. Densitometric analysis of CAVB protein expression obtained by Western blot after treating HEK293 clones for 48 h with unbuffered medium at a pHe of 7.4 and 6.8. Student’s <span class="html-italic">t</span>-test was used to determine the statistical significance. (<b>I</b>) CAVB activity after 6, 24, and 48 h treatment, measured as the time required for the CO<sub>2</sub> in the Maren buffer to dissolve. Two-way ANOVA with the Bonferroni test was used in (<b>I</b>). Data are represented as mean ± SD. * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01. *, significantly different from scrambled cells. <span>$</span>, #, significantly different from the other two groups.</p> Full article ">Figure 5
<p>SIRT3 interacts with CAVB. (<b>A</b>) Mitochondrial extract from MDA-MB-231 scrambled cells was immunoprecipitated with an anti-CAVB antibody, electrophoresed on an SDS-polyacrylamide gel, and immunoblotted with an anti-SIRT3 antibody. (<b>B</b>) Proximity ligation assay of SIRT3 and CAVB; the interactions are shown as red dots, and nuclei are stained with Sytox green. Images were taken at 60×, and the scale bar is indicated in the figure. (<b>C</b>) The number of interactions (red dots in the confocal images) for scramble, o/e SIRT3, and sh SIRT3 cells is reported as means ± standard deviations. ** <span class="html-italic">p</span> &lt; 0.01, and *** <span class="html-italic">p</span> &lt; 0.001. Fifty cells for each group were analyzed using Image J software v1.51 (NIH, Bethesda, MD, USA).</p> Full article ">Figure 6
<p>Low pHe increases SIRT3 and CAVB but not GDH activities. (<b>A</b>) SIRT3 activity in MDA-MB 231 scramble, o/e SIRT3, and sh SIRT3 cells. (<b>B</b>) CAVB activity is measured as the time required for the CO<sub>2</sub> in the Maren buffer to dissolve. (<b>C</b>) GDH activity in MDA-MB 231 scrambled SIRT3-overexpressing and SIRT3-silenced. Data are represented as mean ± SD. The bar charts in (<b>A</b>–<b>C</b>) were compared by a Two-way ANOVA with the Bonferroni test. Data are represented as mean ± SD. * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01. *, significantly different from scrambled cells. #, §, &amp; significantly different from the other two groups.</p> Full article ">Figure 7
<p>Decreased SIRT3 expression increases autophagy in MDA-MB-231 and HEK293 cells. (<b>A</b>) LC3I, LC3II, ATG5, and ATG7 protein expression was analyzed in MDA-MB-231 clones after treatment with unbuffered medium at a pHe of 7.4 and 6.8 for 6 h. During the last two hours, cells were either left untreated or treated with Bafilomicyn A1 (BAF) at 100 nM. Actin was used as a loading control. (<b>B</b>) Densitometric analysis of LC3II/LC3I ratio and ATG5 and ATG7 protein expression obtained by Western blot as in (<b>A</b>). Data are represented as mean ± SD. * <span class="html-italic">p</span>&lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, and *** <span class="html-italic">p</span> &lt; 0.001. (<b>C</b>) HEK293 scramble, o/e SIRT3, and sh SIRT3 cells were grown in unbuffered medium at a pHe of 7.4 or 6.8 for 6 h in the presence or absence of Bafilomycin A1 for the last two hours. LC3I, LC3II, ATG5, and ATG7 protein expression was analyzed by Western blot. (<b>D</b>) Densitometric analysis of protein expression as in (<b>C</b>). Data are represented as mean ± SD. * <span class="html-italic">p</span>&lt; 0.05.</p> Full article ">Figure 8
<p>Morphology and autophagosome formation in MDA-MB-231 scramble, o/e SIRT3, and sh SIRT3 cells. (<b>A</b>) MDA-MB-231 scramble, o/e SIRT3 and sh SIRT3 cells were grown in unbuffered medium at pHe 7.4 or 6.8 for 8 h. Afterward, cells were analyzed by transmission electron microscope (TEM). (<b>B</b>) High magnification images of MDA-MB-231 clones by TEM. N = nucleus, M = mitochondria, ER = Endoplasmic Reticulum, E = Exosome, MVB = Multi vesicular body, AV = autophagic vacuole. Scale bar = 10 µm.</p> Full article ">Figure 9
<p>Chemical structure of SIRT3 activator MC2791.</p> Full article ">

Review

Jump to: Research, Other

27 pages, 837 KiB  
Review
Sirtuins and Their Implications in the Physiopathology of Gestational Diabetes Mellitus
by Katarzyna Zgutka, Marta Tkacz, Marta Grabowska, Wioletta Mikołajek-Bedner and Maciej Tarnowski
Pharmaceuticals 2025, 18(1), 41; https://doi.org/10.3390/ph18010041 - 1 Jan 2025
Viewed by 988
Abstract
Gestational diabetes mellitus (GDM) imposes serious short- and long-term health problems for the mother and her child. An effective therapeutic that can reduce the incidence of GDM and improve long-term outcomes is a major research priority and is very important for public health. [...] Read more.
Gestational diabetes mellitus (GDM) imposes serious short- and long-term health problems for the mother and her child. An effective therapeutic that can reduce the incidence of GDM and improve long-term outcomes is a major research priority and is very important for public health. Unfortunately, despite numerous studies, the molecular mechanisms underlying GDM are not fully defined and require further study. Chronic low-grade inflammation, oxidative stress, and insulin resistance are central features of pregnancies complicated by GDM. There is evidence of the involvement of sirtuins, which are NAD+-dependent histone deacetylases, in energy metabolism and inflammation. Taking these facts into consideration, the role of sirtuins in the pathomechanism of GDM will be discussed. Full article
(This article belongs to the Special Issue Sirtuins as Novel Biological Targets for Pharmacological Intervention in Physiology and Pathology)
►▼ Show Figures

Figure 1

Figure 1
<p>Overview and summary of pathological features, symptoms, and diagnostic strategy of gestational diabetes mellitus.</p> Full article ">
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
Cited by 2 | Viewed by 2017
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)
►▼ Show Figures

Figure 1

Figure 1
<p>Endothelial silent information regulator 1 (SIRT1) exerts microcirculatory vasoprotective effects by upregulating antioxidant proteins, mitochondrial function, mitophagy, microcirculatory nitric oxide (NO) bioavailability, cholesterol export, and tight junction protein expression while suppressing inflammation and endothelial glycocalyx shedding, alongside optimizing autophagic flux.</p> Full article ">Figure 2
<p>SIRT1 suppresses HIF-1α activity during hypoxia to prevent pathological angiogenesis. (<b>a</b>) Under normoxic conditions, hypoxia-inducible factor-1a (HIF-1α) is degraded via the ubiquitin-proteasome pathway, while Notch signaling is inhibited by SIRT1 via promoting Notch sensitivity to Jagged1 and deacetylating the Notch intracellular domain, which promotes healthy angiogenesis. (<b>b</b>) Under hypoxic conditions, acetylated HIF-1α leads to complete recruitment of p300 to the HIF-1α-HIF-1β complex, resulting in a high activity state on the hypoxia response element (HRE) and drastic upregulation of vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFR) to induce pathogenic angiogenesis. (<b>c</b>) SIRT1 upregulation during hypoxia deacetylates HIF-1a, blocking the recruitment of p300 and reducing its activity on the HRE. In addition, SIRT1 promotes healthy angiogenesis by inhibiting Notch signaling.</p> Full article ">
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 1809
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)
►▼ Show Figures

Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Summary of SIRT2-mediated deacylation. SIRT2 KDAC consumes co-factor NAD<sup>+</sup> to deacylate a substrate protein, producing the deacylated product protein, nicotinamide, and 2′-<span class="html-italic">O</span>-ADP-ribose (2’-<span class="html-italic">O</span>-AADPR). R in the substrate protein stands for the acyl chain that can be of varying length, degree of saturation, and charge, along with other chemically diverse substituents.</p> Full article ">Figure 2
<p>Structures of SIRT2 modulators bound within the SIRT2 active site. (<b>a</b>) Binding pockets within the SIRT2 active site (demarcated by a purple cloud) accommodate NAD<sup>+</sup> (purple carbon atoms, PDB ID 4X3P) as follows: the A pocket binds the adenine ring, the B pocket binds the diphosphate group, and the C pocket binds the nicotinamide ring (orange carbon atoms, PDB ID 6L71). The extended C pocket (EC pocket) binds inhibitors, such as FLS-359 and SirReal2, and acetyl peptides (acetyl-lysine peptide, green carbon atoms, PDB ID 4RMH; myristoyl-lysine peptide, cyan carbon atoms, PDB ID 4X3P). The peptide-binding channel is a solvent-exposed, hydrophobic tunnel that extends from the protein surface to the catalytic site, accommodating acyl lysine residues within substrate proteins. (<b>b</b>–<b>e</b>) The acetyl peptide (green carbon atoms) was superimposed on the structures, as well as the portion of NAD<sup>+</sup> sitting within the C pocket (purple carbon atoms), except for (<b>b</b>) where the solved crystal structure included NAD<sup>+</sup>. (<b>b</b>) Crystal structure of SirReal2 (PDB: 4RMG) and NAD<sup>+</sup> bound to SIRT2. (<b>c</b>) Crystal structure of FLS-359 bound to SIRT2 (PDB ID 7T1D). (<b>d</b>,<b>e</b>) To dock modulators into SIRT2, crystal structures of the target proteins were retrieved from the Protein Data Bank (PDB) and prepared using the Schrodinger Maestro software (Release 2024-2, Version 14.0). Hydrogens were added, missing residues were added, and the protein was optimized by minimizing its energy through the OPLS_2005 force field in the Maestro protein preparation module. The ligand structures were prepared and the energy was minimized prior to docking using the Maestro Ligprep module. Docking simulations were performed using the Schrodinger Glide module (Release 2024-2). Glide’s extra precision (XP) mode was employed to generate docking poses, with a grid box centered on the FLS-359 ligand (PDB ID 7T1D). Post-docking minimization was performed on all poses generated from the Glide docking. (<b>d</b>) Lowest energy docking model of AGK2 bound to SIRT2. (<b>e</b>) Lowest energy docking model of sirtinol bound to SIRT2.</p> Full article ">Figure 3
<p>SIRT2.1 modulation of the AKT pathway during infection. AKT is activated by the phosphorylation of S473 via the PI3K pathway. SIRT2.1 is stimulated to bind to AKT via AMPK-mediated phosphorylation at SIRT2.1 T101. SIRT2.1 T101P binds to AKT through its PH and catalytic domains, and presumably deacylates a target lysine within AKT to stimulate maximal interaction with PI3K, leading to phosphorylation and activation of AKT. Activated AKT potentially has many consequences in the cytoplasm, including induction of anti-apoptotic Bcl-2 family members such as Mcl-1, Bcl-xL, and XIAP. The PP2C family members PPM1A and PPM1B, which are present in both cytoplasm and the nucleus, can dephosphylate SIRT2.1 S25, which then accumulates in the nucleus. Nuclear SIRT2 then deacetylates H3K18 and alters the cell’s transcriptome to favor growth of the pathogen.</p> Full article ">
26 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
Cited by 1 | Viewed by 1859
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)
►▼ Show Figures

Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Flow diagram representing the screening process for articles investigating sirtuins in hearing loss. Created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p> Full article ">Figure 2
<p>Sirtuin and hearing loss research over time by the number of publications in each sirtuin paralog * Up to May 2024.</p> Full article ">Figure 3
<p>Potential roles of sirtuins in hearing loss. SIRT1 and SIRT3 can modulate ROS in the pathologies leading to hearing loss, evidenced by studies in cell cultures and animal models. The major mechanism is the inhibition of intrinsic apoptosis pathway in IHCs, OHCs, and SGNs. Autophagy and mitophagy, which are triggered by pathways involving SIRT1 and SIRT3, can keep the cells under the threshold of caspase-3 activity sufficient for triggering apoptosis, providing protective roles. Inhibition of SIRT2 may be beneficial in NIHL. It is unclear if SIRT4, SIRT5, and SIRT6 are involved in hearing loss or hearing protection. Created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p> Full article ">

Other

Jump to: Research, Review

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
Cited by 1 | Viewed by 2591
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)
►▼ Show Figures

Figure 1

Figure 1
<p>The PRISMA flow diagram used to illustrate the flow of information process.</p> Full article ">Figure 2
<p>Pathways and mechanisms through which the gut microbiota, especially sulfate-reducing bacteria, produce H<sub>2</sub>S—steps involving sulfur compounds, such as cysteine and methionine metabolism, to clarify the microbial role in H<sub>2</sub>S synthesis. Gut dysbiosis can significantly alter H<sub>2</sub>S production, leading to pathological outcomes. An overgrowth of SRB can result in excessive H<sub>2</sub>S, impairing gut barrier function and contributing to systemic inflammation, which can induce neuroinflammation. The impact of dysbiosis on H<sub>2</sub>S production extends to its effects on the gut-brain axis, where a disrupted microbial balance influences neuroimmune and neuroinflammatory pathways. This disruption can enhance the risk of neurodegenerative diseases by increasing systemic inflammation and impairing mitochondrial function, highlighting the importance of maintaining a balanced gut microbiota for neurological health. Chronic systemic inflammation, fueled by elevated H<sub>2</sub>S levels, has been implicated in the pathogenesis of neurodegenerative disorders like AD and PD [<a href="#B32-pharmaceuticals-17-01480" class="html-bibr">32</a>].</p> Full article ">Figure 3
<p>Mechanistic model of the H<sub>2</sub>S–gut microbiota–sirtuins axis involved in neuroprotection.</p> Full article ">
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-7
Back to TopTop