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Kojja V, Kumar D, Kalavagunta PK, Bhukya B, Tangutur AD, Nayak PK. 2-(Diarylalkyl)aminobenzothiazole derivatives induce autophagy and apoptotic death through SIRT inhibition and P53 activation In MCF7 breast cancer cells. Comput Biol Chem 2025; 116:108395. [PMID: 39987744 DOI: 10.1016/j.compbiolchem.2025.108395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 02/11/2025] [Accepted: 02/17/2025] [Indexed: 02/25/2025]
Abstract
Sirtuins (SIRTs) are multifunctional proteins that exhibit a wide range of substrate preferences and cellular localizations. They are reliant on NAD+ and are essential for the regulation of several cellular functions. The SIRT proteins play important role towards tumor survival and resistance mechanisms in tumor cells. Therefore, molecules targeting SIRT proteins gained significant recognition in cancer research. In this work, we explored the anticancer property, potential and mode of action of 2-(diarylalkyl)aminobenzothiazole derivatives on MCF7 human breast cancer cells. Our studies established that 2-(diarylalkyl)aminobenzothiazole derivatives 1-((6-chlorobenzo[d]thiazol-2-ylamino)(3,4-dichlorophenyl)methyl)naphthalen-2-ol (7ab) and 1-((6-chlorobenzo[d]thiazol-2-ylamino)(4-bromophenyl)methyl)naphthalen-2-ol (7ba) treatment in a dose dependent manner drastically lowered the cell proliferation in MCF7 cells and the IC50 values of 7ab and 7ba was found to be 11.4 µM and 9.6 µM at 24 hr in these cells. Docking and molecular dynamic simulation studies further revealed that 7ab and 7ba show significant binding with SIRT1 protein. Consistently, treatment with 7ab and 7ba reduced the expression levels of SIRT1 protein while increasing acetylation of p53, a known SIRT protein target in MCF-7 cells. We observed that SIRT1inhibition was associated with activation of p53, an essential protein for apoptotic cell death, in MCF-7 cell lines. Furthermore, 7ab and 7ba treatment induced LC3-II expression and vacuole formation in the cytoplasm leading to autophagic cell death. Our findings together reveal the plausible cellular targets and specificity of these new small molecules as SIRT inhibitors, which increase p53 acetylation and suppress the proliferation of MCF-7 human breast cancer cells by triggering autophagic and apoptotic cell death.
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Affiliation(s)
- Venkateswarlu Kojja
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, India
| | - Dinesh Kumar
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana State 500007, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh 201002, India
| | - Praveen Kumar Kalavagunta
- Crop Protection Chemicals Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana State 500007, India
| | - Bhima Bhukya
- Centre for Microbial and Fermentation Technology, Department of Microbiology, University College of Science, Osmania University, Hyderabad, Telangana State 500007, India
| | - Anjana Devi Tangutur
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana State 500007, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh 201002, India.
| | - Prasanta Kumar Nayak
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, India.
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Peng J, Zou J, Zhao J, Chen A. Genome-wide identification and expression analysis of the SIRT gene family in Nile tilapia (Oreochromis niloticus). COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2025; 54:101425. [PMID: 39889587 DOI: 10.1016/j.cbd.2025.101425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 01/07/2025] [Accepted: 01/19/2025] [Indexed: 02/03/2025]
Abstract
The sirtuin (SIRT) family is a nicotine adenine dinucleotide (NAD+)-dependent class III histone deacetylase, which is widely involved in numerous physiological processes of organisms, such as metabolism, reproduction, and immunity. Here, based on the genomics database, comprehensive analysis of the SIRT gene in Nile tilapia (Oreochromis niloticus) was analyzed using bioinformatics methods and quantitative real-time PCR. The nine SIRT genes of O. niloticus (OnSIRT) were distributed on eight chromosomes. The OnSIRTs contain distinct sequences from 3 exons in OnSIRT4 to 16 exons in OnSIRT2, however, they share conserved domains and protein motifs. Phylogenetic analysis shows that the OnSIRTs belong to four subfamilies and are highly conserved in teleosts, and evolution is characterized primarily by purification selection. The OnSIRT genes showed diversified expression patterns in fourteen tissues of O. niloticus. OnSIRT2, OnSIRT3, OnSIRT3.2, OnSIRT6, and OnSIRT7 are mainly expressed in the gonads, especially in the ovary. OnSIRT1 and OnSIRT4 are mainly expressed in the kidney. OnSIRT5a is mainly expressed in the stomach, however, OnSIRT5b is mainly expressed in the liver and spleen. The results of this study provide a basis information for further exploration of the function and molecular mechanism of the SIRT gene family in teleosts.
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Affiliation(s)
- Jiabao Peng
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai 201306, China; Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China
| | - Jiaqi Zou
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai 201306, China; Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China
| | - Jinliang Zhao
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai 201306, China; Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai 201306, China; Shanghai Collaborative Innovation for Aquatic Animal Genetics and Breeding, Shanghai Ocean University, Shanghai 201306, China.
| | - Aqin Chen
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai 201306, China; Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China.
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Zaky HS, El-Said NT, Aboutaleb AS, Allam A, Mansour M, Ahmed HI, Abdel-Sattar SA. Mito-TEMPO Mitigates Fibromyalgia Induced by Reserpine in Rats: Orchestration Between SIRT1, Mitochondrial Dynamics, Endoplasmic Reticulum and miRNA-320. Neurochem Res 2025; 50:172. [PMID: 40434586 PMCID: PMC12119751 DOI: 10.1007/s11064-025-04424-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 04/28/2025] [Accepted: 05/12/2025] [Indexed: 05/29/2025]
Abstract
Fibromyalgia (FM) is a chronic disorder that lacks both well-defined underlying causes and effective treatments. Mito-TEMPO (MIT) is a mitochondrial-specific antioxidant that has demonstrated benefits in many cancerous, renal, cardiovascular, and neurodegenerative disorders. However, the therapeutic effect of MIT on FM remains ambiguous. The objective of the current work is to illuminate the use of MIT for FM and its prospective mechanisms. Here, we used the FM rat model induced by three days of subcutaneous reserpine injection (1 mg/kg) and examined the role of MIT on SIRT1 activation and other implicated molecular pathways. Behavioral tests showed that MIT (0.7 mg/kg) can effectively alleviate the locomotor, nociceptive, and depressive-like behaviors in reserpinized rats, an effect that simultaneously reconciles the balance of monoamines in the rat brain. Western blot analysis showed that MIT up-regulates SIRT1 and improves the expression of mitochondrial dynamics proteins (DRP1 and OPA1) and the endoplasmic reticulum protein (CHOP). Furthermore, MIT treatment significantly enhanced the SOD and CAT activities and decreased the brain contents of NF-κB, TNF-α, and BAX, but significantly enriching the Bcl-2 content. Lastly, MIT treatment significantly reduced the genetic expression of miRNA-320 following RES treatment. All the measured parameters showed a significant correlation with SIRT1 expression. Our results suggest that MIT provides antioxidant, anti-apoptotic, and anti-inflammatory impacts on the FM rat model, with proposed mechanisms involved activating the SIRT1 pathway to regulate mitochondrial dynamics, endoplasmic reticulum stress, as well as miRNA-320. Thus, MIT has the potential to be an effectual drug candidate for FM treatment.
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Affiliation(s)
- Heba S Zaky
- Pharmacology and Toxicology Department, Faculty of Pharmacy for Girls, Al-Azhar University, Nasr City, Cairo, P.N.11754, Egypt
| | - Nermin T El-Said
- Pharmacology and Toxicology Department, Faculty of Pharmacy for Girls, Al-Azhar University, Nasr City, Cairo, P.N.11754, Egypt
| | - Amany S Aboutaleb
- Pharmacology and Toxicology Department, Faculty of Pharmacy for Girls, Al-Azhar University, Nasr City, Cairo, P.N.11754, Egypt
| | - Albatoul Allam
- Pharmacology and Toxicology Department, Faculty of Pharmacy for Girls, Al-Azhar University, Nasr City, Cairo, P.N.11754, Egypt.
| | - Mona Mansour
- Pharmacology and Toxicology Department, Faculty of Pharmacy for Girls, Al-Azhar University, Nasr City, Cairo, P.N.11754, Egypt
| | - Hebatalla I Ahmed
- Pharmacology and Toxicology Department, Faculty of Pharmacy for Girls, Al-Azhar University, Nasr City, Cairo, P.N.11754, Egypt
| | - Somaia A Abdel-Sattar
- Pharmacology and Toxicology Department, Faculty of Pharmacy for Girls, Al-Azhar University, Nasr City, Cairo, P.N.11754, Egypt
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El-Haddad ME, El-Refaie WM, Hammad GO, El-Massik MA. Intra-articular metformin-curcumin cationic PLGA nanoparticles rejuvenate articular structure in MIA induced osteoarthritis model via modulating the crosstalk between miR93, TNFAIP3/TLR/NF-κB and AMPK/SIRT1 trajectories. Int J Biol Macromol 2025; 315:144482. [PMID: 40412692 DOI: 10.1016/j.ijbiomac.2025.144482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Revised: 04/28/2025] [Accepted: 05/20/2025] [Indexed: 05/27/2025]
Abstract
Osteoarthritis (OA), a degenerative bone disease, restrains patient's productivity and quality of life. Herein, the potential of uncoated and hyaluronic acid (HA)-coated cationic - PLGA (cPL) nanoparticles loaded with metformin (MT) and curcumin (Cu) was investigated for IA administration for the first time. Optimized MT-Cu-cPL2 showed particle size 266.2 ± 2.35 nm, zeta potential +13.6 ± 0.6 mV; entrapment efficiency of 42.56 % ± 0.04 and 93.65 % ± 0.017 for MT and Cu, respectively. Optimized HA-MT-Cu-cPL4 displayed particle size 254.1 ± 3.96 nm, zeta potential -21.6 ± 0.4 mV; and entrapment efficiency of 71.4 % ± 1.06 and 93.2 % ± 0.93 for MT and Cu, respectively. HA-MT-Cu-cPL4 demonstrated a sustained release of MT and Cu over 24 h and stability over 3-months at 4 °C. The IA administration of MT-Cu-cPL2 and HA-MT-Cu-cPL4 to MIA-induced OA rats revealed their significant antiarthritic potential. Treatment with HA-MT-Cu-cPL4 showed the most significant repression of OA advancement due to enhancement of miR-93 and TNFAIP3 knee tissue expression levels that have been correlated to upregulation of AMPK/SIRT1 activity and downstream inhibition of TLR4/NF-κB signaling pathway. The optimized nano-formulations also exhibited anti-edematous, anti-nociceptive, and locomotor-enhancing activity, highlighting the IA MT-Cu combinational therapy as a prosperous approach for management of OA.
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Affiliation(s)
- Mennatallah E El-Haddad
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Pharos University in Alexandria, Egypt
| | - Wessam M El-Refaie
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Pharos University in Alexandria, Egypt.
| | - Ghada O Hammad
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Egypt
| | - Magda A El-Massik
- Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Egypt
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Rana R, Mukherjee R, Mehan S, Khan Z, Das Gupta G, Narula AS. Molecular mechanisms of neuroprotection: The interplay of Klotho, SIRT-1, Nrf2, and HO-1 in neurological health. Behav Brain Res 2025; 485:115545. [PMID: 40120944 DOI: 10.1016/j.bbr.2025.115545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 03/06/2025] [Accepted: 03/16/2025] [Indexed: 03/25/2025]
Abstract
Neurological disorders significantly impair neuronal function and lead to cognitive and motor deficits. This review manuscript explores the therapeutic potential of key proteins-Klotho, SIRT-1, Nrf2, and HO-1-in combating these disorders. Neurological conditions encompass neurotraumatic, neurodegenerative, and neuropsychiatric diseases, all characterized by neuronal loss and dysfunction. The complex functions of Klotho, an anti-aging protein, and SIRT-1, a histone deacetylase, highlight their roles in neuronal survival and neuroprotection through the enhancement of antioxidant defences and the modulation of stress responses. Nrf2 functions as the principal regulator of the antioxidant response, whereas HO-1 facilitates the control of oxidative stress and the resolution of inflammation. Evidence suggests that the interplay between these proteins facilitates neuroprotection by decreasing oxidative damage and promoting cognitive function. The study emphasises the significance of signalling pathways, particularly the Nrf2/HO-1 axis, which are essential in mitigating oxidative stress and inflammation linked to neurodegenerative disorders. Future therapeutic strategies must consider personalized approaches, innovative drug delivery systems, and early intervention to optimize outcomes. This review provides a comprehensive framework for understanding how targeting these pathways can mitigate the burden of neurological disorders, advancing the development of effective interventions for enhancing brain health.
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Affiliation(s)
- Ravi Rana
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India; Affiliated to IK Gujral Punjab Technical University, Jalandhar, Punjab 144603, India
| | - Ritam Mukherjee
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India; Affiliated to IK Gujral Punjab Technical University, Jalandhar, Punjab 144603, India
| | - Sidharth Mehan
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India; Affiliated to IK Gujral Punjab Technical University, Jalandhar, Punjab 144603, India.
| | - Zuber Khan
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India; Affiliated to IK Gujral Punjab Technical University, Jalandhar, Punjab 144603, India
| | - Ghanshyam Das Gupta
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, Punjab, India; Affiliated to IK Gujral Punjab Technical University, Jalandhar, Punjab 144603, India
| | - Acharan S Narula
- Narula Research, LLC, 107 Boulder Bluff, Chapel Hill, NC 27516, USA
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Ruggiero M, Motti ML, Meccariello R, Mazzeo F. Resveratrol and Physical Activity: A Successful Combination for the Maintenance of Health and Wellbeing? Nutrients 2025; 17:837. [PMID: 40077707 PMCID: PMC11902109 DOI: 10.3390/nu17050837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 02/21/2025] [Accepted: 02/24/2025] [Indexed: 03/14/2025] Open
Abstract
Physical exercise is an essential component of human health. In recent years, scientific research has focused on identifying natural compounds and formulating new supplements aimed at enhancing athletic performance, accelerating muscle recovery, and minimizing the damage caused by physical exertion. The use of antioxidants to counteract the formation of reactive oxygen species (ROS) following physical activity (PA) is already a widely adopted practice. Resveratrol (RES), a polyphenol belonging to the stilbene class, is well known for its potent antioxidant activity and anti-inflammatory effects primarily attributed to the activation of sirtuins. RES possesses multiple nutraceutical properties used for the prevention and treatment of inflammatory, cardiovascular, neoplastic, and infectious diseases, thus attracting attention to study its use in combination with physical exercise to promote well-being. Animal trials combining RES and PA have mainly reported improvements in muscle, energy, and cardiovascular functions. The data presented and discussed in this narrative review are from Pubmed, Scopus, and the Human Gene Database (search limited to 2011 to 2025 with the keywords RES, sirtuins, and physical activity altogether or in combination with each other). This review gathers several studies on RES focusing on its nutraceutical properties, epigenetic activities via sirtuins, and the potential benefits of combining RES with PA in maintaining health and well-being based on trials performed first in animals and later in humans. Human studies have been conducted on various populations, including active adults, sedentary individuals, patients with diseases, and elderly individuals. Some studies have confirmed the benefits of RES observed in animal experiments. However, in some cases, no substantial differences were found between RES supplementation and the control group. In conclusion, the benefits of RES on PA reported in the literature are still not fully evident, given the contrasting studies and the still limited number of trials, but both RES and PA are successful tools for the maintenance of health and wellbeing.
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Affiliation(s)
- Mario Ruggiero
- Department of Medical, Human Movement and Well-Being Sciences, University of Naples Parthenope, 80133 Naples, Italy; (M.R.); (M.L.M.); (R.M.)
| | - Maria Letizia Motti
- Department of Medical, Human Movement and Well-Being Sciences, University of Naples Parthenope, 80133 Naples, Italy; (M.R.); (M.L.M.); (R.M.)
| | - Rosaria Meccariello
- Department of Medical, Human Movement and Well-Being Sciences, University of Naples Parthenope, 80133 Naples, Italy; (M.R.); (M.L.M.); (R.M.)
| | - Filomena Mazzeo
- Department of Economics, Law, Cybersecurity and Sports Sciences, University of Naples Parthenope, 80035 Nola, Italy
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Li J, Cui S, Li Y, Zhang C, Chang C, Jian F. Sirtuin1 in Spinal Cord Injury: Regulatory Mechanisms, Microenvironment Remodeling and Therapeutic Potential. CNS Neurosci Ther 2025; 31:e70244. [PMID: 39915897 PMCID: PMC11802336 DOI: 10.1111/cns.70244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 01/12/2025] [Accepted: 01/17/2025] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND Spinal cord injury (SCI) is a complex central nervous system disorder characterized by multifaceted pathological processes, including inflammation, oxidative stress, programmed cell death, autophagy, and mitochondrial dysfunction. Sirtuin 1 (Sirt1), a critical NAD+-dependent deacetylase, has emerged as a promising therapeutic target for SCI repair due to its potential to protect neurons, regulate glial and vascular cells, and optimize the injury microenvironment. However, the regulatory roles of Sirt1 in SCI are complex and challenging, as its effects vary depending on activation timing, expression levels, and cell types. METHODS A systematic literature review was conducted using PubMed, Scopus, and Web of Science to identify studies investigating Sirt1 in SCI. Relevant publications were analyzed to synthesize current evidence on Sirt1's mechanisms, therapeutic effects, and challenges in SCI repair. RESULTS Sirt1 exerts broad regulatory effects across diverse pathological processes and cell types post-SCI. It promotes neuronal survival and axonal regeneration, modulates astrocytes and microglia to resolve inflammation, supports oligodendrocyte-mediated myelination, and enhances vascular endothelial function. Proper Sirt1 activation may mitigate secondary injury, whereas excessive or prolonged activation could impair inflammatory resolution or disrupt cellular homeostasis. This review highlights Sirt1 activation as potential therapies, but challenges include optimizing spatiotemporal activation and addressing dual roles in different cell types. CONCLUSION Targeting Sirt1 represents a viable strategy for SCI repair, given its multifaceted regulation of neuroprotection, immunomodulation, and tissue remodeling. However, translating these findings into therapies requires resolving critical issues such as cell type-specific delivery, precise activation timing, and dosage control. This review provides a theoretical foundation and practical insights for advancing Sirt1-based treatments for SCI.
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Affiliation(s)
- Jinze Li
- Department of NeurosurgeryXuanwu Hospital, Capital Medical UniversityBeijingChina
- Spine CenterChina International Neuroscience Institute (CHINA‐INI)BeijingChina
- Lab of Spinal Cord Injury and Functional ReconstructionChina International Neuroscience Institute (CHINA‐INI), Xuanwu Hospital, Capital Medical UniversityBeijingChina
| | - Shengyu Cui
- Department of NeurosurgeryXuanwu Hospital, Capital Medical UniversityBeijingChina
- Spine CenterChina International Neuroscience Institute (CHINA‐INI)BeijingChina
- Lab of Spinal Cord Injury and Functional ReconstructionChina International Neuroscience Institute (CHINA‐INI), Xuanwu Hospital, Capital Medical UniversityBeijingChina
| | - Yanqiu Li
- Center for Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingChina
| | - Can Zhang
- Lab of Spinal Cord Injury and Functional ReconstructionChina International Neuroscience Institute (CHINA‐INI), Xuanwu Hospital, Capital Medical UniversityBeijingChina
- Department of NeurosurgeryThe First Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Chao Chang
- Department of NeurosurgeryXuanwu Hospital, Capital Medical UniversityBeijingChina
- Spine CenterChina International Neuroscience Institute (CHINA‐INI)BeijingChina
| | - Fengzeng Jian
- Department of NeurosurgeryXuanwu Hospital, Capital Medical UniversityBeijingChina
- Spine CenterChina International Neuroscience Institute (CHINA‐INI)BeijingChina
- Lab of Spinal Cord Injury and Functional ReconstructionChina International Neuroscience Institute (CHINA‐INI), Xuanwu Hospital, Capital Medical UniversityBeijingChina
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Liu ZZ, Ji FH, Piao Y. Non-coding RNAs participate in interactions between senescence and gastrointestinal cancers. Front Genet 2025; 15:1461404. [PMID: 39831201 PMCID: PMC11739115 DOI: 10.3389/fgene.2024.1461404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 12/04/2024] [Indexed: 01/22/2025] Open
Abstract
Relationships between cellular senescence and gastrointestinal cancers have gained prominence in recent years. The currently accepted theory suggests that cellular senescence and cancer occurrence exhibit "double-edged sword" effects. Cellular senescence is related to cancer via four "meta-hallmarks" i.e., genomic instability, epigenetic alterations, chronic inflammation, and dysbiosis, along with two "antagonistic hallmarks" i.e., telomere attrition and stem cell exhaustion. These relationships are characterized by both agonistic and antagonistic elements, but the existence of an intricate dynamic balance remains unknown. Non-coding RNAs (ncRNAs) have vital roles in post-transcriptional regulation, but how they participate in agonistic and antagonistic relationships between cellular senescence and gastrointestinal cancers remains to be fully investigated. In this article, we systematically review how ncRNAs (including microRNAs (miRNAs), long ncRNAs (lncRNAs), and circularRNAs (circRNAs)) participate in interactions between cellular senescence and gastrointestinal cancers. Our aim is to elucidate a triangular relationship between "ncRNAs-senescence-gastrointestinal cancers" which considered these three elements as an equal important standing. We are keen to identify prognostic or therapeutic targets for gastrointestinal cancers from, i.e., aging-related ncRNAs, or discover novel strategies to treat and manage in the elderly. We seek to clarify complex relationships where ncRNAs participate in "senescence-gastrointestinal cancers" interactions.
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Affiliation(s)
| | | | - Ying Piao
- Department of Oncology, General Hospital of Northern Theater Command, Shenyang, China
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Sood S, Tiwari A, Sangwan J, Vohra M, Sinha NR, Tripathi R, Sangwan VS, Mohan RR. Role of epigenetics in corneal health and disease. Prog Retin Eye Res 2025; 104:101318. [PMID: 39547455 PMCID: PMC11710990 DOI: 10.1016/j.preteyeres.2024.101318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 11/12/2024] [Accepted: 11/13/2024] [Indexed: 11/17/2024]
Abstract
Epigenetics plays a vital role in corneal health and diseases. Epigenetic changes regulate the expression of genes by altering the accessibility of chromatin via histone modifications, DNA methylation and miRNAs without altering DNA sequence. Ocular trauma and infections are common causes of corneal damage, vision impairment, and mono/bilateral blindness worldwide. Mounting literature shows that epigenetic modifications can modulate corneal clarity, function, and pathogenesis including inflammation, wound healing, fibrosis, and neovascularization. Additionally, epigenetic modifications can be targeted to reverse corneal pathologies and develop interventional therapies. However, current understanding on how epigenetic modifications lead to corneal abnormalities and diseases is limited. This review provides in-depth knowledge and mechanistic understanding of epigenetics alterations in corneal pathogenesis, and information on potential epigenetic targets for treatment of corneal diseases.
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Affiliation(s)
- Swati Sood
- Departments of Veterinary Medicine & Surgery, College of Veterinary Medicine University of Missouri, Columbia, MO, USA
| | - Anil Tiwari
- Departments of Veterinary Medicine & Surgery, College of Veterinary Medicine University of Missouri, Columbia, MO, USA; Eicher-Shroff Centre for Stem Cells Research (ESC-SCR), Dr. Shroff Charity Eye Hospital, Delhi, India
| | - Jyoti Sangwan
- Eicher-Shroff Centre for Stem Cells Research (ESC-SCR), Dr. Shroff Charity Eye Hospital, Delhi, India
| | - Mehak Vohra
- Eicher-Shroff Centre for Stem Cells Research (ESC-SCR), Dr. Shroff Charity Eye Hospital, Delhi, India
| | - Nishant R Sinha
- Departments of Veterinary Medicine & Surgery, College of Veterinary Medicine University of Missouri, Columbia, MO, USA; Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, USA; Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Ratnakar Tripathi
- Departments of Veterinary Medicine & Surgery, College of Veterinary Medicine University of Missouri, Columbia, MO, USA; Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, USA
| | - Virender S Sangwan
- Eicher-Shroff Centre for Stem Cells Research (ESC-SCR), Dr. Shroff Charity Eye Hospital, Delhi, India
| | - Rajiv R Mohan
- Departments of Veterinary Medicine & Surgery, College of Veterinary Medicine University of Missouri, Columbia, MO, USA; Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, USA; Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, MO, USA.
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Karuga FF, Kaczmarski P, Sochal M, Szmyd B, Białasiewicz P, Gabryelska A. Cross-Sectional Analysis of Hypoxia-Regulated miRNA-181a, miRNA-199a, HIF-1α, and SIRT1 in the Development of Type 2 Diabetes in Patients with Obstructive Sleep Apnea-Preliminary Study. J Clin Med 2024; 13:7644. [PMID: 39768567 PMCID: PMC11728235 DOI: 10.3390/jcm13247644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/06/2024] [Accepted: 12/09/2024] [Indexed: 01/16/2025] Open
Abstract
Introduction: Obstructive sleep apnea (OSA) is recognized as an independent risk factor for diabetes mellitus type 2 (T2DM) development, which is twice as common in patients with OSA compared to non-OSA patients. Objectives: This study aimed to investigate changes in oxygen metabolism and their role in T2DM development among OSA patients through epigenetic processes via miRNA-181a, miRNA-199a, and enzymatic processes via SIRT1 and HIF-1α. Methods: Based on polysomnography, apnea-hypopnea index and the presence of T2DM patients were divided into three groups: control group (n = 17), OSA group (n = 11), OSA&T2DM (n = 20) group. Total RNA was extracted from the buffy coat. Moreover, HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) was counted. Results: Morning miRNA-181a expression was significantly higher in the OSA&T2DM group than in the control group: 67.618 vs. 32.685 (p = 0.036). Evening miRNA-199a expression was significantly higher in the OSA group than in the control group: 5.043 vs. 2.081 (p = 0.042), while its morning expression was significantly higher in the OSA&T2DM group when compared to the control: 4.065 vs. 1.605 (p = 0.036). MiRNA-181a evening expression revealed a negative correlation with the SIRT1 evening and morning expressions (R = -0.367, p = 0.010 and R = -0.405, p = 0.004, respectively). Moreover, morning miRNA-181a was positively correlated with HOMA-IR (R = 0.321, p = 0.034). MiRNA-199a evening expression presented a moderate positive correlation with the SIRT1 morning expressions (R = 0.48, p < 0.001) and HOMA-IR (R = 0.35, p = 0.02). Conclusions: Patients suffering from OSA and T2DM had an increased expression of miRNA-181a. Moreover, a negative correlation between miRNA-181a and SIRT1 expression was observed, while a correlation between miRNA-181a and insulin resistance was positive. This phenomenon might suggest a possible epigenetic pathway for an increased incidence of T2DM in OSA patients however further research is needed.
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Affiliation(s)
- Filip Franciszek Karuga
- Department of Sleep Medicine and Metabolic Disorders, Medical University of Lodz, 90-419 Lodz, Poland; (P.K.); (M.S.); (P.B.)
| | - Piotr Kaczmarski
- Department of Sleep Medicine and Metabolic Disorders, Medical University of Lodz, 90-419 Lodz, Poland; (P.K.); (M.S.); (P.B.)
| | - Marcin Sochal
- Department of Sleep Medicine and Metabolic Disorders, Medical University of Lodz, 90-419 Lodz, Poland; (P.K.); (M.S.); (P.B.)
| | - Bartosz Szmyd
- Department of Neurosurgery and Neuro-Oncology, Barlicki University Hospital, Medical University of Lodz, 90-419 Lodz, Poland;
- Department of Pediatrics, Oncology, and Hematology, Medical University of Lodz, 90-419 Lodz, Poland
| | - Piotr Białasiewicz
- Department of Sleep Medicine and Metabolic Disorders, Medical University of Lodz, 90-419 Lodz, Poland; (P.K.); (M.S.); (P.B.)
| | - Agata Gabryelska
- Department of Sleep Medicine and Metabolic Disorders, Medical University of Lodz, 90-419 Lodz, Poland; (P.K.); (M.S.); (P.B.)
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11
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Wen SY, Ng SC, Chiu YT, Tai PY, Chen TJ, Chen CJ, Huang CY, Kuo WW. Enhanced SIRT1 Activity by Galangin Mitigates UVB-Induced Senescence in Dermal Fibroblasts via p53 Acetylation Regulation and Activation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:23286-23294. [PMID: 39401943 DOI: 10.1021/acs.jafc.4c05945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
Human skin aging, a complex process influenced by intrinsic aging and extrinsic photoaging, is marked by the accumulation of reactive oxygen species (ROS) that cause DNA damage, impaired dermal fibroblast function, and wrinkle formation. External stressors, such as ultraviolet (UV) radiation, can trigger cellular senescence. Sirtuin-1 (SIRT1), an NAD+-dependent enzyme in the sirtuin family, plays a crucial role in deacetylating p53, thereby inhibiting its nuclear translocation and reducing skin senescence. Galangin, a flavonoid found in honey and Alpinia officinarum root, has antioxidant and anti-inflammatory properties. This study investigates the protective mechanism of galangin against UVB-induced senescence in human dermal fibroblasts (HDFs) by examining its effects on SIRT1 and its target, acetylated-p53. An in vitro model of UVB-induced senescence using HDFs and an in vivo model using nude mice were employed to assess the dermal protective effects of galangin. The results demonstrate that while UVB exposure does not decrease SIRT1 protein levels, it impairs its enzymatic function. However, galangin treatment counteracts these adverse effects. Additionally, UVB exposure significantly reduces cell viability and upregulates senescence markers like p16, p21, and p53 nuclear transactivation. An increase in senescence-associated β-galactosidase (SA-β-gal) positive cells was observed in UVB-exposed dermal fibroblasts. Galangin treatment mitigates UVB-induced cellular senescence by enhancing SIRT1-mediated p53 deacetylation, thereby inhibiting nuclear translocation and reducing dermal senescence. These findings suggest that galangin is a promising agent for alleviating UVB-induced skin aging and could be a potential component in antiaging cosmetic formulations.
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Affiliation(s)
- Su-Ying Wen
- Department of Dermatology, Taipei City Hospital, Zhongxing Branch, Taipei 103, Taiwan, ROC
- Department of Cosmetic Applications and Management, Mackay Junior College of Medicine, Nursing, and Management, Taipei 112, Taiwan, ROC
- Department of Health and Welfare, University of Taipei, Taipei 111, Taiwan, ROC
| | - Shang-Chuan Ng
- Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung 406, Taiwan, ROC
| | - Yen-Tun Chiu
- Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung 406, Taiwan, ROC
| | - Pei-Yu Tai
- Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung 406, Taiwan, ROC
| | - Tzu-Jung Chen
- Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung 406, Taiwan, ROC
| | - Chih-Jung Chen
- Surgical Department, China Medical University Hospital, Taichung 404, Taiwan, ROC
| | - Chih-Yang Huang
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan, ROC
- Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien 970, Taiwan, ROC
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan, ROC
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan, ROC
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 413, Taiwan, ROC
| | - Wei-Wen Kuo
- Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung 406, Taiwan, ROC
- Ph.D. Program for Biotechnology Industry, China Medical University, Taichung 406, Taiwan, ROC
- School of Pharmacy, China Medical University, Taichung 406, Taiwan, ROC
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12
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You W, Montoya AL, Dana S, Franzini RM, Steegborn C. Elucidating the Unconventional Binding Mode of a DNA-Encoded Library Hit Provides a Blueprint for Sirtuin 6 Inhibitor Development. ChemMedChem 2024; 19:e202400273. [PMID: 38940296 PMCID: PMC11486586 DOI: 10.1002/cmdc.202400273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 06/29/2024]
Abstract
Sirtuin 6 (Sirt6), an NAD+-dependent deacylase, has emerged as a promising target for aging-related diseases and cancer. Advancing the medicinal chemistry of Sirt6 modulators is crucial for the development of chemical probes aimed at unraveling the intricate biological functions of Sirt6 and unlocking its therapeutic potential. A proprietary DNA-encoded library yielded Sirt6 inhibitor 2-Pr, displaying remarkable inhibitory activity and isoform-selectivity, and featuring a chemical structure distinct from reported Sirt6 modulators. In this study, we explore the inhibitory mechanism of 2-Pr, evaluating the impact of chemical modifications and presenting a crystal structure of the Sirt6/ADP-ribose/2-Pr complex. Notably, co-crystal structure analysis reveals an unexpected and unprecedented binding mode of Sirt6, with 2-Pr spanning the acyl channel of the enzyme, extending into the acetyl-lysine binding pocket, and reaching toward the C-site. This unique binding mode guides potential avenues for developing potent and selective Sirt6 inhibitors.
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Affiliation(s)
- Weijie You
- Department of Biochemistry, University of Bayreuth, Universitaetsstr. 30, 95447, Bayreuth, Germany
- Los Alamos National Laboratory, 87544, Los Alamos, NM, USA
| | - Alba L Montoya
- Department of Medicinal Chemistry, Skaggs College of Pharmacy, University of Utah, 30 S 2000 E, Salt Lake City, 84112, UT, USA
| | - Srikanta Dana
- Department of Medicinal Chemistry, Skaggs College of Pharmacy, University of Utah, 30 S 2000 E, Salt Lake City, 84112, UT, USA
- Orion Corporation, Espoo, 84112, Southern Finland, Finland
| | - Raphael M Franzini
- Department of Medicinal Chemistry, Skaggs College of Pharmacy, University of Utah, 30 S 2000 E, Salt Lake City, 84112, UT, USA
- Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA
| | - Clemens Steegborn
- Department of Biochemistry, University of Bayreuth, Universitaetsstr. 30, 95447, Bayreuth, Germany
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13
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Lei Y, Meng J, Shi H, Shi C, Li C, Yang Z, Zhang W, Zuo D, Wang F, Wang M. Mannan-binding lectin inhibits oxidative stress-induced senescence via the NAD+/Sirt1 pathway. Int Immunopharmacol 2024; 137:112468. [PMID: 38906004 DOI: 10.1016/j.intimp.2024.112468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 06/07/2024] [Accepted: 06/09/2024] [Indexed: 06/23/2024]
Abstract
Prolonged or excessive oxidative stress can lead to premature cellular and body aging. Mannan-binding lectin (MBL) is synthesized by the liver and plays an important role in innate immunity, anti-inflammation, and anti-oxidation, and has a positive impact on health and longevity. To date, few studies investigated the role of MBL in attenuating oxidative stress-induced senescence. In this study, we evaluated the role of MBL in oxidative stress-induced premature aging and explored its underlying mechanism in C57BL/6 mice and mouse embryonic fibroblasts (NIH/3T3). First, we established an oxidative premature senescence model induced by D-galactose in C57BL/6 mice. We found that MBL-deficient mice had a marked aging-like appearance, reduced learning and spatial exploration abilities, severe liver pathological damage, and significantly upregulated expression of Senescence-associated proteins (p53 and p21), inflammatory kinesins (IL-1β and IL-6), and the senescence β-galactosidase (SA-β-Gal) positive rate as compared with WT mice. In the H2O2-induced oxidative senescence model of NIH/3T3 cells, consistent results were obtained after MBL intervention. In addition, MBL effectively inhibited G1 phase arrest, ROS levels, DNA damage, and mitochondrial dysfunction in premature senescent cells. Mechanistically, we found that oxidative stress inhibited the nicotinamide adenine dinucleotide (NAD+)/ silent information regulator 1 (Sirt1) signaling pathway, while MBL activated the NAD+/Sirt1 signaling pathway inhibited by oxidative stress. In addition, MBL could activate the NAD+/Sirt1 pathway by upregulating NAMPT, which in turn inhibited p38 phosphorylation by activating the NAD+/Sirt1 pathway. In conclusion, MBL inhibits oxidative aging, which may facilitate the development of therapeutics to delay oxidative aging.
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Affiliation(s)
- Yiming Lei
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, School of Medical Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Jie Meng
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, School of Medical Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Haiqiang Shi
- School of Public Health, Xinxiang Medical University, Xinxiang 453003, China
| | - Chenchen Shi
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, School of Medical Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Chao Li
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, School of Medical Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Ziyi Yang
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, School of Medical Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Wei Zhang
- School of Basic Medical Science, Xinxiang Medical University, Xinxiang 453003, China
| | - Daming Zuo
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, China.
| | - Fanping Wang
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, School of Medical Technology, Xinxiang Medical University, Xinxiang 453003, China.
| | - Mingyong Wang
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, School of Medical Technology, Xinxiang Medical University, Xinxiang 453003, China; School of Medical Technology, Shangqiu Medical College, Shangqiu 476100, China.
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14
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Izadi M, Sadri N, Abdi A, Serajian S, Jalalei D, Tahmasebi S. Epigenetic biomarkers in aging and longevity: Current and future application. Life Sci 2024; 351:122842. [PMID: 38879158 DOI: 10.1016/j.lfs.2024.122842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 06/06/2024] [Accepted: 06/12/2024] [Indexed: 06/20/2024]
Abstract
The aging process has been one of the most necessary research fields in the current century, and knowing different theories of aging and the role of different genetic, epigenetic, molecular, and environmental modulating factors in increasing the knowledge of aging mechanisms and developing appropriate diagnostic, therapeutic, and preventive ways would be helpful. One of the most conserved signs of aging is epigenetic changes, including DNA methylation, histone modifications, chromatin remodeling, noncoding RNAs, and extracellular RNAs. Numerous biological processes and hallmarks are vital in aging development, but epigenomic alterations are especially notable because of their importance in gene regulation and cellular identity. The mounting evidence points to a possible interaction between age-related epigenomic alterations and other aging hallmarks, like genome instability. To extend a healthy lifespan and possibly reverse some facets of aging and aging-related diseases, it will be crucial to comprehend global and locus-specific epigenomic modifications and recognize corresponding regulators of health and longevity. In the current study, we will aim to discuss the role of epigenomic mechanisms in aging and the most recent developments in epigenetic diagnostic biomarkers, which have the potential to focus efforts on reversing the destructive signs of aging and extending the lifespan.
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Affiliation(s)
- Mehran Izadi
- Department of Infectious and Tropical Diseases, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Synapse Laboratory Diagnostic Technologies Accelerator, Tehran, Iran; Department of Research & Technology, Zeenome Longevity Research Institute, Tehran, Iran
| | - Nariman Sadri
- Synapse Laboratory Diagnostic Technologies Accelerator, Tehran, Iran; Department of Research & Technology, Zeenome Longevity Research Institute, Tehran, Iran; School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amirhossein Abdi
- Synapse Laboratory Diagnostic Technologies Accelerator, Tehran, Iran; Department of Research & Technology, Zeenome Longevity Research Institute, Tehran, Iran; Royan Institute for Stem Cell Biology and Technology, Tehran, Iran
| | - Sahar Serajian
- Synapse Laboratory Diagnostic Technologies Accelerator, Tehran, Iran; Department of Research & Technology, Zeenome Longevity Research Institute, Tehran, Iran; Royan Institute for Stem Cell Biology and Technology, Tehran, Iran
| | - Dorsa Jalalei
- Synapse Laboratory Diagnostic Technologies Accelerator, Tehran, Iran; Department of Research & Technology, Zeenome Longevity Research Institute, Tehran, Iran; School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Safa Tahmasebi
- Synapse Laboratory Diagnostic Technologies Accelerator, Tehran, Iran; Department of Research & Technology, Zeenome Longevity Research Institute, Tehran, Iran; Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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15
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Della Torre S, Dell'Omo G, Dellavedova J, Palazzolo L, Scanziani E, Eberini I, Pinto A, Mitro N, Conti P, Villa A, Ciana P. Discovery and characterization of a new class of NAD +-independent SIRT1 activators. Pharmacol Res 2024; 206:107296. [PMID: 38971269 DOI: 10.1016/j.phrs.2024.107296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 06/22/2024] [Accepted: 07/03/2024] [Indexed: 07/08/2024]
Abstract
The activity of sirtuin 1 (SIRT1, a member of the NAD+-dependent deacetylases family) decreases during aging as NAD+ levels naturally decline, thus increasing the risk of several age-associated diseases. Several sirtuin-activating compounds (STACs) have been developed to counteract the age-associated reduction in SIRT1 activity, and some of them are currently under development in clinical trials. STACs induce SIRT1 activation, either through allosteric activation of the enzyme in the presence of NAD+, or by increasing NAD+ levels by inhibiting its degradation or by supplying a key precursor in biosynthesis. In this study, we have identified (E)-2'-des-methyl sulindac analogues as a novel class of STACs that act also in the absence of NAD+, a peculiar behavior demonstrated through enzymatic and mass spectrometry experiments, both in vitro and in cell lines. The activation of the SIRT1 pathway was confirmed in vivo through gene expression and metabolomics analysis. Our data suggest that these compounds could serve as candidate leads for a novel therapeutic strategy aimed at addressing a key metabolic deficiency that may contribute to metabolic and age-associated diseases.
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Affiliation(s)
- Sara Della Torre
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Giulia Dell'Omo
- Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Jessica Dellavedova
- Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Luca Palazzolo
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università degli Studi di Milano, Milan, Italy
| | - Eugenio Scanziani
- Department of Veterinary Medicine and Animal Sciences, Università degli Studi di Milano Milan, Italy
| | - Ivano Eberini
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università degli Studi di Milano, Milan, Italy
| | - Andrea Pinto
- Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, Milan, Italy
| | - Nico Mitro
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università degli Studi di Milano, Milan, Italy; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Paola Conti
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Alessandro Villa
- Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Paolo Ciana
- Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
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16
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Izadi M, Sadri N, Abdi A, Zadeh MMR, Jalaei D, Ghazimoradi MM, Shouri S, Tahmasebi S. Longevity and anti-aging effects of curcumin supplementation. GeroScience 2024; 46:2933-2950. [PMID: 38409646 PMCID: PMC11009219 DOI: 10.1007/s11357-024-01092-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 02/03/2024] [Indexed: 02/28/2024] Open
Abstract
Aging is a gradual and irreversible process that is accompanied by an overall decline in cellular function and a significant increase in the risk of age-associated disorders. Generally, delaying aging is a more effective method than treating diseases associated with aging. Currently, researchers are focused on natural compounds and their therapeutic and health benefits. Curcumin is the main active substance that is present in turmeric, a spice that is made up of the roots and rhizomes of the Curcuma longa plant. Curcumin demonstrated a positive impact on slowing down the aging process by postponing age-related changes. This compound may have anti-aging properties by changing levels of proteins involved in the aging process, such as sirtuins and AMPK, and inhibiting pro-aging proteins, such as NF-κB and mTOR. In clinical research, this herbal compound has been extensively examined in terms of safety, efficacy, and pharmacokinetics. There are numerous effects of curcumin on mechanisms related to aging and human diseases, so we discuss many of them in detail in this review.
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Affiliation(s)
- Mehran Izadi
- Department of Infectious and Tropical Diseases, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Synapse Laboratory Diagnostic Technologies Accelerator, Tehran, Iran
- Department of Research & Technology, Zeenome Longevity Research Institute, Tehran, Iran
| | - Nariman Sadri
- Synapse Laboratory Diagnostic Technologies Accelerator, Tehran, Iran
- Department of Research & Technology, Zeenome Longevity Research Institute, Tehran, Iran
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amirhossein Abdi
- Synapse Laboratory Diagnostic Technologies Accelerator, Tehran, Iran
- Department of Research & Technology, Zeenome Longevity Research Institute, Tehran, Iran
- School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Mahdi Raeis Zadeh
- Synapse Laboratory Diagnostic Technologies Accelerator, Tehran, Iran
- Department of Research & Technology, Zeenome Longevity Research Institute, Tehran, Iran
- School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Dorsa Jalaei
- Synapse Laboratory Diagnostic Technologies Accelerator, Tehran, Iran
- Department of Research & Technology, Zeenome Longevity Research Institute, Tehran, Iran
- School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohammad Mahdi Ghazimoradi
- Synapse Laboratory Diagnostic Technologies Accelerator, Tehran, Iran
- Department of Research & Technology, Zeenome Longevity Research Institute, Tehran, Iran
- School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Sara Shouri
- Synapse Laboratory Diagnostic Technologies Accelerator, Tehran, Iran
- Department of Research & Technology, Zeenome Longevity Research Institute, Tehran, Iran
- School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Safa Tahmasebi
- Synapse Laboratory Diagnostic Technologies Accelerator, Tehran, Iran.
- Department of Research & Technology, Zeenome Longevity Research Institute, Tehran, Iran.
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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17
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Marco M, Jansen M, van der Weiden G, Reich E, Maatuf YH, Mastbergen SC, Dvir-Ginzberg M. Two-year post-distraction cartilage-related structural improvement is accompanied by increased serum full-length SIRT1. Arthritis Res Ther 2024; 26:106. [PMID: 38790038 PMCID: PMC11127335 DOI: 10.1186/s13075-024-03342-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 05/14/2024] [Indexed: 05/26/2024] Open
Abstract
BACKGROUND Previously, fragments from Sirtuin 1 (SIRT1) were identified in preclinical and clinical samples to display an increase in serum levels for N-terminal (NT) SIRT1 vs. C-terminal (CT) SIRT1, indicative of early signs of OA. Here we tested NT/CT SIRT1 levels as well as a novel formulated sandwich assay to simultaneously detect both domains of SIRT1 in a manner that may inform us about the levels of full-length SIRT1 in the circulation (flSIRT1) of clinical cohorts undergoing knee joint distraction (KJD). METHODS We employed an indirect ELISA assay to test NT- and CT-SIRT1 levels and calculated their ratio. Further, to test flSIRT1 we utilized novel antibodies (Ab), which were validated for site specificity and used in a sandwich ELISA method, wherein the CT-reactive served as capture Ab, and its NT-reactive served as primary detection Ab. This method was employed in human serum samples derived from a two-year longitudinal study of KJD patients. Two-year clinical and structural outcomes were correlated with serum levels of flSIRT1 compared to baseline. RESULTS Assessing the cohort, exhibited a significant increase of NT/CT SIRT1 serum levels with increased osteophytes and PIIANP/CTX-II at baseline, while a contradictory increase in NT/CT SIRT1 was associated with less denuded bone, post-KJD. On the other hand, flSIRT1 exhibited an upward trend in serum level, accompanied by reduced denuded bone for 2-year adjusted values. Moreover, 2 year-adjusted flSIRT1 levels displayed a steeper linear regression for cartilage and bone-related structural improvement than those observed for NT/CT SIRT1. CONCLUSIONS Our data support that increased flSIRT1 serum levels are a potential molecular endotype for cartilage-related structural improvement post-KJD, while NT/CT SIRT1 appears to correlate with osteophyte and PIIANP/CTX-II reduction at baseline, to potentially indicate baseline OA severity.
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Affiliation(s)
- Miya Marco
- Laboratory of Cartilage Biology, Institute of Bio-Medical and Oral Research, Faculty of Dental Medicine, Hadassah-Hebrew University of Jerusalem, P. O. Box 12272, Jerusalem, 9112102, Israel
| | - Mylène Jansen
- Rheumatology & Clinical Immunology, University Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Goran van der Weiden
- Rheumatology & Clinical Immunology, University Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Eli Reich
- Laboratory of Cartilage Biology, Institute of Bio-Medical and Oral Research, Faculty of Dental Medicine, Hadassah-Hebrew University of Jerusalem, P. O. Box 12272, Jerusalem, 9112102, Israel
| | - Yonathan H Maatuf
- Laboratory of Cartilage Biology, Institute of Bio-Medical and Oral Research, Faculty of Dental Medicine, Hadassah-Hebrew University of Jerusalem, P. O. Box 12272, Jerusalem, 9112102, Israel
| | - Simon C Mastbergen
- Rheumatology & Clinical Immunology, University Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Mona Dvir-Ginzberg
- Laboratory of Cartilage Biology, Institute of Bio-Medical and Oral Research, Faculty of Dental Medicine, Hadassah-Hebrew University of Jerusalem, P. O. Box 12272, Jerusalem, 9112102, Israel.
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18
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Garneau L, Mulvihill EE, Smith SR, Sparks LM, Aguer C. Myokine Secretion following an Aerobic Exercise Intervention in Individuals with Type 2 Diabetes with or without Exercise Resistance. Int J Mol Sci 2024; 25:4889. [PMID: 38732106 PMCID: PMC11084395 DOI: 10.3390/ijms25094889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 04/19/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
Type 2 diabetes (T2D) is characterized by muscle metabolic dysfunction that exercise can minimize, but some patients do not respond to an exercise intervention. Myokine secretion is intrinsically altered in patients with T2D, but the role of myokines in exercise resistance in this patient population has never been studied. We sought to determine if changes in myokine secretion were linked to the response to an exercise intervention in patients with T2D. The participants followed a 10-week aerobic exercise training intervention, and patients with T2D were grouped based on muscle mitochondrial function improvement (responders versus non-responders). We measured myokines in serum and cell-culture medium of myotubes derived from participants pre- and post-intervention and in response to an in vitro model of muscle contraction. We also quantified the expression of genes related to inflammation in the myotubes pre- and post-intervention. No significant differences were detected depending on T2D status or response to exercise in the biological markers measured, with the exception of modest differences in expression patterns for certain myokines (IL-1β, IL-8, IL-10, and IL-15). Further investigation into the molecular mechanisms involving myokines may explain exercise resistance with T2D; however, the role in metabolic adaptations to exercise in T2D requires further investigation.
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Affiliation(s)
- Léa Garneau
- Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (L.G.); (E.E.M.)
- Institut du Savoir Montfort, Ottawa, ON K1K 0T2, Canada
| | - Erin E. Mulvihill
- Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (L.G.); (E.E.M.)
- University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada
| | - Steven R. Smith
- Translational Research Institute for Metabolism and Diabetes, AdventHealth Orlando, Orlando, FL 32804, USA; (S.R.S.); (L.M.S.)
| | - Lauren M. Sparks
- Translational Research Institute for Metabolism and Diabetes, AdventHealth Orlando, Orlando, FL 32804, USA; (S.R.S.); (L.M.S.)
| | - Céline Aguer
- Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (L.G.); (E.E.M.)
- Institut du Savoir Montfort, Ottawa, ON K1K 0T2, Canada
- Faculty of Medicine and Health Sciences, Department of Physiology, McGill University–Campus Outaouais, Gatineau, QC J8V 3T4, Canada
- Faculty of Health Sciences, School of Human Kinetics, University of Ottawa, Ottawa, ON K1N 6N5, Canada
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19
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Badran MM, Abbas SH, Tateishi H, Maemoto Y, Toma T, Ito A, Fujita M, Otsuka M, Abdel-Aziz M, Radwan MO. Ligand-based design and synthesis of new trityl histamine and trityl cysteamine derivatives as SIRT2 inhibitors for cancer therapy. Eur J Med Chem 2024; 269:116302. [PMID: 38484678 DOI: 10.1016/j.ejmech.2024.116302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 02/12/2024] [Accepted: 03/01/2024] [Indexed: 04/07/2024]
Abstract
The relentless pursuit of novel therapeutic agents against cancer has led to the identification of multiple molecular targets, among which Sirtuin 2 (SIRT2) has garnered significant attention. This study presents an extensive SAR study of our reported trityl scaffold-based SIRT2 inhibitors. This study encompasses a range of different medicinal chemistry approaches to improve the activity of the lead compounds TH-3 and STCY1. The rationally designed and synthesized structures were confirmed using NMR and high-resolution mass spectroscopy before performing SIRT2 inhibition assay, NCI60 cytotoxicity test, and cell cycle analysis. Indeed, our strategies afforded hitherto unreported SIRT2 inhibitors with high activity, particularly 2a, 4a, 7c, and 7f. Remarkably, the presence of a lipophilic para substitution on the phenyl group of a freely rotating or a locked trityl moiety enhanced activity SIRT2 inhibition. Concomitantly, the synthesized compounds showed prominent activity against different cancer lines from the NCI60 assay. Of interest, compound 7c stands out as a potent and highly selective antiproliferative agent against leukemia and colon cancer panels. Furthermore, 7c treatment resulted in cell cycle arrest in MCF-7 cells at G2 phase and did not cause in vitro DNA cleavage.
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Affiliation(s)
- Mostafa M Badran
- Department of Medicinal Chemistry, Faculty of Pharmacy, South Valley University, Qena, 83523, Egypt; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519-Minia, Egypt; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.
| | - Samar H Abbas
- Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519-Minia, Egypt.
| | - Hiroshi Tateishi
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan; Research & Development, Hirata Corporation, 111 Hitotsugi Uekimachi, Kita-ku, Kumamoto, 861-0135, Japan.
| | - Yuki Maemoto
- Laboratory of Cell Signaling, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan.
| | - Tsugumasa Toma
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.
| | - Akihiro Ito
- Laboratory of Cell Signaling, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan.
| | - Mikako Fujita
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.
| | - Masami Otsuka
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan; Department of Drug Discovery, Science Farm Ltd., Kumamoto, 862-0976, Japan.
| | - Mohamed Abdel-Aziz
- Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519-Minia, Egypt.
| | - Mohamed O Radwan
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan; Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Cairo, 12622, Egypt.
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20
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Kumar S, Shenoy S, Swamy RS, Ravichandiran V, Kumar N. Fluoride-Induced Mitochondrial Dysfunction and Approaches for Its Intervention. Biol Trace Elem Res 2024; 202:835-849. [PMID: 37300595 DOI: 10.1007/s12011-023-03720-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 05/28/2023] [Indexed: 06/12/2023]
Abstract
Fluoride is present everywhere in nature. The primary way that individuals are exposed to fluoride is by drinking water. It's interesting to note that while low fluoride levels are good for bone and tooth growth, prolonged fluoride exposure is bad for human health. Additionally, preclinical studies link oxidative stress, inflammation, and programmed cell death to fluoride toxicity. Moreover, mitochondria play a crucial role in the production of reactive oxygen species (ROS). On the other hand, little is known about fluoride's impact on mitophagy, biogenesis, and mitochondrial dynamics. These actions control the growth, composition, and organisation of mitochondria, and the purification of mitochondrial DNA helps to inhibit the production of reactive oxygen species and the release of cytochrome c, which enables cells to survive the effects of fluoride poisoning. In this review, we discuss the different pathways involved in mitochondrial toxicity and dysfunction induced by fluoride. For therapeutic approaches, we discussed different phytochemical and pharmacological agents which reduce the toxicity of fluoride via maintained by imbalanced cellular processes, mitochondrial dynamics, and scavenging the ROS.
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Affiliation(s)
- Sachindra Kumar
- National Institute of Pharmaceutical Education and Research, Hajipur, Industrial Area Hajipur, Vaishali, 844102, India
| | - Smita Shenoy
- Department of Pharmacology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education (MAHE), Manipal, 576104, India
| | - Ravindra Shantakumar Swamy
- Division of Anatomy, Department of Basic Medical Sciences (DBMS), Manipal Academy of Higher Education (MAHE), Manipal, 576104, India
| | - V Ravichandiran
- National Institute of Pharmaceutical Education and Research, Hajipur, Industrial Area Hajipur, Vaishali, 844102, India
| | - Nitesh Kumar
- National Institute of Pharmaceutical Education and Research, Hajipur, Industrial Area Hajipur, Vaishali, 844102, India.
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21
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Sevgin K, Erguven P. SIRT1 overexpression by melatonin and resveratrol combined treatment attenuates premature ovarian failure through activation of SIRT1/FOXO3a/BCL2 pathway. Biochem Biophys Res Commun 2024; 696:149506. [PMID: 38224665 DOI: 10.1016/j.bbrc.2024.149506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 01/04/2024] [Accepted: 01/08/2024] [Indexed: 01/17/2024]
Abstract
AIM To evaluate the synergistic effect of combined treatment with melatonin (MEL) and resveratrol (RES) in cisplatin (CIS)-induced premature ovarian failure (POF) model in rats and to elucidate the molecular mechanism of this therapeutic effect. MATERIAL & METHODS Female Sprague Dawley rats were divided into 7 experimental groups as follows; CONT (Control), CIS, MEL, RES, POF + MEL, POF + RES, and POF + MEL + RES. H&E staining was performed to evaluate follicular cell vacuolization/degeneration, vascular congestion/hemorrhage, and inflammation, by using an ordinal scale from 0 to 4 to grade the severity of observed changes (0 = normal, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe). Zona pellucida integrity and connective tissue amount in the ovarian tissue were detected using PAS & Masson Trichrome staining. The immunofluorescence method was used to determine the immune localizations of pH2Ax, SIRT1, FOXO3a, and BCL2. The connective tissue amounts and immunoreactivity staining intensities were measured using ImageJ. The gene expression of SIRT1, FOXO3a, and BCL2 was determined using RT-PCR. Serum estrogen hormone levels were measured by ELISA. Statistically, Bonferroni correction was performed, and p < 0.002 were considered significant. RESULTS A significant difference was observed in the POF group compared to the CONT group in all parameters except tertiary follicle count and hemorrhage. The decrease in the number of atretic follicles in the POF + MEL + RES group was found significant compared to both POF + MEL and POF + RES groups. The expression of pH2Ax, SIRT1, FOXO3a, and BCL2 at the protein level and SIRT1 and BCL2 at the mRNA level were significant in the POF + MEL + RES group compared to the POF group. Between the single and combination treatment groups, the difference in protein level was found in pH2Ax, SIRT1, FOXO3a, and BCL2 expression. The POF + MEL + RES group exhibited significantly higher SIRT1 mRNA expression compared to the groups receiving single treatments. CONCLUSION The present study provides evidence that MEL and RES have synergistic effects in preventing the decrease in follicle reserve and increase in DNA break (pH2Ax) and follicle atresia in POF ovaries. This therapeutic effect is mediated by SIRT1 overexpression and activation of the SIRT1/FOXO3a/BCL2 pathway.
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Affiliation(s)
- Kubra Sevgin
- Department of Histology and Embryology, International Faculty of Medicine, University of Health Sciences, Istanbul 34668, Turkey.
| | - Pelin Erguven
- Department of Histology and Embryology, International Faculty of Medicine, University of Health Sciences, Istanbul 34668, Turkey
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22
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Pannek M, Alhalabi Z, Tomaselli D, Menna M, Fiorentino F, Robaa D, Weyand M, Puhlmann M, Tomassi S, Barreca F, Tafani M, Zaganjor E, Haigis MC, Sippl W, Rotili D, Mai A, Steegborn C. Specific Inhibitors of Mitochondrial Deacylase Sirtuin 4 Endowed with Cellular Activity. J Med Chem 2024; 67:1843-1860. [PMID: 38253001 DOI: 10.1021/acs.jmedchem.3c01496] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Sirtuins are NAD+-dependent protein lysine deacylases implicated in aging-related diseases. Mammalian Sirtuin 4 (Sirt4) is located in mitochondria and a potential therapeutic target for cancer and metabolic diseases, but no potent and selective Sirt4 inhibitors have been reported. Here, we describe the identification of potent Sirt4-specific small-molecule inhibitors. Testing hits from a target-based virtual screen revealed 12 active compounds. A focused screen based on two top compounds, followed by structure-assisted design of derivatives, yielded four first-in-class potent Sirt4 inhibitors. Kinetic analyses indicate compound competition with the acyl peptide substrate, consistent with the docking models and implicating Sirt4's unique acyl binding site. The compounds indeed show preference for Sirt4 over other isoforms, with one of them (69) being highly isoform selective, and they are active in cells. Our results provide first lead compounds and mechanistic insights for optimization toward Sirt4-specific inhibitors useful as experimental tools and potential therapeutics.
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Affiliation(s)
- Martin Pannek
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | - Zayan Alhalabi
- Department of Pharmaceutical Chemistry, Martin-Luther-University Halle-Wittenberg, 06108 Halle, Germany
| | - Daniela Tomaselli
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 Rome, Italy
| | - Martina Menna
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 Rome, Italy
| | - Francesco Fiorentino
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 Rome, Italy
| | - Dina Robaa
- Department of Pharmaceutical Chemistry, Martin-Luther-University Halle-Wittenberg, 06108 Halle, Germany
| | - Michael Weyand
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | | | - Stefano Tomassi
- Department of Pharmacy, University of Naples "Federico II", 80131 Naples, Italy
| | - Federica Barreca
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Marco Tafani
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Elma Zaganjor
- Department of Cell Biology, Harvard Medical School, Boston, 02115 Massachusetts, United States
| | - Marcia C Haigis
- Department of Cell Biology, Harvard Medical School, Boston, 02115 Massachusetts, United States
| | - Wolfgang Sippl
- Department of Pharmaceutical Chemistry, Martin-Luther-University Halle-Wittenberg, 06108 Halle, Germany
| | - Dante Rotili
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 Rome, Italy
| | - Antonello Mai
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 Rome, Italy
- Pasteur Institute Italy, Cenci-Bolognetti Foundation, Sapienza University of Rome, 00185 Rome, Italy
| | - Clemens Steegborn
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
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23
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Bostanci E, Kirkik D, Kalkanli Tas S, Uyeturk U. Genetic insights into bladder cancer: the impact of SIRT1 gene polymorphism. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2024; 43:1447-1458. [PMID: 38305254 DOI: 10.1080/15257770.2024.2310710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 01/22/2024] [Accepted: 01/22/2024] [Indexed: 02/03/2024]
Abstract
Bladder cancer (BC) has shown a significant global health concern with distinct pathological, genetic, and epigenetic characteristics. Its prevalence is influenced by various risk factors, including age, gender, and genetic predisposition. This study investigates the association between BC and the Sirtuin 1 (SIRT1) gene polymorphism rs369274325 in the Turkish population. Genomic DNA was isolated from peripheral blood samples and genotyping of rs369274325 polymorphism in SIRT 1 was investigated in 200 individuals (in 100 Turkish bladder cancer patients and 100 healthy individuals as the control group.) by real-time PCR. Demographic information, smoking and alcohol consumption status was analyzed by statistical analysis. Statistical analysis was performed by Pearson's Chi-square test. Smoking and alcohol consumption were significantly higher in BC patients compared to controls (p < 0.00018 and p < 0.0001, respectively). The genotypic distribution of SIRT1 rs369274325 did not show a significant difference between BC patients and controls (p = 0.5550). BC, influenced by genetic and environmental factors, has been linked to various gene mutations. SIRT1, involved in diverse physiological processes, is proposed to play a role in BC. However, our study did not find a significant association between SIRT1 rs369274325 polymorphism and BC in the Turkish population.
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Affiliation(s)
- Emre Bostanci
- Medicine Faculty, Department of Urology, Abant Izzet Baysal University, Bolu, Turkey
| | - Duygu Kirkik
- Hamidiye Medicine Faculty, Department of Medical Biology, University of Health Sciences, Istanbul, Turkey
| | - Sevgi Kalkanli Tas
- Hamidiye Medicine Faculty, Department of Immunology, University of Health Sciences, Istanbul, Turkey
| | - Ugur Uyeturk
- Medicine Faculty, Department of Urology, Abant Izzet Baysal University, Bolu, Turkey
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24
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Shibata S, Kon S. Functional Ingredients Associated with the Prevention and Suppression of Locomotive Syndrome: A Review. Biol Pharm Bull 2024; 47:1978-1991. [PMID: 39617444 DOI: 10.1248/bpb.b24-00443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/01/2025]
Abstract
In 2007, the Japanese Orthopaedic Association proposed the concept of locomotive syndrome, a comprehensive description of conditions involving the functional decline of the locomotor system. Locomotive syndrome includes bone-related diseases such as osteoporosis, joint cartilage and disc-related diseases such as osteoarthritis and lumbar spondylosis, and sarcopenia and locomotive syndrome-related diseases. If left untreated, these diseases are likely to reduce mobility, necessitating nursing care. To prevent the progression of locomotive syndrome, a daily exercise routine and well-balanced diet are important, in addition to recognizing one's own decline in mobility. Therefore, research on the effectiveness of functional ingredients in the prevention and suppression of locomotive syndrome progression is ongoing. In this review, we summarize the latest reports on the effectiveness of five functional ingredients, namely, epigallocatechin gallate, resveratrol, curcumin, ellagic acid, and carnosic acid, in the treatment of osteoarthritis, osteoporosis, and rheumatoid arthritis, which are considered representative diseases of the locomotive syndrome.
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Affiliation(s)
- Sachi Shibata
- Department of Nutritional Science, Faculty of Health and Welfare Science, Okayama Prefectural University
| | - Shigeyuki Kon
- Department of Molecular Immunology, Faculty of Pharmaceutical Sciences, Fukuyama University
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25
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Kojima J, Dai Y, Suzuki T, Ono M, Nishi H. Sirtuin 1 is a potential therapeutic candidate gene for fetal growth restriction via insulin-like 4. J Matern Fetal Neonatal Med 2023; 36:2253486. [PMID: 37661175 DOI: 10.1080/14767058.2023.2253486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 08/10/2023] [Accepted: 08/25/2023] [Indexed: 09/05/2023]
Abstract
OBJECTIVE Insufficient placental development causes various obstetric complications, including fetal growth restriction (FGR). The Sirtuin 1 (SIRT1) and insulin-like 4 (INSL4) protein-coding genes have been demonstrated to play an important role in placental development. However, no treatment for FGR is available due to placental dysfunction. Therefore, this study aimed to examine the potential of the SIRT1-INSL4 axis as a treatment candidate for FGR caused by insufficient placental development. METHODS Twenty patients were enrolled, including 10 with FGR and 10 full-term controls. FGR and control placental samples were collected. Quantitative real-time polymerase chain reaction, immunohistochemical analysis, and western blotting were used to analyze INSL4 and SIRT1 expression. An in-vitro loss-of-function approach with the human choriocarcinoma cell line BeWo was applied for functional analyses of SIRT1 in placental development. BeWo cells were differentiated into syncytiotrophoblasts by silencing SIRT1 using small interfering RNA. SIRT1 activator was added during differentiation of SIRT1-knockdown BeWo cells into syncytiotrophoblasts. RESULTS The FGR samples had lower INSL4 and SIRT1 mRNA and protein expression levels than the control samples. Immunohistochemistry showed that both SIRT1 and INSL4 were expressed mainly in syncytiotrophoblasts. In-vitro analyses showed that SIRT1 knockdown decreased INSL4 expression; however, SIRT1 activator restored SIRT1 expression in SIRT1-silenced BeWo cells. CONCLUSIONS SIRT1 and INSL4 are downregulated in the placenta of FGR, and INSL4 is regulated by SIRT1. These findings indicate that the SIRT1-INSL4 axis may be a potential therapeutic target for FGR.
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Affiliation(s)
- Junya Kojima
- Department of Obstetrics and Gynecology, Tokyo Medical University, Tokyo, Japan
| | - Yidan Dai
- Department of Obstetrics and Gynecology, Tokyo Medical University, Tokyo, Japan
| | - Tomoo Suzuki
- Department of Obstetrics and Gynecology, Tokyo Medical University, Tokyo, Japan
| | - Masanori Ono
- Department of Obstetrics and Gynecology, Tokyo Medical University, Tokyo, Japan
| | - Hirotaka Nishi
- Department of Obstetrics and Gynecology, Tokyo Medical University, Tokyo, Japan
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26
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Cai H, Wang Y, Zhang J, Wei Z, Yan T, Feng C, Xu Z, Zhou A, Wu Y. Discovery of Novel SIRT1/2 Inhibitors with Effective Cytotoxicity against Human Leukemia Cells. J Chem Inf Model 2023; 63:4780-4790. [PMID: 37486605 DOI: 10.1021/acs.jcim.3c00556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/25/2023]
Abstract
The sirtuin enzyme family members, SIRT1 and SIRT2, play both tumor-promoting and tumor-suppressing roles, depending on the context and experimental conditions. Compounds that inhibit either SIRT1 or SIRT2 show promising antitumor effects in several types of cancer models, both in vitro and in vivo. The simultaneous inhibition of SIRT1 and SIRT2 is helpful in treating cancer by completely blocking p53 deacetylation, leading to cell death. However, only a few SIRT1/2 dual inhibitors have been developed. Here, we report the discovery of a novel series of SIRT1/2 dual inhibitors via a rational drug design that involved virtual screening and a substructure search. Eleven of the derived compounds exhibited high inhibitory activities, with IC50 < 5 μM and high specificity for both SIRT1 and SIRT2. Compounds hsa55 and PS9 strongly induced apoptosis and showed antiproliferative effects against human leukemia cell lines, which could be due to their ability to increase of p53 and α-tubulin acetylation, as we observed in MOLM-13 cells. Therefore, the new scaffolds of these compounds and their efficacy in leukemia cell lines provide important clues for the further development of novel anti-leukemia drugs.
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Affiliation(s)
- Haiyan Cai
- Department of Hematology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yingying Wang
- Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai 200025, China
| | - Jing Zhang
- Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhenquan Wei
- Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Teng Yan
- Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Chenxi Feng
- Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhijian Xu
- Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Aiwu Zhou
- Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yingli Wu
- Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai 200025, China
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Liu Y, Zhang Z, Lu X, Liu C, Zhang H. Senescence-responsive miR-33-5p promotes chondrocyte senescence and osteoarthritis progression by targeting SIRT6. Int Immunopharmacol 2023; 121:110506. [PMID: 37343371 DOI: 10.1016/j.intimp.2023.110506] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 05/31/2023] [Accepted: 06/12/2023] [Indexed: 06/23/2023]
Abstract
Osteoarthritis (OA) is a prevalent disease among elderly individuals that is caused by cartilage degeneration. Chondrocyte senescence involved in the development of OA, and antisenescence therapies have been proposed for OA treatment. In our study, we identified the role of a microRNA, miR-33-5p, in promoting chondrocyte senescence and OA progression. miR-33-5p expression was upregulated under senescence conditions. miR-33-5p-mimic transfection can induce cellular senescence, while transfection of a miR-33-5p-inhibitor in chondrocytes alleviated senescence induced by IL-1β. Moreover, SIRT6 expression was downregulated under IL-1β treatment, and could be restored by miR-33-5p-inhibitor transfection. Luciferase assays revealed that miR-33-5p targeted the SIRT6 mRNA 3' UTR. In addition, SIRT6 mRNA expression showed negative correlations with senescence and OA degree in human cartilage. Bioinformatic analysis also confirmed the pro-senescence effect of miR-33-5p. Furthermore, periodic intraarticular injection of agomiR-33-5p induced cartilage loss and OA-like cartilage changes. To conclude, we revealed the pro-senescence and cartilage-destructive effect of miR-33-5p, whose expression was elevated under various senescence conditions, and showed that SIRT6 was one of its targets. Therefore, miR-33-5p is a potential therapeutic target for treating OA.
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Affiliation(s)
- Yikai Liu
- Department of Joint Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China.
| | - Zian Zhang
- Department of Joint Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Xinzhe Lu
- Department of Joint Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Chang Liu
- Department of Joint Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Haining Zhang
- Department of Joint Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China.
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Mayor E. Neurotrophic effects of intermittent fasting, calorie restriction and exercise: a review and annotated bibliography. FRONTIERS IN AGING 2023; 4:1161814. [PMID: 37334045 PMCID: PMC10273285 DOI: 10.3389/fragi.2023.1161814] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 05/09/2023] [Indexed: 06/20/2023]
Abstract
In the last decades, important progress has been achieved in the understanding of the neurotrophic effects of intermittent fasting (IF), calorie restriction (CR) and exercise. Improved neuroprotection, synaptic plasticity and adult neurogenesis (NSPAN) are essential examples of these neurotrophic effects. The importance in this respect of the metabolic switch from glucose to ketone bodies as cellular fuel has been highlighted. More recently, calorie restriction mimetics (CRMs; resveratrol and other polyphenols in particular) have been investigated thoroughly in relation to NSPAN. In the narrative review sections of this manuscript, recent findings on these essential functions are synthesized and the most important molecules involved are presented. The most researched signaling pathways (PI3K, Akt, mTOR, AMPK, GSK3β, ULK, MAPK, PGC-1α, NF-κB, sirtuins, Notch, Sonic hedgehog and Wnt) and processes (e.g., anti-inflammation, autophagy, apoptosis) that support or thwart neuroprotection, synaptic plasticity and neurogenesis are then briefly presented. This provides an accessible entry point to the literature. In the annotated bibliography section of this contribution, brief summaries are provided of about 30 literature reviews relating to the neurotrophic effects of interest in relation to IF, CR, CRMs and exercise. Most of the selected reviews address these essential functions from the perspective of healthier aging (sometimes discussing epigenetic factors) and the reduction of the risk for neurodegenerative diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease) and depression or the improvement of cognitive function.
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Zhao Y, Xie M, Wang C, Wang Y, Peng Y, Nie X. Effects of atorvastatin on the Sirtuin/PXR signaling pathway in Mugilogobius chulae. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:60009-60022. [PMID: 37016258 DOI: 10.1007/s11356-023-26736-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 03/27/2023] [Indexed: 05/10/2023]
Abstract
Atorvastatin (ATV) is a hypolipidemic drug widely detected in the aquatic environment. Nevertheless, limited information is provided about the toxic effects of ATV on estuary or coastal species and the underlying mechanisms. In the present study, the responses of genes expression in pregnane X receptor (PXR) signaling pathway and enzymatic activities in the liver of the estuarine benthic fish (Mugilogobius chulae) were investigated under acute and sub-chronic ATV exposure. Results showed that PXR was significantly inhibited in the highest exposure concentration of ATV for a shorter time (24 h, 500 μg L-1) but induced in a lower concentration (72 h, 5 μg L-1). The downstream genes in PXR signaling pathway such as CYP3A, SULT, UGT, and GST showed similar trends to PXR. P-gp and MRP1 were repressed in most treatments. GCLC associated with GSH synthesis was mostly induced under ATV exposure for a long time (168 h), suggesting that reactive oxygen species (ROS) were generated under ATV exposure. Similarly, GST and SOD enzymatic activities significantly increased in most exposure treatments. Under ATV exposure, SIRT1 and SIRT2 displayed induction to some extent in most treatments, suggesting that SIRTs may affect PXR expression by regulating the acetylation levels of PXR. The investigation demonstrated that ATV exposure affected the expression of the Sirtuin/PXR signaling pathway, thus further interfered adaption of M. chulae to the environment.
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Affiliation(s)
- Yufei Zhao
- Department of Ecology, Jinan University, Guangzhou, 510632, China
| | - Meinan Xie
- Department of Ecology, Jinan University, Guangzhou, 510632, China
| | - Chao Wang
- Department of Ecology, Jinan University, Guangzhou, 510632, China
| | - Yimeng Wang
- Department of Ecology, Jinan University, Guangzhou, 510632, China
| | - Ying Peng
- Research and Development Center for Watershed Environmental Eco-Engineering, Beijing Normal University, Zhuhai, China
| | - Xiangping Nie
- Department of Ecology, Jinan University, Guangzhou, 510632, China.
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30
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Adolph RS, Beck E, Schweimer K, Di Fonzo A, Weyand M, Rösch P, Wöhrl BM, Steegborn C. Molecular Mechanism of Sirtuin 1 Inhibition by Human Immunodeficiency Virus 1 Tat Protein. Life (Basel) 2023; 13:life13040949. [PMID: 37109478 PMCID: PMC10144703 DOI: 10.3390/life13040949] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/20/2023] [Accepted: 03/30/2023] [Indexed: 04/08/2023] Open
Abstract
Sirtuins are NAD+-dependent protein lysine deacylases implicated in metabolic regulation and aging-related dysfunctions. The nuclear isoform Sirt1 deacetylates histones and transcription factors and contributes, e.g., to brain and immune cell functions. Upon infection by human immunodeficiency virus 1 (HIV1), Sirt1 deacetylates the viral transactivator of transcription (Tat) protein to promote the expression of the viral genome. Tat, in turn, inhibits Sirt1, leading to the T cell hyperactivation associated with HIV infection. Here, we describe the molecular mechanism of Tat-dependent sirtuin inhibition. Using Tat-derived peptides and recombinant Tat protein, we mapped the inhibitory activity to Tat residues 34–59, comprising Tat core and basic regions and including the Sirt1 deacetylation site Lys50. Tat binds to the sirtuin catalytic core and inhibits Sirt1, Sirt2, and Sirt3 with comparable potencies. Biochemical data and crystal structures of sirtuin complexes with Tat peptides reveal that Tat exploits its intrinsically extended basic region for binding to the sirtuin substrate binding cleft through substrate-like β-strand interactions, supported by charge complementarity. Tat Lys50 is positioned in the sirtuin substrate lysine pocket, although binding and inhibition do not require prior acetylation and rely on subtle differences to the binding of regular substrates. Our results provide mechanistic insights into sirtuin regulation by Tat, improving our understanding of physiological sirtuin regulation and the role of this interaction during HIV1 infection.
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Affiliation(s)
- Ramona S. Adolph
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | - Eileen Beck
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | - Kristian Schweimer
- Department of Biopolymers, University of Bayreuth, 95440 Bayreuth, Germany
| | - Andrea Di Fonzo
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | - Michael Weyand
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | - Paul Rösch
- Department of Biopolymers, University of Bayreuth, 95440 Bayreuth, Germany
| | - Birgitta M. Wöhrl
- Department of Biopolymers, University of Bayreuth, 95440 Bayreuth, Germany
| | - Clemens Steegborn
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
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Zhang Z, Sun W, Zhang G, Fang Z, Chen X, Li L. Design, synthesis, and biological screening of a series of pyrazolo [1,5-a]quina-zoline derivatives as SIRT6 activators. Eur J Pharm Sci 2023; 185:106424. [PMID: 36918058 DOI: 10.1016/j.ejps.2023.106424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 03/02/2023] [Accepted: 03/11/2023] [Indexed: 03/14/2023]
Abstract
SIRT6 has emerged as a novel therapeutic target for a variety of diseases. In this study, a total of 102 pyrazolo [1,5-a]quinazoline derivatives were designed and synthesized. The result revealed that 2-methyl-N-(4-phenoxy-phenyl)pyrazolo [1,5-a]quinazoline-5-amine (21q) was the most active compound by structure-activity relationship study, which significantly enhanced SIRT6 defatty-acylation activity with an EC1.5 value of 1.85±0.41 μM and EC50 value of 11.15±0.33 μM. The biological activity of 21q was further verified by differential scanning fluorimetry assay (DSF) and surface plasmon resonance assay (SPR). Molecular docking showed that the pyrazolo [1,5-a]quinazoline of 21q formed a hydrogen bond with Val115 and four π- π interactions with Phe64, Phe82 and Phe86. 21q can significantly improve the thermal stability of SIRT6 protein and inhibit the PI3K/Akt signaling pathway in mouse embryonic fibroblasts (MEFs), thereby inhibiting the proliferation of MEFs. Collectively, we discovered a new potent SIRT6 activator, which can be taken as a lead compound for later studies.
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Affiliation(s)
- Ziling Zhang
- Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Weining Sun
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Guo Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Zhen Fang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xiuli Chen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Linli Li
- Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
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Poniewierska-Baran A, Bochniak O, Warias P, Pawlik A. Role of Sirtuins in the Pathogenesis of Rheumatoid Arthritis. Int J Mol Sci 2023; 24:ijms24021532. [PMID: 36675041 PMCID: PMC9864987 DOI: 10.3390/ijms24021532] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 01/07/2023] [Accepted: 01/10/2023] [Indexed: 01/14/2023] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease leading to joint destruction. The causes of RA are not fully known. Most likely, the development of the disease depends on the coexistence of many factors, such as hereditary factors, immune system defects, gender, infectious agents, nicotine, and stress. Various epigenetic changes have been identified and correlated with the aggressive phenotype of RA, including the involvement of sirtuins, which are enzymes found in all living organisms. Their high content in the human body can slow down the aging processes, reduce cell death, counteract the appearance of inflammation, and regulate metabolic processes. Sirtuins can participate in several steps of RA pathogenesis. This narrative review presents, collects, and discusses the role of all sirtuins (1-7) in the pathogenesis of rheumatoid arthritis.
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Affiliation(s)
| | - Oliwia Bochniak
- Department of Physiology, Pomeranian Medical University in Szczecin, Powstancow Wielkopolskich 72, 70-111 Szczecin, Poland
| | - Paulina Warias
- Department of Physiology, Pomeranian Medical University in Szczecin, Powstancow Wielkopolskich 72, 70-111 Szczecin, Poland
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University in Szczecin, Powstancow Wielkopolskich 72, 70-111 Szczecin, Poland
- Correspondence:
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Liu Y, Zhang Z, Liu C, Zhang H. Sirtuins in osteoarthritis: current understanding. Front Immunol 2023; 14:1140653. [PMID: 37138887 PMCID: PMC10150098 DOI: 10.3389/fimmu.2023.1140653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 03/27/2023] [Indexed: 05/05/2023] Open
Abstract
Osteoarthritis (OA) is a common disease characterized by severe chronic joint pain, that imposes a large burden on elderly people. OA is a highly heterogeneous disease, and multiple etiologies contribute to its progression. Sirtuins (SIRTs) are Class III histone deacetylases (HDACs) that regulate a comprehensive range of biological processes such as gene expression, cell differentiation, and organism development, and lifespan. Over the past three decades, increasing evidence has revealed that SIRTs are not only important energy sensors but also protectors against metabolic stresses and aging, and an increasing number of studies have focused on the functions of SIRTs in OA pathogenesis. In this review, we illustrate the biological functions of SIRTs in OA pathogenesis from the perspectives of energy metabolism, inflammation, autophagy and cellular senescence. Moreover, we offer insights into the role played by SIRTs in regulating circadian rhythm, which has recently been recognized to be crucial in OA development. Here, we provide the current understanding of SIRTs in OA to guide a new direction for OA treatment exploration.
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Vo KCT, Sato Y, Kawamura K. Improvement of oocyte quality through the SIRT signaling pathway. Reprod Med Biol 2023; 22:e12510. [PMID: 36845003 PMCID: PMC9949364 DOI: 10.1002/rmb2.12510] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 01/23/2023] [Accepted: 02/05/2023] [Indexed: 02/25/2023] Open
Abstract
Background Oocyte quality is one of the major deciding factors in female fertility competence. Methods PubMed database was searched for reviews by using the following keyword "oocyte quality" AND "Sirtuins". The methodological quality of each literature review was assessed using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 statement. Main Findings Oxidative stress has been recognized as the mechanism attenuating oocyte quality. Increasing evidence from animal experiments and clinical studies has confirmed the protective roles of the sirtuin family in improving oocyte quality via an antioxidant effect. Conclusion The protective roles in the oocyte quality of the sirtuin family have been increasingly recognized.
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Affiliation(s)
- Kim Cat Tuyen Vo
- Graduate School of MedicineInternational University of Health and Welfare School of MedicineNarita‐shiJapan
- Department of Obstetrics & GynaecologyUniversity of Medicine and Pharmacy at Ho Chi Minh CityHo Chi Minh CityVietnam
| | - Yorino Sato
- Graduate School of MedicineInternational University of Health and Welfare School of MedicineNarita‐shiJapan
- Department of Obstetrics and GynecologyJuntendo University Faculty of MedicineBunkyokuJapan
| | - Kazuhiro Kawamura
- Graduate School of MedicineInternational University of Health and Welfare School of MedicineNarita‐shiJapan
- Department of Obstetrics and GynecologyJuntendo University Faculty of MedicineBunkyokuJapan
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Zhang YX, Ou MY, Yang ZH, Sun Y, Li QF, Zhou SB. Adipose tissue aging is regulated by an altered immune system. Front Immunol 2023; 14:1125395. [PMID: 36875140 PMCID: PMC9981968 DOI: 10.3389/fimmu.2023.1125395] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 01/30/2023] [Indexed: 02/19/2023] Open
Abstract
Adipose tissue is a widely distributed organ that plays a critical role in age-related physiological dysfunctions as an important source of chronic sterile low-grade inflammation. Adipose tissue undergoes diverse changes during aging, including fat depot redistribution, brown and beige fat decrease, functional decline of adipose progenitor and stem cells, senescent cell accumulation, and immune cell dysregulation. Specifically, inflammaging is common in aged adipose tissue. Adipose tissue inflammaging reduces adipose plasticity and pathologically contributes to adipocyte hypertrophy, fibrosis, and ultimately, adipose tissue dysfunction. Adipose tissue inflammaging also contributes to age-related diseases, such as diabetes, cardiovascular disease and cancer. There is an increased infiltration of immune cells into adipose tissue, and these infiltrating immune cells secrete proinflammatory cytokines and chemokines. Several important molecular and signaling pathways mediate the process, including JAK/STAT, NFκB and JNK, etc. The roles of immune cells in aging adipose tissue are complex, and the underlying mechanisms remain largely unclear. In this review, we summarize the consequences and causes of inflammaging in adipose tissue. We further outline the cellular/molecular mechanisms of adipose tissue inflammaging and propose potential therapeutic targets to alleviate age-related problems.
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Affiliation(s)
- Yi-Xiang Zhang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min-Yi Ou
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zi-Han Yang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Sun
- Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Qing-Feng Li
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuang-Bai Zhou
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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36
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Role of Advanced Glycation End Products in Intervertebral Disc Degeneration: Mechanism and Therapeutic Potential. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7299005. [PMID: 36573114 PMCID: PMC9789911 DOI: 10.1155/2022/7299005] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 11/22/2022] [Accepted: 12/05/2022] [Indexed: 12/23/2022]
Abstract
The incidence of low back pain caused by lumbar disc degeneration is high, and it can lead to loss of work ability and impose heavy social and economic burdens. The pathogenesis of low back pain is unclear, and there are no effective treatments. With age, the deposition of advanced glycation end products (AGEs) in intervertebral disc (IVD) gradually increases and is accelerated by diabetes and a high-AGEs diet, leading to destruction of the annulus fibrosus (AF), nucleus pulposus (NP), and cartilage endplate (CEP) and finally intervertebral disc degeneration (IDD). Reducing the accumulation of AGEs in IVD and blocking the transmission of downstream signals caused by AGEs have a significant effect on alleviating IDD. In this review, we summarize the mechanism by which AGEs induce IDD and potential treatment strategies.
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Poniewierska-Baran A, Warias P, Zgutka K. Sirtuins (SIRTs) As a Novel Target in Gastric Cancer. Int J Mol Sci 2022; 23:ijms232315119. [PMID: 36499440 PMCID: PMC9737976 DOI: 10.3390/ijms232315119] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/25/2022] [Accepted: 11/26/2022] [Indexed: 12/03/2022] Open
Abstract
Gastric cancer is a major health burden worldwide. Among all neoplasms, gastric cancer is the fifth most common and the third most deadly type of cancer. It is known that sirtuins (SIRTs), are NAD+-dependent histone deacetylases regulating important metabolic pathways. High expression of SIRTs in the human body can regulate metabolic processes; they prevent inflammation but also resist cell death and aging processes. The seven members of this family enzymes can also play a fundamental role in process of carcinogenesis by influencing cell viability, apoptosis and metastasis. This review collects and discusses the role of all seven sirtuins (SIRT1-SIRT7) in the pathogenesis of gastric cancer (GC).
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Affiliation(s)
- Agata Poniewierska-Baran
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland
- Correspondence:
| | - Paulina Warias
- Department of Physiology, Pomeranian Medical University in Szczecin, Powstancow Wielkopolskich 72, 70-111 Szczecin, Poland
| | - Katarzyna Zgutka
- Department of Physiology in Health Sciences, Faculty of Health Sciences, Pomeranian Medical University, Szczecin, Żołnierska 54, 70-210 Szczecin, Poland
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Liu Y, Zhang Z, Li T, Xu H, Zhang H. Senescence in osteoarthritis: from mechanism to potential treatment. Arthritis Res Ther 2022; 24:174. [PMID: 35869508 PMCID: PMC9306208 DOI: 10.1186/s13075-022-02859-x] [Citation(s) in RCA: 89] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 07/05/2022] [Indexed: 12/12/2022] Open
Abstract
Osteoarthritis (OA) is an age-related cartilage degenerative disease, and chondrocyte senescence has been extensively studied in recent years. Increased numbers of senescent chondrocytes are found in OA cartilage. Selective clearance of senescent chondrocytes in a post-traumatic osteoarthritis (PTOA) mouse model ameliorated OA development, while intraarticular injection of senescent cells induced mouse OA. However, the means and extent to which senescence affects OA remain unclear. Here, we review the latent mechanism of senescence in OA and propose potential therapeutic methods to target OA-related senescence, with an emphasis on immunotherapies. Natural killer (NK) cells participate in the elimination of senescent cells in multiple organs. A relatively comprehensive discussion is presented in that section. Risk factors for OA are ageing, obesity, metabolic disorders and mechanical overload. Determining the relationship between known risk factors and senescence will help elucidate OA pathogenesis and identify optimal treatments.
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Andrikakou P, Reebye V, Vasconcelos D, Yoon S, Voutila J, George AJT, Swiderski P, Habib R, Catley M, Blakey D, Habib NA, Rossi JJ, Huang KW. Enhancing SIRT1 Gene Expression Using Small Activating RNAs: A Novel Approach for Reversing Metabolic Syndrome. Nucleic Acid Ther 2022; 32:486-496. [PMID: 35895511 DOI: 10.1089/nat.2021.0115] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Metabolic syndrome (MetS) is a pathological condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. Sirtuin 1 (SIRT1), a highly conserved histone deacetylase, is characterized as a key metabolic regulator and protector against aging-associated pathologies, including MetS. In this study, we investigate the therapeutic potential of activating SIRT1 using small activating RNAs (saRNA), thereby reducing inflammatory-like responses and re-establishing normal lipid metabolism. SIRT1 saRNA significantly increased SIRT1 messenger RNA (mRNA) and protein levels in both lipopolysaccharide-stimulated and nonstimulated macrophages. SIRT1 saRNA significantly decreased inflammatory-like responses, by reducing mRNA levels of key inflammatory cytokines, such as Tumor Necrosis Factor alpha, Interleukin 1 beta (IL-1β), Interleukin 6 (IL-6), and chemokines Monocyte Chemoattractant Protein-1 and keratinocyte chemoattractant. SIRT1 overexpression also significantly reduced phosphorylation of nuclear factor-κB and c-Jun N-terminal kinase, both key signaling molecules for the inflammatory pathway. To investigate the therapeutic effect of SIRT1 upregulation, we treated a high-fat diet model with SIRT1 saRNA conjugated to a transferrin receptor aptamer for delivery to the liver and cellular internalization. Animals in the SIRT1 saRNA treatment arm demonstrated significantly decreased weight gain with a significant reduction in white adipose tissue, triglycerides, fasting glucose levels, and intracellular lipid accumulation. These suggest treatment-induced changes to lipid and glucose metabolism in the animals. The results of this study demonstrate that targeted activation of SIRT1 by saRNAs is a potential strategy to reverse MetS.
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Affiliation(s)
- Pinelopi Andrikakou
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Vikash Reebye
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Daniel Vasconcelos
- MiNA Therapeutics Limited, London, United Kingdom
- Center for Drug Discovery and Innovative Medicines (MedInUP), University of Porto, Porto, Portugal
| | - Sorah Yoon
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, California, USA
| | - Jon Voutila
- MiNA Therapeutics Limited, London, United Kingdom
| | | | - Piotr Swiderski
- DNA/RNA Synthesis Core Facility, Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California, USA
| | - Robert Habib
- MiNA Therapeutics Limited, London, United Kingdom
| | | | - David Blakey
- MiNA Therapeutics Limited, London, United Kingdom
| | - Nagy A Habib
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
- MiNA Therapeutics Limited, London, United Kingdom
| | - John J Rossi
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, California, USA
| | - Kai-Wen Huang
- Department of Surgery, Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan
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Suenkel B, Valente S, Zwergel C, Weiss S, Di Bello E, Fioravanti R, Aventaggiato M, Amorim JA, Garg N, Kumar S, Lombard DB, Hu T, Singh PK, Tafani M, Palmeira CM, Sinclair D, Mai A, Steegborn C. Potent and Specific Activators for Mitochondrial Sirtuins Sirt3 and Sirt5. J Med Chem 2022; 65:14015-14031. [PMID: 36228194 PMCID: PMC9653166 DOI: 10.1021/acs.jmedchem.2c01215] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Sirtuins are NAD+-dependent protein deacylases involved in metabolic regulation and aging-related diseases. Specific activators for seven human Sirtuin isoforms would be important chemical tools and potential therapeutic drugs. Activators have been described for Sirt1 and act via a unique N-terminal domain of this isoform. For most other Sirtuin isoforms, including mitochondrial Sirt3-5, no potent and specific activators have yet been identified. We here describe the identification and characterization of 1,4-dihydropyridine-based compounds that either act as pan Sirtuin activators or specifically stimulate Sirt3 or Sirt5. The activators bind to the Sirtuin catalytic cores independent of NAD+ and acylated peptides and stimulate turnover of peptide and protein substrates. The compounds also activate Sirt3 or Sirt5 in cellular systems regulating, e.g., apoptosis and electron transport chain. Our results provide a scaffold for potent Sirtuin activation and derivatives specific for Sirt3 and Sirt5 as an excellent basis for further drug development.
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Affiliation(s)
- Benjamin Suenkel
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | - Sergio Valente
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, and Pasteur Institute, Cenci-Bolognetti Foundation, 00185 Rome, Italy
| | - Clemens Zwergel
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, and Pasteur Institute, Cenci-Bolognetti Foundation, 00185 Rome, Italy
| | - Sandra Weiss
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | - Elisabetta Di Bello
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, and Pasteur Institute, Cenci-Bolognetti Foundation, 00185 Rome, Italy
| | - Rossella Fioravanti
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, and Pasteur Institute, Cenci-Bolognetti Foundation, 00185 Rome, Italy
| | - Michele Aventaggiato
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - João A. Amorim
- Department of Life Sciences, University of Coimbra, 3004-504 Coimbra, Portugal
- Center for Neurosciences and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
- Genetics Department, Blavatnik Institute, Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA 02115, USA
| | - Neha Garg
- Genetics Department, Blavatnik Institute, Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA 02115, USA
| | - Surinder Kumar
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109-2800, USA
| | - David B. Lombard
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109-2800, USA
- Institute of Gerontology, University of Michigan, Ann Arbor, MI 48109-2800, USA
| | - Tuo Hu
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA
| | - Pankaj K. Singh
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA
| | - Marco Tafani
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Carlos M. Palmeira
- Department of Life Sciences, University of Coimbra, 3004-504 Coimbra, Portugal
- Center for Neurosciences and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
| | - David Sinclair
- Genetics Department, Blavatnik Institute, Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA 02115, USA
| | - Antonello Mai
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, and Pasteur Institute, Cenci-Bolognetti Foundation, 00185 Rome, Italy
| | - Clemens Steegborn
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
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Weiss S, Adolph RS, Schweimer K, DiFonzo A, Meleshin M, Schutkowski M, Steegborn C. Molecular Mechanism of Sirtuin 1 Modulation by the AROS Protein. Int J Mol Sci 2022; 23:12764. [PMID: 36361557 PMCID: PMC9654219 DOI: 10.3390/ijms232112764] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/17/2022] [Accepted: 10/18/2022] [Indexed: 03/17/2025] Open
Abstract
The protein lysine deacylases of the NAD+-dependent Sirtuin family contribute to metabolic regulation, stress responses, and aging processes, and the human Sirtuin isoforms, Sirt1-7, are considered drug targets for aging-related diseases. The nuclear isoform Sirt1 deacetylates histones and transcription factors to regulate, e.g., metabolic adaptations and circadian mechanisms, and it is used as a therapeutic target for Huntington's disease and psoriasis. Sirt1 is regulated through a multitude of mechanisms, including the interaction with regulatory proteins such as the inhibitors Tat and Dbc1 or the activator AROS. Here, we describe a molecular characterization of AROS and how it regulates Sirt1. We find that AROS is a partly intrinsically disordered protein (IDP) that inhibits rather than activates Sirt1. A biochemical characterization of the interaction including binding and stability assays, NMR spectroscopy, mass spectrometry, and a crystal structure of Sirtuin/AROS peptide complex reveal that AROS acts as a competitive inhibitor, through binding to the Sirt1 substrate peptide site. Our results provide molecular insights in the physiological regulation of Sirt1 by a regulator protein and suggest the peptide site as an opportunity for Sirt1-targeted drug development.
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Affiliation(s)
- Sandra Weiss
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | - Ramona S. Adolph
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | - Kristian Schweimer
- Department of Biopolymers, University of Bayreuth, 95440 Bayreuth, Germany
| | - Andrea DiFonzo
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
| | - Marat Meleshin
- Department of Enzymology, Charles Tanford Protein Center, Institute for Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany
| | - Mike Schutkowski
- Department of Enzymology, Charles Tanford Protein Center, Institute for Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany
| | - Clemens Steegborn
- Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
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Leite PLDA, Maciel LA, Santos PA, Barbosa LP, Gutierrez SD, Corrêa HDL, de Deus LA, Araújo MC, Aguiar SDS, Rosa TDS, Lewis JE, Simões HG. HIGHER SIRT1 IS ASSOCIATED WITH A BETTER BODY COMPOSITION IN MASTER SPRINTERS AND UNTRAINED PEERS. Eur J Sport Sci 2022:1-8. [PMID: 36259465 DOI: 10.1080/17461391.2022.2138556] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Sirt1 is an enzyme involved in several anti-aging pathways. Associations between Sirt1, age, and body fat (BF) were assessed in master sprinters (MS; n = 35; 50.25 ±5.93 yr.), untrained young non-athletes (UY; n = 32; 23.78 ±3.98 yr.), and untrained middle-aged (UMA; n = 24; 47.29 ±8.04 yr.). BF was assessed using a skinfold protocol, and Sirt1 was measured in plasma by using commercial kits. Sirt1 of MS (17.18 ±4.77 ng/mL) was higher than UMA (6.36 ±2.29 ng/mL; p<0.0001) and did not differ from UY (20.26 ±6.20 ng/mL). Relative BF of MS was lower than UMA (12.71 ±4.07% vs. 22.13 ±4.18%; p<0.0001). Sirt1 was negatively correlated with chronological age (r =-0.735; p<0.0001) when combining UY and UMA in the analysis. However, when Sirt1 of MS and UY were analyzed together, no significant relationship between Sirt1 and chronological age was observed (r= -0.243; p=0.083). Sirt1 correlated inversely with BF (r= -0.743; p<0.0001) for UY and UMA. Stepwise multiple regression revealed that being either a young or master athlete, as well as body adiposity, are possible predictors of Sirt1 levels. MS and UY were associated with higher levels of Sirt1, while UMA and increased BF were associated with lower levels of this enzyme. The relationships among Sirt1, BF, and chronological age of young and middle-aged non-athletes were not statistically significant when the middle-aged participants were MS. These findings suggest possible links between Sirt1 and body composition, which may play roles in the rate of biological aging.Highlights Lower levels of Sirt1 are associated with higher body fat.Master Athlete lifestyle seems to promote higher Sirt1 Levels.
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Affiliation(s)
| | - Larissa Alves Maciel
- Graduate Program in Physical Education, Catholic University of Brasilia, Taguatinga DF, Brazil
| | - Patrick Anderson Santos
- Graduate Program in Physical Education, Catholic University of Brasilia, Taguatinga DF, Brazil
| | - Lucas Pinheiro Barbosa
- Graduate Program in Physical Education, Catholic University of Brasilia, Taguatinga DF, Brazil
| | - Sara Duarte Gutierrez
- Graduate Program in Physical Education, Catholic University of Brasilia, Taguatinga DF, Brazil.,Graduate Program in Medicine, Catholic University of Brasilia, DF, Brazil
| | | | - Lysleine Alves de Deus
- Graduate Program in Physical Education, Catholic University of Brasilia, Taguatinga DF, Brazil
| | - Marcia Cristina Araújo
- Graduate Program in Physical Education, Catholic University of Brasilia, Taguatinga DF, Brazil
| | - Samuel da Silva Aguiar
- Graduate Program in Medicine, Catholic University of Brasilia, DF, Brazil.,Postgraduate Program in Physical Education-Federal University of Mato Grosso-UFMT, Cuiabá, Brazil
| | - Thiago Dos Santos Rosa
- Graduate Program in Physical Education, Catholic University of Brasilia, Taguatinga DF, Brazil
| | - John E Lewis
- Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Herbert Gustavo Simões
- Graduate Program in Physical Education, Catholic University of Brasilia, Taguatinga DF, Brazil
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Han HF, Liu SZ, Zhang X, Wei M, Huang X, Yu WB. Duodenal-jejunal bypass increases intraduodenal bile acids and upregulates duodenal SIRT1 expression in high-fat diet and streptozotocin-induced diabetic rats. World J Gastroenterol 2022; 28:4338-4350. [PMID: 36159018 PMCID: PMC9453763 DOI: 10.3748/wjg.v28.i31.4338] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/28/2022] [Accepted: 07/25/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The mechanisms underlying diabetes remission after duodenal-jejunal bypass (DJB) remain elusive. In DJB surgery, the duodenum is excluded. However, the duodenum has emerged as an important regulator of glucose homeostasis, and elevated duodenal SIRT1 leads to improved hepatic insulin sensitivity. After DJB, bile acids (BAs) in the duodenum are not mixed and diluted by the ingested food. And activation of BA receptors promotes SIRT1 expression in many tissues. We hypothesized that BA-mediated upregulation of SIRT1 may contribute to diabetic control after DJB.
AIM To investigate the surgical effects of DJB on duodenal SIRT1 expression and uncover the potential crosslinks between BAs and SIRT1.
METHODS Twenty diabetic rats were randomly allocated to the sham (n = 10) and DJB (n = 10) groups. Body weight, food intake, fasting blood glucose (FBG), serum and intraduodenal total BA (TBA) levels were measured accordingly. Oral glucose tolerance test (OGTT) and intraperitoneal pyruvate tolerance test (ipPTT) were performed to evaluate the effects of surgeries on systemic glucose disposal and hepatic gluconeogenesis. The key genes of BA signaling pathway in the duodenal mucosa, including farnesoid X receptor (FXR), small heterodimer partner (SHP), and Takeda G-protein-coupled receptor 5 (TGR5) were evaluated by real-time quantitative polymerase chain reaction 8 wk postoperatively. The duodenal SIRT1, AMPK, and phosphorylated AMPK (p-AMPK) levels were evaluated by western blotting. Rat small intestine epithelial IEC-6 cells were treated with GW4064 and INT-777 to verify the effects of BAs on SIRT1 expression in enterocytes.
RESULTS The DJB group exhibited body weight and food intake comparable to those of the sham group at all postoperative time points. The FBG level and area under the curve for the OGTT and ipPTT were significantly lower in the DJB group. The DJB group exhibited higher fasting and postprandial serum TBA levels than the sham group at both 2 and 8 wk postoperatively. At 8 wk after surgery, the DJB group showed higher intraluminal TBA concentration, upregulated mRNA expression of FXR and SHP, and elevated protein expression of SIRT1 and p-AMPK in the descending and horizontal segments of the duodenum. Activation of FXR and TGR5 receptors by GW4064 and INT-777 increased the mRNA and protein expression of SIRT1 and promoted the phosphorylation of AMPK in IEC-6 cells.
CONCLUSION DJB elevates intraduodenal BA levels and activates the duodenal BA signaling pathway, which may upregulate duodenal SIRT1 and further contribute to improved glucose homeostasis after DJB.
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Affiliation(s)
- Hai-Feng Han
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Shao-Zhuang Liu
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Xiang Zhang
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Meng Wei
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Xin Huang
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Wen-Bin Yu
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
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Therapeutic Effect of Melatonin in Premature Ovarian Insufficiency: Hippo Pathway Is Involved. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3425877. [PMID: 36017238 PMCID: PMC9398856 DOI: 10.1155/2022/3425877] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 07/20/2022] [Accepted: 08/01/2022] [Indexed: 11/23/2022]
Abstract
Objective Premature ovarian insufficiency (POI) is a female reproductive disorder of unknown etiology with no definite pathogenesis. Melatonin (MT) is an endogenous hormone synthesized mainly by pineal cells and has strong endogenous effects in regulating ovarian function. To systematically explore the pharmacological mechanism of MT on POI therapy, a literature review approach was conducted at the signaling pathways level. Methods Relevant literatures were searched and downloaded from databases, including PubMed and China National Knowledge Infrastructure, using the keywords “premature ovarian insufficiency,” “Hippo signaling pathways,” and “melatonin.” The search criteria were from 2010 to 2022. Text mining was also performed. Results MT is involved in the regulation of Hippo signaling pathway in a variety of modes and has been correlated with ovarian function. Conclusions The purpose of this review is to summarize the research progress of Hippo signaling pathways and significance of MT in POI, the potential crosstalk between MT and Hippo signaling pathways, and the prospective therapy.
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Donlon TA, Morris BJ, Masaki KH, Chen R, Davy PMC, Kallianpur KJ, Nakagawa K, Owens JB, Willcox DC, Allsopp RC, Willcox BJ. FOXO3, a Resilience Gene: Impact on Lifespan, Healthspan, and Deathspan. J Gerontol A Biol Sci Med Sci 2022; 77:1479-1484. [PMID: 35960854 PMCID: PMC9373965 DOI: 10.1093/gerona/glac132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Timothy A Donlon
- Center of Biomedical Research Excellence for Translational Research on Aging and Department of Research, Kuakini Medical Center, Honolulu, Hawaii, USA
- Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA
| | - Brian J Morris
- Center of Biomedical Research Excellence for Translational Research on Aging and Department of Research, Kuakini Medical Center, Honolulu, Hawaii, USA
- Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA
- School of Medical Sciences, University of Sydney, Sydney, New South Wales, Australia
| | - Kamal H Masaki
- Center of Biomedical Research Excellence for Translational Research on Aging and Department of Research, Kuakini Medical Center, Honolulu, Hawaii, USA
- Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA
| | - Randi Chen
- Center of Biomedical Research Excellence for Translational Research on Aging and Department of Research, Kuakini Medical Center, Honolulu, Hawaii, USA
| | - Phillip M C Davy
- Center of Biomedical Research Excellence for Translational Research on Aging and Department of Research, Kuakini Medical Center, Honolulu, Hawaii, USA
- Institute for Biogenesis Research, University of Hawaii, Honolulu, Hawaii, USA
| | - Kalpana J Kallianpur
- Center of Biomedical Research Excellence for Translational Research on Aging and Department of Research, Kuakini Medical Center, Honolulu, Hawaii, USA
- Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA
| | - Kazuma Nakagawa
- Center of Biomedical Research Excellence for Translational Research on Aging and Department of Research, Kuakini Medical Center, Honolulu, Hawaii, USA
- Neuroscience Institute, The Queen’s Medical Center, Honolulu, Hawaii, USA
- Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA
| | - Jesse B Owens
- Center of Biomedical Research Excellence for Translational Research on Aging and Department of Research, Kuakini Medical Center, Honolulu, Hawaii, USA
- Institute for Biogenesis Research, University of Hawaii, Honolulu, Hawaii, USA
| | - D Craig Willcox
- Center of Biomedical Research Excellence for Translational Research on Aging and Department of Research, Kuakini Medical Center, Honolulu, Hawaii, USA
- Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA
- Department of Human Welfare, Okinawa International University, Ginowan, Okinawa, Japan
| | - Richard C Allsopp
- Center of Biomedical Research Excellence for Translational Research on Aging and Department of Research, Kuakini Medical Center, Honolulu, Hawaii, USA
- Institute for Biogenesis Research, University of Hawaii, Honolulu, Hawaii, USA
| | - Bradley J Willcox
- Center of Biomedical Research Excellence for Translational Research on Aging and Department of Research, Kuakini Medical Center, Honolulu, Hawaii, USA
- Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA
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Qin K, Tang H, Ren Y, Yang D, Li Y, Huang W, Wu Y, Yin Z. Melatonin promotes sirtuin 1 expression and inhibits IRE1α–XBP1S–CHOP to reduce endoplasmic reticulum stress–mediated apoptosis in chondrocytes. Front Pharmacol 2022; 13:940629. [PMID: 36034777 PMCID: PMC9404507 DOI: 10.3389/fphar.2022.940629] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/15/2022] [Indexed: 11/13/2022] Open
Abstract
Osteoarthritis (OA) is the most common chronic disease characterized by a loss of chondrocytes and the degeneration of cartilage. Inflammation plays an important role in the pathogenesis and progression of OA via the activation of the endoplasmic reticulum (ER) stress signaling pathway. In this study, we stimulated human primary chondrocytes with lipopolysaccharide (LPS) to reduce cell viability and induce chondrocyte apoptosis. LPS–stimulated human primary chondrocytes induced ER stress and significantly upregulated the ER chaperone glucose–regulated protein 78 (GRP78) and increased the expression level of C/EBP–homologous protein (CHOP), a key mediator of ER stress––induced apoptosis. Interestingly, melatonin treatment attenuated ER stress–mediated chondrocyte apoptosis. Melatonin inhibited the expression of cleaved caspase-3, cleaved caspase-10, Bax, CHOP, GRP78, cleaved caspase-4, phospho–inositol–requiring enzyme 1α (P-IRE1α), and spliced X-box-binding protein 1 (XBP1S). In an anterior cruciate ligament transection mouse model of OA, melatonin (50 and 150 mg/kg) dose–dependently relieved joint cartilage degeneration and inhibitied of chondrocyte apoptosis. Immunohistochemical analysis indicated that melatonin could promote SIRT1 the expression and inhibit CHOP and cleaved caspase-3 expression in OA mice. In conclusion, our findings demonstrate for the first time that melatonin inhibits the IRE1α-XBP1S-CHOP signaling pathway by promoting the expression of SIRT1 in LPS-treated human chondrocytes and delaying OA progression in vivo.
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Affiliation(s)
- Kunpeng Qin
- Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hao Tang
- Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yi Ren
- Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Di Yang
- Department of Orthopaedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yetian Li
- Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wei Huang
- Department of Orthopaedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yunfeng Wu
- Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- *Correspondence: Yunfeng Wu, ; Zongsheng Yin,
| | - Zongsheng Yin
- Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- *Correspondence: Yunfeng Wu, ; Zongsheng Yin,
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Iskander A, Yan LJ. Cisplatin-Induced Kidney Toxicity: Potential Roles of Major NAD +-Dependent Enzymes and Plant-Derived Natural Products. Biomolecules 2022; 12:1078. [PMID: 36008971 PMCID: PMC9405866 DOI: 10.3390/biom12081078] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 07/25/2022] [Accepted: 08/03/2022] [Indexed: 11/16/2022] Open
Abstract
Cisplatin is an FDA approved anti-cancer drug that is widely used for the treatment of a variety of solid tumors. However, the severe adverse effects of cisplatin, particularly kidney toxicity, restrict its clinical and medication applications. The major mechanisms of cisplatin-induced renal toxicity involve oxidative stress, inflammation, and renal fibrosis, which are covered in this short review. In particular, we review the underlying mechanisms of cisplatin kidney injury in the context of NAD+-dependent redox enzymes including mitochondrial complex I, NAD kinase, CD38, sirtuins, poly-ADP ribosylase polymerase, and nicotinamide nucleotide transhydrogenase (NNT) and their potential contributing roles in the amelioration of cisplatin-induced kidney injury conferred by natural products derived from plants. We also cover general procedures used to create animal models of cisplatin-induced kidney injury involving mice and rats. We highlight the fact that more studies will be needed to dissect the role of each NAD+-dependent redox enzyme and its involvement in modulating cisplatin-induced kidney injury, in conjunction with intensive research in NAD+ redox biology and the protective effects of natural products against cisplatin-induced kidney injury.
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Affiliation(s)
| | - Liang-Jun Yan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
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Wu X, Fan X, Crawford R, Xiao Y, Prasadam I. The Metabolic Landscape in Osteoarthritis. Aging Dis 2022; 13:1166-1182. [PMID: 35855332 PMCID: PMC9286923 DOI: 10.14336/ad.2021.1228] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 12/28/2021] [Indexed: 11/01/2022] Open
Abstract
Articular cartilage function depends on the temporal and zonal distribution of coordinated metabolic regulation in chondrocytes. Emerging evidence shows the importance of cellular metabolism in the molecular control of the cartilage and its dysregulation in degenerative diseases like osteoarthritis (OA). Compared to most other tissues, chondrocytes are sparsely located in the extracellular matrix, lacking the typical proximity of neural, vascular, and lymphatic tissue. Making up under 5% of the total tissue weight of cartilage, chondrocytes have a relative deficiency of access to nutrients and oxygen, as well as limited pathways for metabolite removal. This makes cartilage a unique tissue with hypocellularity, prolonged metabolic rate, and tissue turnover. Studies in the past decade have shown that several pathways of central carbon metabolism are essential for cartilage homeostasis. Here, we summarised the literature findings on the role of cellular metabolism in determining the chondrocyte function and how this metabolic dysregulation led to cartilage aging in OA and provided an outlook on how the field may evolve in the coming years. Although the various energy metabolism pathways are inextricably linked with one another, for the purpose of this review, we initially endeavoured to examine them individually and in relative isolation. Subsequently, we comment on what is known regarding the integration and linked signalling pathways between these systems and the therapeutic opportunities for targeting OA metabolism.
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Affiliation(s)
- Xiaoxin Wu
- Centre for Biomedical Technologies, Faculty of Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
- Department of Orthopaedic Surgery, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Xiwei Fan
- Centre for Biomedical Technologies, Faculty of Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
| | - Ross Crawford
- Centre for Biomedical Technologies, Faculty of Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
- The Prince Charles Hospital, Orthopedic Department, Brisbane, Queensland, Australia.
| | - Yin Xiao
- Centre for Biomedical Technologies, Faculty of Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
- Australia-China Centre for Tissue Engineering and Regenerative Medicine, Queensland University of Technology, Brisbane, Queensland, Australia.
| | - Indira Prasadam
- Centre for Biomedical Technologies, Faculty of Engineering, Queensland University of Technology, Brisbane, Queensland, Australia.
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Garg SS, Gupta J. Polyol pathway and redox balance in diabetes. Pharmacol Res 2022; 182:106326. [PMID: 35752357 DOI: 10.1016/j.phrs.2022.106326] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/25/2022] [Accepted: 06/20/2022] [Indexed: 12/12/2022]
Abstract
Diabetes is a major public health disease that is globally approaching epidemic proportions. One of the major causes of type 2 diabetes is either a defect in insulin secretion or insulin action which is usually caused by a combination of genetic and environmental factors. Not only these factors but others such as deregulation of various pathways, and oxidative stress are also known to trigger the redox imbalance in diabetics. Increasing evidences suggest that there are tight interactions between the development of diabetes and redox imbalance. An alternate pathway of glucose metabolism, the polyol pathway, becomes active in patients with diabetes that disturbs the balance between NADH and NAD+ . The occurrence of such redox imbalance supports other pathways that lead to oxidative damage to DNA, lipids, and proteins and consequently to oxidative stress which further ascend diabetes and its complications. However, the precise mechanism through which oxidative stress regulates diabetes progression remains to be elucidated. The understanding of how antioxidants and oxidants are controlled and impact the generation of oxidative stress and progression of diabetes is essential. The main focus of this review is to provide an overview of redox imbalance caused by oxidative stress through the polyol pathway. Understanding the pathological role of oxidative stress in diabetes will help to design potential therapeutic strategies against diabetes.
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Affiliation(s)
- Sourbh Suren Garg
- Department of Biochemistry, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India
| | - Jeena Gupta
- Department of Biochemistry, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India.
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50
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Yuan Z, Zeng Y, Tian Y, Wang S, Hong B, Yang M. SIRT6 serves as a polyhedron in glycolytic metabolism and ageing-related diseases. Exp Gerontol 2022; 162:111765. [DOI: 10.1016/j.exger.2022.111765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/24/2022] [Accepted: 03/07/2022] [Indexed: 11/04/2022]
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