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Liu H, Shi W, Zhang X, He X, Zhao X. Identifying sex-based disparities in porcine mitochondrial function. Anim Biotechnol 2025; 36:2488068. [PMID: 40208306 DOI: 10.1080/10495398.2025.2488068] [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: 09/01/2024] [Accepted: 03/27/2025] [Indexed: 04/11/2025]
Abstract
In pigs, the effect of sex on production and reproductive traits has been largely reported, however, whether sex exerts its influence through regulating mitochondrial function is still unclear. In this study, we constructed 15 male cells and 15 female fibroblasts derived from 35-day and 50-day fetuses, newborn piglets and 1-year-old pigs to identify the sex effect on mitochondrial functions. Results indicated significant differences on cellular and molecular characteristics between male and female cells, including energy metabolic trait, mitochondrial DNA (mtDNA) replication and transcription, and mRNA expressions of mitochondrial biogenesis genes and mitoprotease genes. Referring to sex, males exhibited significantly higher oxygen consumption rate productions, levels of reactive oxygen species (ROS) and mtDNA copy numbers than those with females in muscle and ear fibroblasts. And the expressions of mtDNA, mitochondrial biogenesis genes (POLG, PPARGC1A, TFAM and TWNK) and XPNPEP3 were higher in males than females in ear fibroblasts derived from 1-year-old adult pigs (EFA cells). While, the cell proliferation and expressions of genes related to ROS metabolism were not influenced by sex. The results highlight the effect of sex on mitochondrial function and gene expression, and provide important data for a comprehensive understanding of the mechanisms underlying sex regulation of energy metabolism-related traits in pigs.
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Affiliation(s)
- Hao Liu
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Wenshu Shi
- State Key Laboratory of Animal Biotech Breeding, China Agricultural University, Beijing, China
| | - Xing Zhang
- State Key Laboratory of Animal Biotech Breeding, China Agricultural University, Beijing, China
| | - Xinmiao He
- Institute of Animal Husbandry, Heilongjiang Academy of Agricultural Sciences, Harbin, China
| | - Xingbo Zhao
- State Key Laboratory of Animal Biotech Breeding, China Agricultural University, Beijing, China
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2
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Wang Z, Zhou T, Shao M, Du J, Li Y, Wang S, Wu X. Maternal β-Nicotinamide Mononucleotide Supplementation Reduces the IUGR Rate by Improving Mitochondrial Function in the Placenta of Sows via AMPK/PGC-1α Pathway. Mol Nutr Food Res 2025:e70061. [PMID: 40420689 DOI: 10.1002/mnfr.70061] [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: 11/08/2024] [Revised: 03/24/2025] [Accepted: 03/26/2025] [Indexed: 05/28/2025]
Abstract
Metabolic disturbances in late gestation contributes to oxidative stress and mitochondrial dysfunction in the placenta, leading to intrauterine growth retardation (IUGR), all of which are associated with reduced nicotinamide adenine dinucleotide (NAD+) levels. This study aimed to investigate the effects of maternal supplementation of β-nicotinamide mononucleotide (NMN), a nutraceutical NAD+ precursor, on IUGR rate and its underlying mechanisms. A total of 24 sows were randomly divided into either the control or NMN group, with each sow in the NMN group receiving 0.2 g of NMN per day. The results demonstrated that NMN supplementation significantly reduced the IUGR rate and increased NAD+ levels in the placenta of sows. Furthermore, NMN supplements upregulated mRNA and protein expressions of key mitochondrial regulators, such as PGC-1α, declined oxidative stress and apoptosis, and improved lipid metabolism in the placenta. These effects were linked to the upregulation of p-AMPK and the downregulation expression of p-mTOR. Taken together, this study indicates that maternal NMN supplementation reduces the IUGR rate by improving mitochondria function, enhancing lipid metabolism, and declining oxidative stress in the placenta.
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Affiliation(s)
- Zhefeng Wang
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, Hunan, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Tiantian Zhou
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Muyang Shao
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, Hunan, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Jiajun Du
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China
| | - Yumeng Li
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China
| | - Shujin Wang
- Center for Obesity and Metabolic Diseases Research, School of Basic Medicine, Chongqing Medical University, Chongqing, China
| | - Xin Wu
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, Hunan, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China
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3
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Grossi E, Marchese FP, González J, Goñi E, Fernández-Justel JM, Amadoz A, Herranz N, Puchades-Carrasco L, Montes M, Huarte M. A lncRNA-mediated metabolic rewiring of cell senescence. Cell Rep 2025; 44:115747. [PMID: 40408249 DOI: 10.1016/j.celrep.2025.115747] [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: 08/24/2023] [Revised: 03/21/2025] [Accepted: 05/06/2025] [Indexed: 05/25/2025] Open
Abstract
Despite not proliferating, senescent cells remain metabolically active to maintain the senescence program. However, the mechanisms behind this metabolic reprogramming are not well understood. We identify senescence-induced long noncoding RNA (sin-lncRNA), a previously uncharacterized long noncoding RNA (lncRNA), a key player in this response. While strongly activated in senescence by C/EBPβ, sin-lncRNA loss reinforces the senescence program by altering oxidative phosphorylation and rewiring mitochondrial metabolism. By interacting with dihydrolipoamide S-succinyltransferase (DLST), it facilitates its mitochondrial localization. Depletion of sin-lncRNA causes DLST nuclear translocation, leading to transcriptional changes in oxidative phosphorylation (OXPHOS) genes. While not expressed in highly proliferative cancer cells, it is strongly induced upon cisplatin-induced senescence. Depletion of sin-lncRNA in ovarian cancer cells reduces oxygen consumption and increases extracellular acidification, sensitizing cells to cisplatin treatment. Altogether, these results indicate that sin-lncRNA is specifically induced in senescence to maintain metabolic homeostasis, unveiling an RNA-dependent metabolic rewiring specific to senescent cells.
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Affiliation(s)
- Elena Grossi
- Center for Applied Medical Research, University of Navarra, Pamplona, Spain; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain
| | - Francesco P Marchese
- Center for Applied Medical Research, University of Navarra, Pamplona, Spain; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain
| | - Jovanna González
- Center for Applied Medical Research, University of Navarra, Pamplona, Spain; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain
| | - Enrique Goñi
- Center for Applied Medical Research, University of Navarra, Pamplona, Spain; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain
| | - José Miguel Fernández-Justel
- Center for Applied Medical Research, University of Navarra, Pamplona, Spain; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain
| | - Alicia Amadoz
- Center for Applied Medical Research, University of Navarra, Pamplona, Spain; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain
| | - Nicolás Herranz
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain
| | - Leonor Puchades-Carrasco
- Drug Discovery Unit, Instituto de Investigación Sanitaria La Fe (IISLAFE), 46026 Valencia, Spain
| | - Marta Montes
- Center for Applied Medical Research, University of Navarra, Pamplona, Spain; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain.
| | - Maite Huarte
- Center for Applied Medical Research, University of Navarra, Pamplona, Spain; Institute of Health Research of Navarra (IdiSNA), Pamplona, Spain.
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4
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Ryan P, Lee J. In vitro senescence and senolytic functional assays. Biomater Sci 2025. [PMID: 40375674 DOI: 10.1039/d4bm01684j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2025]
Abstract
A detailed understanding of aging biology and the development of anti-aging therapeutic strategies remain imperative yet inherently challenging due to the protracted nature of aging. Cellular senescence arises naturally through replicative exhaustion and is accelerated by clinical treatments or environmental stressors. The accumulation of senescent cells-defined by a loss of mitogenic potential, resistance to apoptosis, and acquisition of a pro-inflammatory secretory phenotype-has been implicated as a key driver of chronic disease, tissue degeneration, and organismal aging. Recent studies have highlighted the therapeutic promise of senolytic drugs, which selectively eliminate senescent cells. Compelling results from preclinical animal studies and ongoing clinical trials underscore this potential. However, the clinical translation of senolytics requires further pharmacological validation to refine selectivity, minimize toxicity, and determine optimal dosing. Equally important is the evaluation of senolytics' potential to restore tissue structure and function by reducing the senescent cell burden. In vitro tissue culture models offer a powerful platform to advance these efforts. This review summarizes the current landscape of in vitro systems used for inducing cellular senescence-referred to as "senescence assays"-and for screening senolytic drugs-referred to as "senolytic assays". We conclude by discussing key challenges to improving mechanistic insight, predictive accuracy, and clinical relevance in senolytic drug development, as well as emerging applications of senolytic therapies.
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Affiliation(s)
- Patrick Ryan
- Molecular & Cellular Biology Graduate Program, University of Massachusetts, Amherst, Massachusetts, 01003, USA.
| | - Jungwoo Lee
- Molecular & Cellular Biology Graduate Program, University of Massachusetts, Amherst, Massachusetts, 01003, USA.
- Department of Chemical Engineering, University of Massachusetts, Amherst, Massachusetts, 01003, USA
- Department of Biomedical Engineering, University of Massachusetts, Amherst, Massachusetts, 01003, USA
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Saleh T, Greenberg EF, Faber AC, Harada H, Gewirtz DA. A Critical Appraisal of the Utility of Targeting Therapy-Induced Senescence for Cancer Treatment. Cancer Res 2025; 85:1755-1768. [PMID: 40036150 DOI: 10.1158/0008-5472.can-24-2219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 01/03/2025] [Accepted: 02/21/2025] [Indexed: 03/06/2025]
Abstract
Cancer chemotherapy and radiotherapy are rarely successful in eliminating the entire tumor population, often leaving behind a subpopulation of senescent cells that can contribute to disease recurrence. These senescent tumor cells also secrete various chemokines and cytokines that may be tumor promoting and immunosuppressive. Recognition of the deleterious impact of therapy-induced senescence has led to the preclinical development of senolytic compounds that eliminate senescent cells, representing a potential strategy to enhance the efficacy of conventional and targeted anticancer therapy. However, it remains uncertain whether this strategy can or will be translated to the clinic. This review provides a summary of the recent preclinical literature supporting the use of senolytics as an adjunct for cancer treatment, discusses the limitations associated with their use in the current preclinical models, and provides perspectives on the clinical development of senolytics in cancer treatment regimens. Overall, preclinical studies support the potential of senolytics to enhance efficacy and prolong the antitumor activity of current standard-of-care cancer therapies that promote senescence. However, further work is needed to develop optimal senolytic agents with the appropriate combination of properties for clinical testing, specifically, activity in the context of therapy-induced senescence with acceptable tolerability.
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Affiliation(s)
- Tareq Saleh
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Bahrain
- Department of Pharmacology and Public Health, Faculty of Medicine, The Hashemite University, Zarqa, Jordan
| | | | - Anthony C Faber
- Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University, Richmond, Virginia
- Department of Pediatrics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
- Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, Virginia
| | - Hisashi Harada
- Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University, Richmond, Virginia
- Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, Virginia
| | - David A Gewirtz
- Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, Virginia
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
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Da J, Hu H, Wang L, Wang Z, Chen H, Xie Y, Li T, Wang J, Zhong M, Dang W, Liu Y, Tan W. Senescence-to-Pyroptosis Nanotuners: Navigating Tumor Inflammatory Microenvironment for Enhanced Immunotherapy. NANO LETTERS 2025; 25:8033-8042. [PMID: 40326155 DOI: 10.1021/acs.nanolett.5c01741] [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: 05/07/2025]
Abstract
Modulating cancer-related chronic inflammation (CCI) is essential to reverse the immunosuppressive tumor microenvironment (TME) for improved therapeutic outcomes. However, the complexity and dynamism of inflammatory processes within the TME pose formidable challenges. Here, we identify senescent tumor cells as a novel "nest"-like target and design a tailored nanotuner that transforms these cells from adversaries to allies in TME remodeling. Specifically, this nanotuner targets metabolic abnormalities and initiates cascading artificial reactions via chemiluminescence resonance energy transfer mechanisms, which trigger self-initiated and self-sustaining photodynamic processes for boosted 1O2, converting cellular senescence into pyroptosis. Such conversion fosters multifaceted immune activation, including blocking CCI networks, downregulating PD-L1, and enhancing dendritic cell maturation and T-cell recruitment in tumors. Assessments in two tumor models further demonstrate its durable antitumor effects against primary and distant solid tumors when combined with a PD-1 blockade. This work provides a paradigm shift for novel insights into tumor development and immunoregulatory tactics.
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Affiliation(s)
- Jun Da
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo and Biosensing, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China
| | - Haolan Hu
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo and Biosensing, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China
| | - Linlin Wang
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo and Biosensing, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China
| | - Zhiqiang Wang
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo and Biosensing, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China
| | - Hong Chen
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo and Biosensing, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China
| | - Yuqi Xie
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo and Biosensing, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China
| | - Ting Li
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo and Biosensing, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China
| | - Jian Wang
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo and Biosensing, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China
| | - Minjuan Zhong
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo and Biosensing, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China
| | - Wenya Dang
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo and Biosensing, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China
| | - Yanlan Liu
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo and Biosensing, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China
| | - Weihong Tan
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo and Biosensing, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China
- The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
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7
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Mazzone V, Alessio N, Aprile D, Galano G, De Rosa R, Schiraldi C, Di Bernardo G, Galderisi U. Terpenes: natural compounds found in plants as potential senotherapeutics targeting senescent mesenchymal stromal cells and promoting apoptosis. Stem Cell Res Ther 2025; 16:231. [PMID: 40346705 PMCID: PMC12065172 DOI: 10.1186/s13287-025-04310-9] [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: 02/05/2025] [Accepted: 04/01/2025] [Indexed: 05/11/2025] Open
Abstract
BACKGROUND Senescence in stem cells and progenitor cells can be particularly detrimental because these cells are essential for tissue renewal and overall organismal homeostasis. In mesenchymal stromal cells (MSCs), which comprise a heterogeneous mix of stem cells, progenitors, fibroblasts, and other stromal cells, senescence poses a significant challenge, as it impairs their ability to support tissue repair and maintenance. This decline in regenerative capacity can contribute to aging-related diseases, impaired wound healing, and degenerative disorders. One hallmark of senescence is resistance to apoptosis, mediated by activation of anti-apoptotic pathways. Consequently, senotherapeutics have emerged as a promising strategy to selectively eliminate senescent cells and promote healthy aging. Plant secondary metabolites, notably polyphenols and terpenes, exhibit diverse effects on living organisms and have served as medicinal agents. METHODS In this study, we investigated four terpenes-carvacrol, thymol, eugenol, and lycopene-for their senolytic potential in human senescent MSCs. RESULTS We found that these compounds induce apoptosis through both caspase-dependent and caspase-independent mechanisms, involving the activation of BAX, cytochrome c release, and translocation of apoptosis-inducing factor (AIF) from mitochondria to nuclei. Importantly, terpene-induced apoptosis was associated with a significant increase in reactive oxygen species, and pre-incubation with glutathione partially rescued cell viability, confirming oxidative stress as a central trigger. Moreover, we identified SRC pathway modulation as a critical determinant of the senescence-to-apoptosis shift, highlighting a key regulatory switch in terpene action. CONCLUSIONS These findings provide a detailed mechanistic dissection of terpene-induced senolysis and underscore their potential as promising candidates for senotherapeutics targeting senescent cells.
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Affiliation(s)
- Valeria Mazzone
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, via Luigi De Crecchio 7, 80138, Naples, Italy
| | - Nicola Alessio
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, via Luigi De Crecchio 7, 80138, Naples, Italy
| | - Domenico Aprile
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, via Luigi De Crecchio 7, 80138, Naples, Italy
| | - Giovanni Galano
- ASL Naples 1 Centro P.S.I. Napoli Est-Barra, 80147, Naples, Italy
| | - Roberto De Rosa
- ASL Naples 1 Centro P.S.I. Napoli Est-Barra, 80147, Naples, Italy
| | - Chiara Schiraldi
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, via Luigi De Crecchio 7, 80138, Naples, Italy
| | - Giovanni Di Bernardo
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, via Luigi De Crecchio 7, 80138, Naples, Italy.
| | - Umberto Galderisi
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, via Luigi De Crecchio 7, 80138, Naples, Italy.
- Genome and Stem Cell Center (GENKÖK), Erciyes University, Kayseri, Turkey.
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA, USA.
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Wang C, Li H, Li F, Yang Y, Xu Z, Gao T, Li R, Zhang R, Mu Y, Guo Z, Guo Q, Liu S. The mitochondrial protectant SS31 optimized decellularized Wharton's jelly scaffold improves allogeneic chondrocyte implantation-mediated articular cartilage repair. J Orthop Translat 2025; 52:126-137. [PMID: 40291636 PMCID: PMC12032180 DOI: 10.1016/j.jot.2025.03.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 03/24/2025] [Accepted: 03/31/2025] [Indexed: 04/30/2025] Open
Abstract
Background The process of allogeneic chondrocyte implantation entails obtaining donor chondrocytes, culturing them in a medium enriched with growth factors, and then introducing them-either individually or in conjunction with biocompatible scaffolds-into areas of cartilage damage. While promising, this approach is hindered by mitochondrial dysfunction in the implanted chondrocytes. Methods This research introduced an innovative approach by creating a new type of scaffold derived from Decellularized Umbilical Cord Wharton's Jelly (DUCWJ) extracted from human umbilical cords. The scaffold was manufactured using procedures involving decellularization and lyophilization. The resulting scaffold demonstrated superior characteristics, including high porosity, hydrophilic properties, and excellent biocompatibility. To enhance its function, SS31 peptides, known for their mitochondrial-protective properties, were chemically bonded to the scaffold surface, creating an SS31@DUCWJ system. This system aims to protect chondrocytes and regulate the mitochondrial respiratory chain (MRC), thereby improving cartilage repair mediated by allogeneic chondrocyte implantation. Results In vitro studies have shown that SS31 effectively attenuates metabolic dysfunction, extracellular matrix degradation, oxidative stress, inflammation, and mitochondrial damage induced by serial cell passages. Complementary in vivo experiments showed that the SS31@DUCWJ scaffold promoted regeneration of healthy articular cartilage in femoral condylar defects in rabbits. Conclusions This SS31-modified porous decellularized scaffold represents an innovative biomaterial with anti-inflammatory properties and targeted mitochondrial regulation. It offers a promising new approach for treating articular cartilage injuries. The translational potential of this article Our study was the first to successfully load the mitochondrial protectant SS31 onto a DUCWJ hydrogel scaffold for localized drug delivery. This method is highly efficacious in repairing cartilage defects and offers a promising new avenue for the treatment of such conditions.
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Affiliation(s)
- Chao Wang
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Hao Li
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Fakai Li
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Yongkang Yang
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Ziheng Xu
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Tianze Gao
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Runmeng Li
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Ruiyang Zhang
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Yuhao Mu
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Zheng Guo
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Quanyi Guo
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Shuyun Liu
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
- School of Medicine, Nankai University, Tianjin, 300071, China
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Sultana P, Honc O, Hodny Z, Novotny J. Clusterin Deficiency Promotes Cellular Senescence in Human Astrocytes. Mol Neurobiol 2025; 62:5774-5786. [PMID: 39627493 PMCID: PMC11953114 DOI: 10.1007/s12035-024-04650-2] [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: 02/27/2024] [Accepted: 11/25/2024] [Indexed: 03/29/2025]
Abstract
The glycoprotein clusterin (CLU) is involved in cell proliferation and DNA damage repair and is highly expressed in tumor cells. Here, we aimed to investigate the effects of CLU dysregulation on two human astrocytic cell lines: CCF-STTG1 astrocytoma cells and SV-40 immortalized normal human astrocytes. We observed that suppression of CLU expression by RNA interference inhibited cell proliferation, triggered the DNA damage response, and resulted in cellular senescence in both cell types tested. To further investigate the underlying mechanism behind these changes, we measured reactive oxygen species, assessed mitochondrial function, and determined selected markers of the senescence-associated secretory phenotype. Our results suggest that CLU deficiency triggers oxidative stress-mediated cellular senescence associated with pronounced alterations in mitochondrial membrane potential, mitochondrial mass, and expression levels of OXPHOS complex I, II, III and IV, indicating mitochondrial dysfunction. This report shows the important role of CLU in cell cycle maintenance in astrocytes. Based on these data, targeting CLU may serve as a potential therapeutic approach valuable for treating gliomas.
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Affiliation(s)
- Pinky Sultana
- Department of Physiology, Faculty of Science, Charles University, Prague, 128 00, Czech Republic
- Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, 142 20, Czech Republic
| | - Ondrej Honc
- Department of Physiology, Faculty of Science, Charles University, Prague, 128 00, Czech Republic
| | - Zdenek Hodny
- Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, 142 20, Czech Republic
| | - Jiri Novotny
- Department of Physiology, Faculty of Science, Charles University, Prague, 128 00, Czech Republic.
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Niu J, Zhu G, Zhang J. Ginseng in delaying brain aging: Progress and Perspectives. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 140:156587. [PMID: 40049102 DOI: 10.1016/j.phymed.2025.156587] [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: 12/02/2024] [Revised: 01/23/2025] [Accepted: 02/26/2025] [Indexed: 03/25/2025]
Abstract
BACKGROUND The Shennong Bencao Jing (Shennong's Classic of Materia Medica) records that Panax ginseng C. A. Mey (ginseng) 'lightens the body and prolongs life'. Many investigations have documented that ginseng exerts neuroprotective effects by mitigating the aging of the brain. However, a comprehensive review of the impacts of ginseng on brain aging remains lacking. PURPOSE This study aims to review the advances in ginseng research regarding its role in delaying brain aging, focusing on its bioactive constituents, underlying mechanisms and potential side effects. The findings provide scientific pieces of evidence to support the medical utilization of ginseng in the delaying senescence and the management of aging-related diseases. METHODS This review includes studies on ginseng and brain aging in humans, retrieved from English-language research articles published between 2017 and the present in the PubMed and Web of Science databases. The work focused on ginseng, brain aging, and aging-related diseases, utilizing keywords such as "Ginseng", "Brain aging", "central nervous system", "intracellular homeostasis", "peripheral system", etc. RESULTS: Ginseng comprises a varied spectrum of biologically bioactive constituents, such as ginsenosides, Maillard reaction products, ginseng polysaccharides, volatile oils, amino acids, proteins, etc. These components work to contribute to their significant medicinal value. Based on the traditional Chinese medicine (TCM) theory that "the heart and brain are interconnected, the liver and brain are mutually supportive, the brain and spleen are related, the brain and lung are linked, and the brain and kidney work in harmony," we summarize that ginseng may sustain neural homeostasis through both central and peripheral perspectives. Additionally, the potential toxic side effects of ginseng are minimal. CONCLUSION Ginseng and its bioactive constituents exhibit considerable promise in delaying brain aging and treating neurodegenerative diseases. Future research should prioritize exploring the direct targets of ginseng and its active ingredients, and work toward establishing precise drug-target-efficacy relationships. This approach will facilitate the translation of these findings into clinically viable therapeutic approaches.
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Affiliation(s)
- Jingwen Niu
- Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, and Key Laboratory of Molecular Biology (Brain diseases), Anhui University of Chinese Medicine, Hefei 230012, China; Key Laboratory of Xin'an Medicine, the Ministry of Education, Anhui University of Chinese Medicine, Hefei 230038, China
| | - Guoqi Zhu
- Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, and Key Laboratory of Molecular Biology (Brain diseases), Anhui University of Chinese Medicine, Hefei 230012, China; Key Laboratory of Xin'an Medicine, the Ministry of Education, Anhui University of Chinese Medicine, Hefei 230038, China.
| | - Junjie Zhang
- Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, and Key Laboratory of Molecular Biology (Brain diseases), Anhui University of Chinese Medicine, Hefei 230012, China; Key Laboratory of Xin'an Medicine, the Ministry of Education, Anhui University of Chinese Medicine, Hefei 230038, China.
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11
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Begum F, Kristof J, Alam MJ, Sadiq AH, Hasan M, Soichiro K, Shimizu K. Exploring the Role of Microplasma for Controlling Cellular Senescence in Saccharomyces cerevisiae. Molecules 2025; 30:1970. [PMID: 40363776 PMCID: PMC12073758 DOI: 10.3390/molecules30091970] [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: 02/28/2025] [Revised: 04/19/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
Cellular senescence plays a pivotal role in aging and stress response mechanisms. Controlling cellular senescence is essential for developing novel techniques to prevent aging or aging-related diseases and promote a healthy lifespan. This study explores the efficiency of cold atmospheric microplasma (CAM) for controlling cellular senescence in yeast Saccharomyces cerevisiae. Reactive oxygen and nitrogen species (RONS) generated by CAM influence key processes, such as the regulation of oxidative stress, alterations in membrane potential, and senescence-related epigenetic modifications. As a marker of cellular senescence, the expression of β-galactosidase was assessed in response to different plasma treatments. At a frequency of 1 kHz and a discharge voltage of 5 kVp-p, a significant reduction in β-galactosidase activity was observed in cells treated for 10 s and 30 s compared to the control, indicating a reduction in cellular senescence. Additionally, cell viability, metabolic activity, and plasma membrane potential were also found to be higher for the treated cells compared to the control under the same conditions. This study confirms that a physiologically tolerable level of ROS and RNS is sufficient for cellular signaling, but not for damage induction. The findings from this study provide insights on the potential of microplasma as a tool for controlling cellular senescence and the development of therapeutic innovations involving eukaryotic cells.
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Affiliation(s)
- Farhana Begum
- Graduate School of Medical Photonics, Shizuoka University, Hamamatsu 832-8561, Japan; (J.K.); (M.J.A.)
| | - Jaroslav Kristof
- Graduate School of Medical Photonics, Shizuoka University, Hamamatsu 832-8561, Japan; (J.K.); (M.J.A.)
| | - Md Jahangir Alam
- Graduate School of Medical Photonics, Shizuoka University, Hamamatsu 832-8561, Japan; (J.K.); (M.J.A.)
| | - Abubakar Hamza Sadiq
- Graduate School of Science and Technology, Shizuoka University, Hamamatsu 432-8561, Japan; (A.H.S.); (M.H.)
| | - Mahedi Hasan
- Graduate School of Science and Technology, Shizuoka University, Hamamatsu 432-8561, Japan; (A.H.S.); (M.H.)
| | - Kinoshita Soichiro
- Graduate School of Integrated Science and Technology, Shizuoka University, Hamamatsu 432-8561, Japan;
| | - Kazuo Shimizu
- Graduate School of Medical Photonics, Shizuoka University, Hamamatsu 832-8561, Japan; (J.K.); (M.J.A.)
- Graduate School of Science and Technology, Shizuoka University, Hamamatsu 432-8561, Japan; (A.H.S.); (M.H.)
- Graduate School of Integrated Science and Technology, Shizuoka University, Hamamatsu 432-8561, Japan;
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12
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Wu Y, Chen L, Pi D, Cui J, Liang Y, Wu P, Ouyang M, Zuo Q. Saikosaponin A induces cellular senescence in triple-negative breast cancer by inhibiting the PI3K/Akt signalling pathway. Front Pharmacol 2025; 16:1532579. [PMID: 40351423 PMCID: PMC12062077 DOI: 10.3389/fphar.2025.1532579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 04/11/2025] [Indexed: 05/14/2025] Open
Abstract
Background Breast cancer has now become the most prevalent cancer worldwide. Existing therapeutic agents are generally accompanied by significant side effects. Here, we highlight Saikosaponin A (SSA), a promising natural metabolite characterized by low toxicity, demonstrating significant efficacy against breast cancer through the induction of cellular senescence. Methods The antitumor property of SSA was determined via MTT colorimetric assay, 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, colony formation, and propidium iodide (PI) staining in vitro, as well as xenograft in vivo model. A network approach was used to predict potential targets of SSA reevant for a potential anti-tumor effect and verified through senescence-associated β-galactosidase (SA-β-gal), flow-cytometry analysis, RT-PCR, Western blotting, and immuno-histochemistry assay. Results SSA significantly suppressed proliferation and triggered cell cycle arrest of SUM159PT and MDA-MB-231 cells. Revealed by network analysis, cellular senescence, and phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway were implemented in the anti-tumor effects of SSA. SSA-stimulated senescence was associated with increased ROS production, distinct senescence-associated secretory phenotype (SASP), and restricted PI3K/Akt signaling, as well as p21 and p53 accumulation. Furthermore, SSA displayed inhibitory effects on tumor growth with minimal toxicity in animal studies, accompanied by activated biomarkers of cellular senescence and decreased expression of p-Akt and p-PI3K. Conclusion Taken together, based on the preliminary results of network analysis and further experimental validation, this study revealed that SSA significantly induced cell cycle arrest and senescence, and the inhibition of ROS-mediated PI3K/Akt pathway may be the potential mechanism in this process.
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Affiliation(s)
- Yingchao Wu
- State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Liushan Chen
- State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Department of Breast, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, China
- Guangdong Academy of Traditional Chinese Medicine, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, Guangdong, China
| | - Dajin Pi
- School of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong, China
| | - Jiaqi Cui
- School of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong, China
| | - Yuqi Liang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Department of Breast, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, China
- Guangdong Academy of Traditional Chinese Medicine, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, Guangdong, China
| | - Peng Wu
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Mingzi Ouyang
- School of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong, China
| | - Qian Zuo
- State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Department of Breast, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, China
- Guangdong Academy of Traditional Chinese Medicine, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, Guangdong, China
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Ene J, Liu C, Syed F, Sun L, Berry D, Durairaj P, Liu ZL, Zeng C, Jung S, Li Y. Biomanufacturing and lipidomics analysis of extracellular vesicles secreted by human blood vessel organoids in a vertical wheel bioreactor. Stem Cell Res Ther 2025; 16:207. [PMID: 40275401 PMCID: PMC12023677 DOI: 10.1186/s13287-025-04317-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 04/07/2025] [Indexed: 04/26/2025] Open
Abstract
BACKGROUND Extracellular vesicles (EVs) derived from human organoids are phospholipid bilayer-bound nanoparticles that carry therapeutic cargo. However, the low yield of EVs remains a critical bottleneck for clinical translation. Vertical-Wheel bioreactors (VWBRs), with unique design features, facilitate the scalable production of EVs secreted by human blood vessel organoids (BVOs) under controlled shear stress, using aggregate- and microcarrier-based culture systems. METHODS Human induced pluripotent stem cell-derived BVOs cultured as aggregates or on Synthemax II microcarriers within VWBRs (40 and 80 rpm) were compared to static controls. The organoids were characterized by metabolite profiling, flow cytometry, and gene expression of EV biogenesis markers. EVs were characterized by nanoparticle tracking analysis, electron microscopy, and Western blotting. Lipidomics provided insights into EV lipid composition, while functional assays assessed the impact of EVs in a D-galactose-induced senescence model. RESULTS VWBR cultures showed more aerobic metabolism and higher expression of EV biogenesis genes compared to the static control. EVs from different conditions were comparable in size, but the yields were significantly higher for microcarrier and dynamic cultures than static aggregates. Lipidomic profiling revealed minimal variation (< 0.36%) in total lipid content; however, distinct differences were identified in lipid chain lengths and saturation levels, affecting key pathways such as sphingolipid and neurotrophin signaling. Human BVO EVs demonstrated the abilities of reducing oxidative stress and increasing cell proliferation in vitro. CONCLUSIONS Human BVOs differentiated in VWBRs (in particular 40 rpm) produce 2-3 fold higher yield of EVs (per mL) than static control. The bio manufactured EVs from VWBRs have exosomal characteristics and therapeutic cargo, showing functional properties in in vitro assays. This innovative approach establishes VWBRs as a scalable platform for producing functional EVs with defined lipid profiles and therapeutic potential, paving the way for future in vivo studies.
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Affiliation(s)
- Justice Ene
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA
| | - Chang Liu
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA
| | - Falak Syed
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA
| | - Li Sun
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, 32306, USA
| | - Danyale Berry
- Department of Industrial and Manufacture Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA
- High Performance Materials Institute, Florida State University, Tallahassee, FL, 32310, USA
| | - Pradeepraj Durairaj
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA
| | - Zixiang Leonardo Liu
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA
| | - Changchun Zeng
- Department of Industrial and Manufacture Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA
- High Performance Materials Institute, Florida State University, Tallahassee, FL, 32310, USA
| | | | - Yan Li
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA.
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Lin M, Tang K, Zheng W, Zheng S, Hu K. Curcumin delivery system based on a chitosan-liposome encapsulated zeolitic imidazolate framework-8: a potential treatment antioxidant and antibacterial treatment after phacoemulsification. Biomed Mater 2025; 20:035013. [PMID: 40081008 DOI: 10.1088/1748-605x/adc05c] [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: 12/25/2024] [Accepted: 03/13/2025] [Indexed: 03/15/2025]
Abstract
Curcumin is a natural polyphenol extracted from plants that can interact with various molecular targets, including antioxidant, antibacterial, anticancer, and anti-aging activities. Due to its variety of pharmacological activities and large margin pf safety, curcumin has been used in the prevention and treatment of various diseases, such as Alzheimer's, heart, and rheumatic immune diseases. To develop curcumin eye drops that can be used as antioxidant and antibacterial agents after phacoemulsification, we have designed a nano-based drug delivery system to improve curcumin bioavailability and duration of action. We successfully prepared zeolitic imidazolate framework-8 (ZIF-8) coated with chitosan-liposome (Cur@ZIF-8/CS-Lip) for curcumin delivery. It can release curcumin for over 20 hin vitroand exhibits excellent biosafety, antioxidant, and antibacterial activities. Therefore, we hypothesized that Cur@ZIF-8/CS-Lip could reduce the incidence of oxidative stress and infection after cataract surgery.
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Affiliation(s)
- Meiting Lin
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Prevention and Treatment on major blinding diseases, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing 400016, People's Republic of China
| | - Kunyuan Tang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Prevention and Treatment on major blinding diseases, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing 400016, People's Republic of China
| | - Wendi Zheng
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Prevention and Treatment on major blinding diseases, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing 400016, People's Republic of China
| | - Shijie Zheng
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Prevention and Treatment on major blinding diseases, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing 400016, People's Republic of China
| | - Ke Hu
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Prevention and Treatment on major blinding diseases, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing 400016, People's Republic of China
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15
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Santoso T, Khairani AF, Bashari MH, Ramadhanti J, Rohmawati E, Oktora MP, Wiraswati HL. Patchouli Ethanol Extract Pogostemon cablin Benth. Against Aging Profiles in Doxorubicin-Induced 3T3-L1 Fibroblast Cell Lines. Aging Med (Milton) 2025; 8:156-163. [PMID: 40353056 PMCID: PMC12064996 DOI: 10.1002/agm2.70014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 01/20/2025] [Accepted: 03/27/2025] [Indexed: 05/14/2025] Open
Abstract
Objectives This research aimed to investigate the potential of Pogostemon cablin Benth's ethanolic extract (PCEE) as an antiaging agent. Methods We treated 3T3-L1 cells induced by doxorubicin with PCEE and assessed them with antiaging markers such as GLB-1 gene and telomere length with polymerase chain reaction (PCR), or reactive oxygen species (ROS) accumulation with 2,7-dichlorofluorescein diacetate (DCFHDA). Results This study demonstrates that PCEE can inhibit ROS accumulation, decrease the expression level of the senescence-associated β-galactosidase (SA-β-gal) gene, GLB-1, and maintain telomere length in doxorubicin-induced 3T3-L1 cells. Conclusion These studies reveal that PCEE is a promising antiaging agent. An in vivo approach should be conducted for further research.
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Affiliation(s)
- Teguh Santoso
- Graduate School of Master Program in Anti‐Aging and Aesthetic MedicineFaculty of Medicine, Universitas PadjadjaranBandungWest JavaIndonesia
| | - Astrid Feinisa Khairani
- Graduate School of Master Program in Anti‐Aging and Aesthetic MedicineFaculty of Medicine, Universitas PadjadjaranBandungWest JavaIndonesia
- Department of Biomedical SciencesFaculty of Medicine, Universitas PadjadjaranBandungWest JavaIndonesia
| | - Muhammad Hasan Bashari
- Graduate School of Master Program in Anti‐Aging and Aesthetic MedicineFaculty of Medicine, Universitas PadjadjaranBandungWest JavaIndonesia
- Department of Biomedical SciencesFaculty of Medicine, Universitas PadjadjaranBandungWest JavaIndonesia
- Oncology and Stem Cell Working GroupFaculty of Medicine, Universitas PadjadjaranBandungWest JavaIndonesia
| | - Julia Ramadhanti
- Graduate School of Master Program in Anti‐Aging and Aesthetic MedicineFaculty of Medicine, Universitas PadjadjaranBandungWest JavaIndonesia
- Oncology and Stem Cell Working GroupFaculty of Medicine, Universitas PadjadjaranBandungWest JavaIndonesia
| | - Enny Rohmawati
- Graduate School of Master Program in Anti‐Aging and Aesthetic MedicineFaculty of Medicine, Universitas PadjadjaranBandungWest JavaIndonesia
- Oncology and Stem Cell Working GroupFaculty of Medicine, Universitas PadjadjaranBandungWest JavaIndonesia
| | - Monika Pury Oktora
- Clinical Pharmacy and Pharmacology DepartmentUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
| | - Hesti Lina Wiraswati
- Graduate School of Master Program in Anti‐Aging and Aesthetic MedicineFaculty of Medicine, Universitas PadjadjaranBandungWest JavaIndonesia
- Department of Biomedical SciencesFaculty of Medicine, Universitas PadjadjaranBandungWest JavaIndonesia
- Oncology and Stem Cell Working GroupFaculty of Medicine, Universitas PadjadjaranBandungWest JavaIndonesia
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Han X, Shi Z, Wu Z, Zeng X, Sun Y, Yao K, Shen Q, Fan X, Luo J, Pan D. AGEs in cooked meat: Production, detection, and mechanisms of its inhibition by plant extracts. Food Res Int 2025; 207:116067. [PMID: 40086958 DOI: 10.1016/j.foodres.2025.116067] [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: 07/07/2024] [Revised: 02/16/2025] [Accepted: 02/22/2025] [Indexed: 03/16/2025]
Abstract
With the growing demand for food safety and nutrition, the challenge of ensuring the quality of cooked meat products while reducing the accumulation of AGEs during processing needs urgent attention. In this study, the patterns of AGEs production, detection methods, quality contribution, and molecular mechanisms of its inhibition by natural plant-based extracts (NPBE) in cooked meat products were comprehensively reviewed. NPBE can effectively reduce the accumulation of AGEs in meat by binding to AGEs precursors and reducing glycosylation sites. It has also been shown to significantly remove off-flavour, and inhibit protein carbonylation. The potential for synergistic inhibition of AGE formation using NPBE and exogenous physical field treatments such as pulsed electric fields, microwave irradiation, thermal cycling of air, and ultrasound was emphasized, as well as the urgent need for the development of portable AGE detectors integrated with artificial intelligence and big data analytical models. This study indicates the future research direction for inhibiting the generation of AGEs in cooked meat products, which can promote and guide the practical application of NPBE in cooked meat products.
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Affiliation(s)
- Xue Han
- State Key Laboratory of Agricultural Products Safety, Ningbo University, Ningbo 315211, China; College of Food Science and Engineering, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Zihang Shi
- State Key Laboratory of Agricultural Products Safety, Ningbo University, Ningbo 315211, China; College of Food Science and Engineering, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Zhen Wu
- State Key Laboratory of Agricultural Products Safety, Ningbo University, Ningbo 315211, China; College of Food Science and Engineering, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Xiaoqun Zeng
- State Key Laboratory of Agricultural Products Safety, Ningbo University, Ningbo 315211, China; College of Food Science and Engineering, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Yangying Sun
- State Key Laboratory of Agricultural Products Safety, Ningbo University, Ningbo 315211, China; College of Food Science and Engineering, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Kaiyong Yao
- Lanhai Ecological Agriculture (Hangzhou) Co., Ltd, Hangzhou 311402, China
| | - Qingwu Shen
- College of Food Science and Technology, Hunan Agricultural University, Changsha 410114, China
| | - Xiankang Fan
- State Key Laboratory of Agricultural Products Safety, Ningbo University, Ningbo 315211, China; College of Food Science and Engineering, Ningbo University, Ningbo, Zhejiang 315211, China; College of Food Science and Technology, Hunan Agricultural University, Changsha 410114, China.
| | - Jie Luo
- College of Food Science and Technology, Hunan Agricultural University, Changsha 410114, China.
| | - Daodong Pan
- State Key Laboratory of Agricultural Products Safety, Ningbo University, Ningbo 315211, China; College of Food Science and Engineering, Ningbo University, Ningbo, Zhejiang 315211, China.
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17
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Augello FR, Lombardi F, Ciafarone A, Altamura S, Marazzato M, Artone S, Cinque B, Palumbo P. Streptococcus thermophilus CNCM I-5570 lysate counteracts the aging process in human dermal fibroblast cells by neutralizing harmful free radicals and impacting antioxidant and anti-inflammatory pathways, thus restoring their physiological functions. Biomed Pharmacother 2025; 185:117975. [PMID: 40081000 DOI: 10.1016/j.biopha.2025.117975] [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: 11/27/2024] [Revised: 02/25/2025] [Accepted: 03/07/2025] [Indexed: 03/15/2025] Open
Abstract
Previous studies have highlighted the in vitro and in vivo anti-aging potential of Streptococcus thermophilus prompting us to investigate the biomolecular mechanisms underlying its effects. We evaluated the reparative ability of S. thermophilus lysate in a hydrogen peroxide (H2O2)-induced senescence model of human dermal fibroblasts (HDFs). Cell proliferation, cell number, and senescence level were evaluated by IncuCyte® Live Cell Imager system, trypan blue dye exclusion test and β-galactosidase activity, respectively. We analyzed p21, prolyl 4-hydroxylase A1, intracellular collagen I, nuclear factor E2-related factor 2 (Nrf2), nuclear factor kappa B (NF-κB) and heme oxygenase-1 expression through western blot. Extracellular levels of collagen I, interleukin-1β, and IL-6 were assessed by ELISA. The oxidative stress markers were assayed using standard methods. The direct antioxidant activity of probiotic was quantified using multiple techniques. The presence of antioxidant genes in probiotic was detected via PCR assay. Probiotic lysate exposure increased the proliferation rate, counteracted the aging by reducing β-galactosidase activity and p21 levels, promoted collagen I synthesis and neutralized oxidative stress by activating Nrf2. The probiotic lysate inhibited the NF-κB pathway with pro-inflammatory marker downregulation. Notably, we revealed that probiotic exhibited strong free radical scavenging ability, iron-chelating properties, and significant ferric reducing power in a concentration-dependent manner. We identified seven genes with antioxidant function in its genome. Our results show that S. thermophilus lysate is efficacious in suppressing the biomolecular events associated with H2O2-induced cellular aging, thus supporting the reparative action of S. thermophilus, helpful in treating skin aging.
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Affiliation(s)
| | - Francesca Lombardi
- Department of Life, Health & Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Alessia Ciafarone
- Department of Life, Health & Environmental Sciences, University of L'Aquila, L'Aquila, Italy; PhD School in Health & Environmental Sciences, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila 67100, Italy
| | - Serena Altamura
- Department of Life, Health & Environmental Sciences, University of L'Aquila, L'Aquila, Italy; PhD School in Medicine and Public Health, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila 67100, Italy
| | - Massimiliano Marazzato
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome 00185, Italy
| | - Serena Artone
- Department of Life, Health & Environmental Sciences, University of L'Aquila, L'Aquila, Italy; PhD School in Medicine and Public Health, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila 67100, Italy
| | - Benedetta Cinque
- Department of Life, Health & Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Paola Palumbo
- Department of Life, Health & Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
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McLarnon T, Watterson S, McCallion S, Cooper E, English AR, Kuan Y, Gibson DS, Murray EK, McCarroll F, Zhang S, Bjourson AJ, Rai TS. Sendotypes predict worsening renal function in chronic kidney disease patients. Clin Transl Med 2025; 15:e70279. [PMID: 40147025 PMCID: PMC11949504 DOI: 10.1002/ctm2.70279] [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: 12/03/2024] [Revised: 03/07/2025] [Accepted: 03/13/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Senescence associated secretory phenotype (SASP) contributes to age-related pathology, however the role of SASP in Chronic Kidney Disease (CKD) is unclear. Here, we employ a variety of omic techniques to show that senescence signatures can separate CKD patients into distinct senescence endotypes (Sendotype). METHODS Using specific numbers of senescent proteins, we clustered CKD patients into two distinct sendotypes based on proteomic expression. These clusters were evaluated with three independent criteria assessing inter and intra cluster distances. Differential expression analysis was then performed to investigate differing proteomic expression between sendotypes. RESULTS These clusters accurately stratified CKD patients, with patients in each sendotype having different clinical profiles. Higher expression of these proteins correlated with worsened disease symptomologies. Biological signalling pathways such as TNF, Janus kinase-signal transducers and activators of transcription (JAK-STAT) and NFKB were differentially enriched between patient sendotypes, suggesting potential mechanisms driving the endotype of CKD. CONCLUSION Our work reveals that, combining clinical features with SASP signatures from CKD patients may help predict whether a patient will have worsening or stable renal trajectory. This has implications for the CKD clinical care pathway and will help clinicians stratify CKD patients accurately. KEY POINTS Senescent proteins are upregulated in severe patients compared to mild patients Senescent proteins can stratify patients based on disease severity High expression of senescent proteins correlates with worsening renal trajectories.
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Affiliation(s)
- Thomas McLarnon
- School of MedicinePersonalised Medicine CentreUlster UniversityLondonderryUK
| | - Steven Watterson
- School of MedicinePersonalised Medicine CentreUlster UniversityLondonderryUK
| | - Sean McCallion
- School of MedicinePersonalised Medicine CentreUlster UniversityLondonderryUK
| | - Eamonn Cooper
- School of MedicinePersonalised Medicine CentreUlster UniversityLondonderryUK
| | - Andrew R. English
- School of MedicinePersonalised Medicine CentreUlster UniversityLondonderryUK
- School of Health and Life SciencesTeesside University, Campus HeartMiddlesbroughUK
| | - Ying Kuan
- Western Health and Social Care Trust, Altnagelvin Area HospitalLondonderryUK
| | - David S. Gibson
- School of MedicinePersonalised Medicine CentreUlster UniversityLondonderryUK
| | - Elaine K. Murray
- School of MedicinePersonalised Medicine CentreUlster UniversityLondonderryUK
| | - Frank McCarroll
- Western Health and Social Care Trust, Altnagelvin Area HospitalLondonderryUK
| | - Shu‐Dong Zhang
- School of MedicinePersonalised Medicine CentreUlster UniversityLondonderryUK
| | - Anthony J. Bjourson
- School of MedicinePersonalised Medicine CentreUlster UniversityLondonderryUK
| | - Taranjit Singh Rai
- School of MedicinePersonalised Medicine CentreUlster UniversityLondonderryUK
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19
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Jian X, Wang J, Hu J, Li Y, Wang Q, Wang H, Huang J, Ke Y, Liao H. Intramuscular Reactivity of the Modified Graphene Oxides and Their Bio-Reactivity in Aging Muscle. J Funct Biomater 2025; 16:115. [PMID: 40278223 PMCID: PMC12027639 DOI: 10.3390/jfb16040115] [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: 01/14/2025] [Revised: 02/24/2025] [Accepted: 03/03/2025] [Indexed: 04/26/2025] Open
Abstract
To enhance the biocompatibility and drug delivery efficiency of graphene oxide (GO), poly(ethylene glycol) (PEG), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), or its triblock copolymer PEG-PHBV-PEG (PPP) were used to chemically modify GO. However, it is still unknown whether non-toxic polymer-modified GO mediates muscle toxicity or triggers intramuscular inflammation. This study aims to investigate the biological reactivity and inflammation/immune response induced by PEG, PHBV, or PPP modified GO when injected into the tibialis anterior (TA) muscle of mice prior to drug loading. The results showed that after muscle exposure, the coating of biocompatible polymers on GO is more likely to provoke muscle necrosis. Muscle regeneration was found to occur earlier and more effectively in muscle treated with hydrophilic PEG-GO and PPP-GO compared to muscle treated with hydrophobic PHBV-GO. When observing the transient muscle macrophage invasion of three modified GOs, PHBV-GO caused severe muscle necrosis in the early stage, induced a delayed peak of macrophage aggregation, and caused severe inflammatory progression. All three kinds of modified GO induced T cell aggregation to varying degrees, but PEG-GO induced early mass muscle recruitment of CD4+ T cells and was more sensitive to cytotoxic T cells. Based on the higher biocompatibility of PPP-GO in muscles, PPP-GO was implanted into the muscles of old or adult mice. Compared to adult mice, aged mice are more vulnerable to the stress from PPP-GO, as demonstrated by a delayed inflammatory response and muscle regeneration.
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Affiliation(s)
- Xiaoting Jian
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Department of Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; (X.J.); (Y.L.); (Q.W.); (H.W.); (J.H.)
| | - Jiayin Wang
- Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Department of Biomedical Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China;
| | - Jijie Hu
- Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China;
| | - Yangyang Li
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Department of Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; (X.J.); (Y.L.); (Q.W.); (H.W.); (J.H.)
| | - Qisen Wang
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Department of Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; (X.J.); (Y.L.); (Q.W.); (H.W.); (J.H.)
| | - Han Wang
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Department of Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; (X.J.); (Y.L.); (Q.W.); (H.W.); (J.H.)
| | - Jingwen Huang
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Department of Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; (X.J.); (Y.L.); (Q.W.); (H.W.); (J.H.)
| | - Yu Ke
- Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Department of Biomedical Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China;
| | - Hua Liao
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Department of Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; (X.J.); (Y.L.); (Q.W.); (H.W.); (J.H.)
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20
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Brandauer K, Lorenz A, Schobesberger S, Schuller P, Frauenlob M, Spitz S, Ertl P. Sensor-integrated gut-on-a-chip for monitoring senescence-mediated changes in the intestinal barrier. LAB ON A CHIP 2025; 25:1694-1706. [PMID: 40007323 DOI: 10.1039/d4lc00896k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/27/2025]
Abstract
The incidence of inflammatory bowel disease among the elderly has significantly risen in recent years, posing a growing socioeconomic burden to aging societies. Moreover, non-gastrointestinal diseases, also prevalent in this demographic, have been linked to intestinal barrier dysfunction, thus highlighting the importance of investigating aged-mediated changes within the human gut. While gastrointestinal pathology often involves an impaired gut barrier, the impact of aging on the human gastrointestinal barrier function remains unclear. To explore the effect of senescence, a key hallmark of aging, on gut barrier integrity, we established and evaluated an in vitro gut-on-a-chip model tailored to investigate barrier changes by the integration of an impedance sensor. Here, a microfluidic gut-on-a-chip system containing integrated membrane-based electrode microarrays is used to non-invasively monitor epithelial barrier formation and senescence-mediated changes in barrier integrity upon treating Caco-2 cells with 0.8 μg mL-1 doxorubicin (DXR), a chemotherapeutic which induces cell cycle arrest. Results of our microfluidic human gut model reveal a DXR-mediated increase in impedance and cell hypertrophy as well as overexpression of p21, and CCL2, indicative of a senescent phenotype. Combined with the integrated electrodes, monitoring ∼57% of the cultivation area in situ and non-invasively, the developed chip-based senescent-gut model is ideally suited to study age-related malfunctions in barrier integrity.
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Affiliation(s)
- Konstanze Brandauer
- TU Wien, Faculty of Technical Chemistry, Getreidemarkt 9, 1060 Vienna, Austria.
| | - Alexandra Lorenz
- TU Wien, Faculty of Technical Chemistry, Getreidemarkt 9, 1060 Vienna, Austria.
| | | | - Patrick Schuller
- TU Wien, Faculty of Technical Chemistry, Getreidemarkt 9, 1060 Vienna, Austria.
| | - Martin Frauenlob
- TU Wien, Faculty of Technical Chemistry, Getreidemarkt 9, 1060 Vienna, Austria.
| | - Sarah Spitz
- TU Wien, Faculty of Technical Chemistry, Getreidemarkt 9, 1060 Vienna, Austria.
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Peter Ertl
- TU Wien, Faculty of Technical Chemistry, Getreidemarkt 9, 1060 Vienna, Austria.
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
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21
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Basu S, Ulbricht Y, Rossol M. Healthy and premature aging of monocytes and macrophages. Front Immunol 2025; 16:1506165. [PMID: 40165963 PMCID: PMC11955604 DOI: 10.3389/fimmu.2025.1506165] [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: 10/04/2024] [Accepted: 02/28/2025] [Indexed: 04/02/2025] Open
Abstract
Aging is associated with immunosenescence, a decline in immune functions, but also with inflammaging, a chronic, low-grade inflammation, contributing to immunosenescence. Monocytes and macrophages belong to the innate immune system and aging has a profound impact on these cells, leading to functional changes and most importantly, to the secretion of pro-inflammatory cytokines and thereby contributing to inflammaging. Rheumatoid arthritis (RA) is an autoimmune disease and age is an important risk factor for developing RA. RA is associated with the early development of age-related co-morbidities like cardiovascular manifestations and osteoporosis. The immune system of RA patients shows signs of premature aging like age-inappropriate increased production of myeloid cells, accelerated telomeric erosion, and the uncontrolled production of pro-inflammatory cytokines. In this review we discuss the influence of aging on monocytes and macrophages during healthy aging and premature aging in rheumatoid arthritis.
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Affiliation(s)
- Syamantak Basu
- Molecular Immunology, Faculty of Health Sciences, Brandenburg University of Technology (BTU) Cottbus-Senftenberg, Senftenberg, Germany
| | - Ying Ulbricht
- Molecular Immunology, Faculty of Health Sciences, Brandenburg University of Technology (BTU) Cottbus-Senftenberg, Senftenberg, Germany
| | - Manuela Rossol
- Molecular Immunology, Faculty of Health Sciences, Brandenburg University of Technology (BTU) Cottbus-Senftenberg, Senftenberg, Germany
- Faculty of Environment and Natural Sciences, Brandenburg University of Technology (BTU) Cottbus-Senftenberg, Senftenberg, Germany
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22
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Spiegel M. Fisetin as a Blueprint for Senotherapeutic Agents - Elucidating Geroprotective and Senolytic Properties with Molecular Modeling. Chemistry 2025; 31:e202403755. [PMID: 39688310 PMCID: PMC11914956 DOI: 10.1002/chem.202403755] [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: 10/16/2024] [Revised: 12/17/2024] [Accepted: 12/17/2024] [Indexed: 12/18/2024]
Abstract
Targeting senescent cells and the factors that accelerate this pathological state has recently emerged as a novel field in medicinal chemistry. As attention shifts to synthetic substances, studies on natural agents are often overlooked. In this paper, we present a detailed computational modeling study that encompasses quantum mechanics and molecular dynamics to elucidate the senotherapeutic activity of fisetin, a natural flavonoid. The mitochondrial environment, serving as a proxy for senescence, received special attention. Throughout the study, fisetin's outstanding geroprotective properties-exhibiting significant potential against ⋅OOH, O2⋅-, and ⋅OH radicals, surpassing those of Trolox or ascorbate-were identified. Furthermore, fisetin demonstrated a high capacity to restore oxidatively damaged biomolecules to their pristine forms, thereby renewing the functionality of proteins and amino acids. The senolytic properties were examined in terms of Bcl-2 and Bcl-xL inhibition. The results indicated that fisetin not only binds effectively to these proteins but also, with appropriate modifications, may exhibit specific selectivity toward either target. This study highlights fisetin's remarkable activity in these areas and provides a molecular description of the underlying processes, paving the way for future research.
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Affiliation(s)
- Maciej Spiegel
- Department of Organic Chemistry and Pharmaceutical TechnologyFaculty of PharmacyWroclaw Medical UniversityBorowska 211A50–556WroclawPoland
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23
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Teng Y, He J, Shen Y, Chen J, Qian Y, Huang Y, Tao X, Xu D, Fan Y. TIMP3 deficiency accelerates UVB-induced HaCaT cell senescence by regulating ferroptosis. Photochem Photobiol Sci 2025; 24:499-509. [PMID: 40117061 DOI: 10.1007/s43630-025-00701-2] [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: 11/20/2024] [Accepted: 02/26/2025] [Indexed: 03/23/2025]
Abstract
Prolonged exposure to ultraviolet B (UVB) light leads to the accumulation of reactive oxygen species (ROS), a key contributor to skin aging. Previous studies have demonstrated that UVB exposure results in a deficiency in the expression of TIMP3 in keratinocytes. The objective of this study was to investigate the specific role of TIMP3 in keratinocytes. UVB-treated HaCaT cells were utilized to establish a cellular photoaging model. We found that UVB significantly increased levels of ROS, promoted senescence and ferroptosis, and inhibited the expression of TIMP3 in HaCaT. This inhibition was notably alleviated by Fer-1, a ferroptosis inhibitor. In addition, the knockdown of TIMP3 in HaCaT enhanced senescence by inducing the ferroptosis. Mechanistically, UVB exposure also led to a decrease in the expression of KLF4, a transcription factor that regulated TIMP3 expression. Futhermore, UVB-induced reduced expression of KLF4 and TIMP3 in vivo. Our results suggest that deletion of the KLF4/TIMP3 axis promotes HaCaT cell senescence by facilitating the progression of ferroptosis. TIMP3 may serve as an effective therapeutic target for preventing skin photoaging.
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Affiliation(s)
- Yan Teng
- Center for Plastic and Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - Junjia He
- Center for Plastic and Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - Yeyu Shen
- Center for Plastic and Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - Jie Chen
- Zhuji Sixth People's Hospital, Zhuji, Zhejiang, People's Republic of China
| | - Ye Qian
- Department of Gastroenterology, Chun'an County First People's Hospital (Zhejiang Provincial People's Hospital, Chun'an Branch), Hangzhou, Zhejiang, People's Republic of China
| | - Youming Huang
- Center for Plastic and Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - Xiaohua Tao
- Center for Plastic and Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - Danfeng Xu
- Center for Plastic and Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, People's Republic of China.
| | - Yibin Fan
- Center for Plastic and Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, People's Republic of China.
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24
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Légaré C, Berglund JA, Duchesne E, Dumont NA. New Horizons in Myotonic Dystrophy Type 1: Cellular Senescence as a Therapeutic Target. Bioessays 2025; 47:e202400216. [PMID: 39723693 PMCID: PMC11848125 DOI: 10.1002/bies.202400216] [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: 09/12/2024] [Revised: 12/02/2024] [Accepted: 12/05/2024] [Indexed: 12/28/2024]
Abstract
Myotonic dystrophy type 1 (DM1) is considered a progeroid disease (i.e., causing premature aging). This hypervariable disease affects multiple systems, such as the musculoskeletal, central nervous, gastrointestinal, and others. Despite advances in understanding the underlying pathogenic mechanism of DM1, numerous gaps persist in our understanding, hindering elucidation of the heterogeneity and severity of its symptoms. Accumulating evidence indicates that the toxic intracellular RNA accumulation associated with DM1 triggers cellular senescence. These cells are in a state of irreversible cell cycle arrest and secrete a cocktail of cytokines, referred to as a senescence-associated secretory phenotype (SASP), that can have harmful effects on neighboring cells and more broadly. We hypothesize that cellular senescence contributes to the pathophysiology of DM1, and clearance of senescent cells is a promising therapeutic approach for DM1. We will discuss the therapeutic potential of different senotherapeutic drugs, especially senolytics that eliminate senescent cells, and senomorphics that reduce SASP expression.
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Affiliation(s)
- Cécilia Légaré
- RNA InstituteCollege of Arts and SciencesUniversity at Albany‐SUNYAlbanyNew YorkUSA
- School of Rehabilitation SciencesFaculty of MedicineUniversité LavalQuebecQuebecCanada
- CHU de Québec – Université Laval Research CenterQuébecQuébecCanada
- Groupe de Recherche Interdisciplinaire sur les Maladies Neuromusculaires (GRIMN)Centre intégré universitaire de santé et de services sociaux du Saguenay‐Lac‐Saint‐JeanSaguenayQuebecCanada
| | - J. Andrew Berglund
- RNA InstituteCollege of Arts and SciencesUniversity at Albany‐SUNYAlbanyNew YorkUSA
- Department of Biological Sciences, College of Arts and SciencesUniversity at Albany‐SUNYAlbanyNew YorkUSA
| | - Elise Duchesne
- School of Rehabilitation SciencesFaculty of MedicineUniversité LavalQuebecQuebecCanada
- CHU de Québec – Université Laval Research CenterQuébecQuébecCanada
- Groupe de Recherche Interdisciplinaire sur les Maladies Neuromusculaires (GRIMN)Centre intégré universitaire de santé et de services sociaux du Saguenay‐Lac‐Saint‐JeanSaguenayQuebecCanada
- Centre Interdisciplinaire de Recherche en Réadaptation et Intégration Sociale (Cirris)Centre Intégré Universitaire de Santé et de Services Sociaux Capitale‐NationaleQuébecQuebecCanada
| | - Nicolas A. Dumont
- CHU Sainte‐Justine Research CenterMontrealQuebecCanada
- School of rehabilitationFaculty of MedicineUniversité de MontréalMontrealQuebecCanada
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25
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Mei Y, Wang L, Chen T, Song C, Cheng K, Cai W, Zhou D, Gao S, Jiang F, Liu S, Liu Z. Ferroptosis: A New Direction in the Treatment of Intervertebral Disc Degeneration. Cell Biochem Biophys 2025; 83:33-42. [PMID: 39102089 DOI: 10.1007/s12013-024-01468-6] [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] [Accepted: 07/26/2024] [Indexed: 08/06/2024]
Abstract
Intervertebral disc degeneration (IVDD) is one of the most common musculoskeletal disorders in middle-aged and elderly people, and lower back pain (LBP) is the main clinical symptom [1, 2], which often causes significant pain and great economic burden to patients [3]. The current molecular mechanisms of IVDD include extracellular matrix degradation, cellular pyroptosis, apoptosis, necrotic apoptosis, senescence, and the newly discovered ferroptosis [4, 5], among which ferroptosis, as a new hot spot of research, has a non-negligible role in IVDD. Ferroptosis is an iron-dependent cell death caused by lipid peroxide accumulation [6]. Its main mechanism is cell death caused by lipid peroxidation by oxygen radicals due to iron overload and inhibition of pathways such as SLC7A11-GSH-GPX4. Currently, more and more studies have found a close relationship between IVDD and ferroptosis [7]. In the process of ferroptosis, the most important factors are abnormal iron metabolism, increased ROS, lipid peroxidation, and abnormal proteins such as GSH, GPX4, and system XC-. Our group has previously elucidated the pathogenesis of IVDD in terms of extracellular matrix degradation, myeloid cell senescence and pyroptosis, apoptosis, and inflammatory immunity. Therefore, this time, we will use ferroptosis as an entry point to discover the new mechanism of IVDD and provide guidance for clinical treatment.
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Affiliation(s)
- Yongliang Mei
- Department of Orthopedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Liquan Wang
- Department of Orthopedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Ting Chen
- Department of Critical Care Medicine, Luzhou maternal's and Children's Health Hospital, Luzhou, 646000, Sichuan, China
| | - Chao Song
- Department of Orthopedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Kang Cheng
- Department of Orthopedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Weiye Cai
- Department of Orthopedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Daqian Zhou
- Department of Orthopedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Silong Gao
- Department of Orthopedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Feng Jiang
- Department of Orthopedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Shigui Liu
- Department of Orthopedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Zongchao Liu
- Department of Orthopedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, Sichuan, China.
- The Third People's Hospital of Luzhou, Luzhou, 646000, Sichuan, China.
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26
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Wu M, Wu B, Huang X, Wang Z, Zhu M, Zhu Y, Yu L, Liu J. Inhibition of the FEN1-PBX1 axis elicits cellular senescence in breast cancer via the increased intracellular reactive oxygen species levels. J Transl Med 2025; 23:248. [PMID: 40022092 PMCID: PMC11871692 DOI: 10.1186/s12967-025-06216-9] [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: 09/18/2024] [Accepted: 02/10/2025] [Indexed: 03/03/2025] Open
Abstract
BACKGROUND Cellular senescence is a state of irreversible cell growth arrest. As such, senescence induction is viewed as an efficacious countermeasure in cancer treatment. Flap endonuclease 1 (FEN1) has been reported to participate in tumor growth, metastasis and immunomodulation. However, the role of FEN1 in cellular senescence of breast cancer and its molecular mechanism remains unclear. METHODS In vitro assessments of breast cancer cell senescence and apoptosis were conducted using CCK-8 assay, cell cycle assay, senescence-associated β-galactosidase (SA-β-gal) staining, and cleaved caspase-3 staining. Western blot, dihydroethidium (DHE) staining, RNA-sequencing, quantitative real-time polymerase chain reaction (qRT-PCR), rescue experiments, and dual-luciferase reporter assay were performed to explore the potential target of FEN1. Co-Immunoprecipitation (Co-IP), Chromatin immunoprecipitation (ChIP)-qPCR assay, and immunostaining were used to evaluate the interaction between FEN1 and Pre-B-cell leukemia homeobox transcription factor 1 (PBX1). A xenograft mouse model was employed to validate the effect of FEN1 on breast cancer cell senescence and apoptosis. RESULTS Functional analysis demonstrated that FEN1 suppressed both senescence and apoptosis of breast cancer cells in vitro, while in vivo experiments demonstrated moderate therapeutic effects. Further studies indicated that FEN1 deficiency promoted the aforementioned effects by increasing intracellular reactive oxygen species (ROS) levels. RNA-sequencing and qRT-PCR assays revealed that FEN1 knockdown enhanced the expressions of several senescence-associated secretory phenotype (SASP) factors and resulted in decreased PBX1 level. The rescue experiments by PBX1 overexpression verified that PBX1 mediated the senescence and apoptosis of breast cancer cells induced by FEN1 inhibition. In detail, FEN1 downregulation inhibited the transcription activity of PBX1, which was partially restored by itself overexpression. Of note, FEN1 directly interacted with PBX1. Furthermore, immunostaining illustrated the colocalization of FEN1 and PBX1 in breast cancer cells and tissues. In our local breast cancer cohort, a positive correlation was identified between the expression levels of FEN1 and PBX1. CONCLUSIONS Knockdown of FEN1 facilitates breast cancer cell senescence through PBX1 down-regulation mediating increase in intracellular ROS levels. This study reveals FEN1 as a negative regulator of cellular senescence and provides support for pro-senescence cancer therapy. Given that FEN1 knockdown exhibited only moderate in vivo effects, these findings underscore the necessity of combining it with senolytic therapy to enhance therapeutic efficacy.
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Affiliation(s)
- Min Wu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China.
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225009, China.
| | - Benmeng Wu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225009, China
| | - Xiaoshan Huang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225009, China
| | - Zirui Wang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225009, China
| | - Miaolin Zhu
- Department of Pathology, Jiangsu Cancer Hospital, Nanjing, 210018, China
| | - Yaqin Zhu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225009, China
| | - Lin Yu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225009, China
| | - Jingjing Liu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China.
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225009, China.
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27
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Armanville S, Tocco C, Haj Mohamad Z, Clarke D, Robitaille R, Drouin-Ouellet J. Chemically Induced Senescence Prompts Functional Changes in Human Microglia-Like Cells. J Immunol Res 2025; 2025:3214633. [PMID: 40041406 PMCID: PMC11876530 DOI: 10.1155/jimr/3214633] [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: 03/26/2024] [Revised: 01/13/2025] [Accepted: 01/22/2025] [Indexed: 03/06/2025] Open
Abstract
In response to various stressors, cells can enter a state called cellular senescence which is characterized by irreversible cell cycle arrest and a senescence-associated secretory phenotype (SASP). The progressive accumulation of senescent glial cells in the central nervous system (CNS) with aging suggests a potential role for senescence as driver of aging and inflammation in the brain. As the main immune cell population residing in the CNS, microglia are thought to play a pivotal role in the progression of age-associated neuroinflammation. Furthermore, due to their slow turnover, microglia are highly susceptible to undergoing cellular senescence. However, current understanding of age-related changes in microglia and their impact on brain aging is limited. Due to the challenge in accessing human primary microglia and the lack of models to adequately recapitulate aging, this knowledge is predominantly limited to rodent studies. Here, we chemically induced senescence in a human immortalized microglia cell line with a cocktail of senescence-inducing molecules. We demonstrate that chemically induced senescent microglia adopt a proinflammatory phenotype, have reduced phagocytic activity, and impaired calcium activity. Our results show that chemically induced senescence can mimic features of cellular aging and can provide insight into the impact of aging and cellular senescence on human microglia.
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Affiliation(s)
- S. Armanville
- Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada
| | - C. Tocco
- Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada
| | - Z. Haj Mohamad
- Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada
| | - D. Clarke
- Department of Neuroscience, University of Montreal, Montreal, Quebec, Canada
| | - R. Robitaille
- Department of Neuroscience, University of Montreal, Montreal, Quebec, Canada
- Research Group on Neural Signalling and Circuits (SNC), University of Montreal, Montreal, Quebec, Canada
- Center for Interdisciplinary Research on Brain and Learning (CIRCA), Montreal, Quebec, Canada
| | - J. Drouin-Ouellet
- Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada
- Research Group on Neural Signalling and Circuits (SNC), University of Montreal, Montreal, Quebec, Canada
- Center for Interdisciplinary Research on Brain and Learning (CIRCA), Montreal, Quebec, Canada
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Wei Y, Zhang Y, Cao W, Cheng N, Xiao Y, Zhu Y, Xu Y, Zhang L, Guo L, Song J, Sha SH, Shao B, Ma F, Yang J, Ying Z, He Z, Chai R, Fang Q, Yang J. RONIN/HCF1-TFEB Axis Protects Against D-Galactose-Induced Cochlear Hair Cell Senescence Through Autophagy Activation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2407880. [PMID: 39985193 DOI: 10.1002/advs.202407880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 01/17/2025] [Indexed: 02/24/2025]
Abstract
Age-related hearing loss is characterized by senescent inner ear hair cells (HCs) and reduced autophagy. Despite the improved understanding of these processes, detailed molecular mechanisms underlying cochlear HC senescence remain unclear. Transcription Factor EB (TFEB), a key regulator of genes associated with autophagy and lysosomes, crucially affects aging-related illnesses. However, intricate regulatory networks that influence TFEB activity remain to be thoroughly elucidated. The findings revealed that RONIN (THAP11), through its interaction with host cell factor C1 (HCF1/HCFC1), modulated the transcriptional activity of Tfeb, thus contributing to the mitigation (D-galatactose [D-gal]) senescent HC loss. Specifically, RONIN overexpression improved autophagy levels and lysosomal activity and attenuated changes associated with the senescence of HCs triggered by D-gal. These findings highlight the possibility of using RONIN as a viable therapeutic target to ameliorate presbycusis by enhancing the TFEB function.
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Affiliation(s)
- Yongjie Wei
- Department of Otolaryngology-Head and Neck Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Yuhua Zhang
- Department of Otolaryngology-Head and Neck Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Wei Cao
- Department of Otolaryngology-Head and Neck Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Nan Cheng
- Department of Otolaryngology-Head and Neck Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Yun Xiao
- Department of Otolaryngology-Head and Neck Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Yongjun Zhu
- Department of Otolaryngology-Head and Neck Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Yan Xu
- Department of Otolaryngology-Head and Neck Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Lei Zhang
- Department of Otolaryngology-Head and Neck Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Lingna Guo
- Department of Otolaryngology-Head and Neck Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Jun Song
- Department of Otolaryngology-Head and Neck Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Su-Hua Sha
- Department of Pathology and Laboratory Medicine, The Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Buwei Shao
- School of Medicine, Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel
| | - Fang Ma
- Center for Scientific Research of Anhui Medical University, Hefei, 230032, China
| | - Jingwen Yang
- International Department of Hefei 168 High School, Hefei, 230601, China
| | - Zheng Ying
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Zuhong He
- Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, School of Medicine, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China
| | - Renjie Chai
- State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, School of Medicine, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China
- Co-Innovation Center of Neuroregeneration Nantong University, Nantong, 226001, China
- Department of Neurology, Aerospace Center Hospital, School of Life Science Beijing Institute of Technology, Beijing, 100081, China
- Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China
- Southeast University Shenzhen Research Institute, Shenzhen, 518063, China
| | - Qiaojun Fang
- Department of Otolaryngology-Head and Neck Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Jianming Yang
- Department of Otolaryngology-Head and Neck Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
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Tang D, Guan W, Yang X, Li Z, Zhao W, Liu X. TIM8 Deficiency in Yeast Induces Endoplasmic Reticulum Stress and Shortens the Chronological Lifespan. Biomolecules 2025; 15:271. [PMID: 40001574 PMCID: PMC11853210 DOI: 10.3390/biom15020271] [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: 11/16/2024] [Revised: 02/08/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Yeast TIM8 was initially identified as a homolog of human TIMM8A/DDP1, which is associated with human deafness-dystonia syndrome. Tim8p is located in the mitochondrial intermembrane space and forms a hetero-oligomeric complex with Tim13p to facilitate protein transport through the TIM22 translocation system. Previous research has indicated that TIM8 is not essential for yeast survival but does affect the import of Tim23p in the absence of the Tim8-Tim13 complex. Previous research on TIM8 has focused mainly on its involvement in the mitochondrial protein transport pathway, and the precise biological function of TIM8 remains incompletely understood. In this study, we provide the first report that yeast TIM8 is associated with the endoplasmic reticulum (ER) stress response and chronological senescence. We found that deletion of TIM8 leads to both oxidative stress and ER stress in yeast cells while increasing resistance to the ER stress inducer tunicamycin (TM), which is accompanied by an enhanced basic unfolded protein response (UPR). More importantly, TIM8 deficiency can lead to a shortened chronological lifespan (CLS) but does not affect the replicative lifespan (RLS). Moreover, we found that improving the antioxidant capacity further increased TM resistance in the tim8Δ strain. Importantly, we provide evidence that the knockdown of TIMM8A in ARPE-19 human retinal pigment epithelium cells can also induce ER stress, suggesting the potential function of the TIM8 gene in ER stress is conserved from budding yeast to higher eukaryotes. In summary, these results suggest novel roles for TIM8 in maintaining ER homeostasis and CLS maintenance.
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Affiliation(s)
- Dong Tang
- Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Institute of Aging Research, Guangdong Medical University, Dongguan 523808, China;
| | - Wenbin Guan
- School of Medical Technology, Guangdong Medical University, Dongguan 523808, China; (W.G.); (X.Y.); (Z.L.)
| | - Xiaodi Yang
- School of Medical Technology, Guangdong Medical University, Dongguan 523808, China; (W.G.); (X.Y.); (Z.L.)
| | - Zhongqin Li
- School of Medical Technology, Guangdong Medical University, Dongguan 523808, China; (W.G.); (X.Y.); (Z.L.)
| | - Wei Zhao
- Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Institute of Aging Research, Guangdong Medical University, Dongguan 523808, China;
| | - Xinguang Liu
- Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Institute of Aging Research, Guangdong Medical University, Dongguan 523808, China;
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Aleksandrova Y, Neganova M. Antioxidant Senotherapy by Natural Compounds: A Beneficial Partner in Cancer Treatment. Antioxidants (Basel) 2025; 14:199. [PMID: 40002385 PMCID: PMC11851806 DOI: 10.3390/antiox14020199] [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: 01/30/2025] [Revised: 02/06/2025] [Accepted: 02/07/2025] [Indexed: 02/27/2025] Open
Abstract
Aging is a general biological process inherent in all living organisms. It is characterized by progressive cellular dysfunction. For many years, aging has been widely recognized as a highly effective mechanism for suppressing the progression of malignant neoplasms. However, in recent years, increasing evidence suggests a "double-edged" role of aging in cancer development. According to these data, aging is not only a tumor suppressor that leads to cell cycle arrest in neoplastic cells, but also a cancer promoter that ensures a chronic proinflammatory and immunosuppressive microenvironment. In this regard, in our review, we discuss recent data on the destructive role of senescent cells in the pathogenesis of cancer. We also identify for the first time correlations between the modulation of the senescence-associated secretory phenotype and the antitumor effects of naturally occurring molecules.
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Affiliation(s)
| | - Margarita Neganova
- Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilova St. 28, Bld. 1, Moscow 119991, Russia;
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Kasem EA, Hamza G, El-Shafai NM, Ghanem NF, Mahmoud S, Sayed SM, Alshehri MA, Al-Shuraym LA, Ghamry HI, Mahfouz ME, Shukry M. Thymoquinone-Loaded Chitosan Nanoparticles Combat Testicular Aging and Oxidative Stress Through SIRT1/FOXO3a Activation: An In Vivo and In Vitro Study. Pharmaceutics 2025; 17:210. [PMID: 40006577 PMCID: PMC11858917 DOI: 10.3390/pharmaceutics17020210] [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: 10/01/2024] [Revised: 01/24/2025] [Accepted: 01/31/2025] [Indexed: 02/27/2025] Open
Abstract
Background: Aging is a complex biological process characterized by the accumulation of molecular and cellular damage over time, often driven by oxidative stress. This oxidative stress is particularly detrimental to the testes, where it causes degeneration, reduced testosterone levels, and compromised fertility. D-galactose (D-gal) is commonly used to model aging as it induces oxidative stress, mimicking age-related cellular and molecular damage. Testicular aging is of significant concern due to its implications for reproductive health and hormonal balance. This research examines the protection by thymoquinone (TQ) or thymoquinone-loaded chitosan nanoparticles (NCPs) against D-galactose (D-gal)-induced aging in rat testes, focusing on biochemical, histological, and molecular changes. Aging, which is driven largely by oxidative stress, leads to significant testicular degeneration, reducing fertility. D-gal is widely used to model aging due to its ability to induce oxidative stress and mimic age-related damage. TQ, a bioactive ingredient of Nigella sativa, has earned a reputation for its anti-inflammatory, anti-apoptotic, and antioxidant characteristics, but its therapeutic application is limited by its poor bioavailability. Methods: Thymoquinone was loaded into chitosan nanoparticles (NCPs) to enhance its efficacy, and this was hypothesized to improve its stability and bioavailability. Four groups of male Wistar rats participated in the study: one for the control, one for D-gal, one for D-gal + TQ, and the last one for D-gal + NCP. Results: The results exhibited that D-gal substantially increased oxidative injury, reduced testosterone levels, and caused testicular damage. Treatment with TQ and NCPs significantly reduced oxidative stress, improved antioxidant enzyme levels, and restored testosterone levels, with NCPs showing a stronger protective effect than TQ alone. A histological analysis confirmed that NCPs better preserved testicular structure and function. Additionally, the NCP treatment upregulated the expression of key genes of oxidative stress resistance, mitochondrial function, and reproductive health, including SIRT1, FOXO3a, and TERT. Conclusions: The findings suggest that NCPs offer enhanced protection against aging-related testicular damage compared with TQ alone, which is likely due to the improved bioavailability and stability provided by the nanoparticle delivery system. This research emphasizes the potential of NCPs as a more effective therapeutic strategy for mitigating oxidative stress and age-related reproductive dysfunction. Future research should further explore the mechanisms underlying these protective effects.
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Affiliation(s)
- Enas A. Kasem
- Faculty of Science, Zoology Department, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Gehan Hamza
- Faculty of Science, Zoology Department, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Nagi M. El-Shafai
- Nanotechnology Center, Chemistry Department, Faculty of Science, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Nora F. Ghanem
- Faculty of Science, Zoology Department, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Shawky Mahmoud
- Department of Physiology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Samy M. Sayed
- Department of Economic Entomology and Pesticides, Faculty of Agriculture, Cairo University, Giza 12613, Egypt
| | - Mohammed Ali Alshehri
- Department of Biology, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Laila A. Al-Shuraym
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia;
| | - Heba I. Ghamry
- Nutrition and Food Science, Department of Biology, College of Science, King Khalid University, P.O. Box 960, Abha 61421, Saudi Arabia;
| | - Magdy E. Mahfouz
- Faculty of Science, Zoology Department, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Mustafa Shukry
- Department of Physiology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
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Ayala-Peña VB, Jaimes AK, Conesa AL, García CC, Sepulveda CS, Dellatorre FG, Latour E, Ponce NMA, Álvarez VA, Lassalle VL. New Insights into Antiviral Natural Formulations: Biopolymeric Films for the Prevention and Treatment of a Wide Gamma of Viral Infections. Viruses 2025; 17:216. [PMID: 40006971 PMCID: PMC11861794 DOI: 10.3390/v17020216] [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: 12/13/2024] [Revised: 01/24/2025] [Accepted: 01/30/2025] [Indexed: 02/27/2025] Open
Abstract
Viral infections remain a major concern, as existing treatments often yield inadequate responses or lead to the development of antiviral resistance in some cases. Fucoidan extracted from Undaria pinnatifida (F) is a natural sulphated polysaccharide that exhibits antiviral action. Despite its potential, the biomedical application of F is limited due to its difficult administration through trans-mucosal, skin, or oral ingestion. The most effective way to solve these problems is to propose novel methods of administration aiming to ensure better contact between the biopolymers and pathogens, leading to their inactivation. In this work, the synthesis of films based on chitosan (Ch)-coupled F is reported, aiming to generate a synergic effect between both biopolymers in terms of their antiviral and antioxidant capability. Biocomposites were prepared by a sonochemical method. They were characterized to infer structural properties, functionality, and possible F-Ch interactions by using Zeta potential, FTIR, and XRD techniques. The biocomposites showed excellent film-forming ability. They also exhibited improved antioxidant activity with respect to F and Ch individually and proved to be non-cytotoxic. These results demonstrate, for the first time, the antiviral activity of F:Ch biocomposites against bovine coronavirus and human viruses (adenovirus, poliovirus, herpes simplex, and respiratory syncytial virus), which could be applied in film form to prevent or treat viral infections.
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Affiliation(s)
- Victoria Belén Ayala-Peña
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, San Juan 670, Bahía Blanca 8000, Argentina;
| | - Ana Karen Jaimes
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires 8000, Argentina; (A.K.J.); (C.C.G.); (C.S.S.); (F.G.D.); (N.M.A.P.); (V.A.Á.)
- INQUISUR, Departamento de Química, Universidad Nacional del Sur, Av. Alem 1253, Bahía Blanca 8000, Argentina
- Facultad de Ingeniería, INTEMA, Universidad Nacional de Mar del Plata (UNMdP), Av. Colón 10850, Mar del Plata 2695, Argentina
| | - Ana Lucía Conesa
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, San Juan 670, Bahía Blanca 8000, Argentina;
| | - Cybele Carina García
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires 8000, Argentina; (A.K.J.); (C.C.G.); (C.S.S.); (F.G.D.); (N.M.A.P.); (V.A.Á.)
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Av. Int. Güiraldes 2610, Buenos Aires 1053, Argentina
| | - Claudia Soledad Sepulveda
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires 8000, Argentina; (A.K.J.); (C.C.G.); (C.S.S.); (F.G.D.); (N.M.A.P.); (V.A.Á.)
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Av. Int. Güiraldes 2610, Buenos Aires 1053, Argentina
| | - Fernando Gaspar Dellatorre
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires 8000, Argentina; (A.K.J.); (C.C.G.); (C.S.S.); (F.G.D.); (N.M.A.P.); (V.A.Á.)
- Facultad Regional Chubut, Grupo de Investigación y Desarrollo Tecnológico en Acuicultura y Pesca (GIDTAP), Universidad Tecnológica Nacional, Av. del Trabajo 1536, Puerto Madryn 3000, Argentina;
| | - Ezequiel Latour
- Facultad Regional Chubut, Grupo de Investigación y Desarrollo Tecnológico en Acuicultura y Pesca (GIDTAP), Universidad Tecnológica Nacional, Av. del Trabajo 1536, Puerto Madryn 3000, Argentina;
| | - Nora Marta Andrea Ponce
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires 8000, Argentina; (A.K.J.); (C.C.G.); (C.S.S.); (F.G.D.); (N.M.A.P.); (V.A.Á.)
- Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales and Centro de Investigaciones en Hidratos de Carbono (CIHIDECAR-UBA), Universidad de Buenos Aires, Intendente Güiraldes 2160, Buenos Aires 1053, Argentina
| | - Vera Alejandra Álvarez
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires 8000, Argentina; (A.K.J.); (C.C.G.); (C.S.S.); (F.G.D.); (N.M.A.P.); (V.A.Á.)
- Facultad de Ingeniería, INTEMA, Universidad Nacional de Mar del Plata (UNMdP), Av. Colón 10850, Mar del Plata 2695, Argentina
| | - Verónica Leticia Lassalle
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires 8000, Argentina; (A.K.J.); (C.C.G.); (C.S.S.); (F.G.D.); (N.M.A.P.); (V.A.Á.)
- INQUISUR, Departamento de Química, Universidad Nacional del Sur, Av. Alem 1253, Bahía Blanca 8000, Argentina
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Zhang YZ, Huo DY, Liu Z, Li XD, Wang Z, Li W. Review on ginseng and its potential active substance G-Rg2 against age-related diseases: Traditional efficacy and mechanism. JOURNAL OF ETHNOPHARMACOLOGY 2025; 337:118781. [PMID: 39260708 DOI: 10.1016/j.jep.2024.118781] [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: 04/09/2024] [Revised: 08/04/2024] [Accepted: 09/02/2024] [Indexed: 09/13/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE According to the Shen Nong Herbal Classic, Ginseng (Panax ginseng C.A. Meyer) is documented to possess life-prolonging effects and is extensively utilized in traditional Chinese medicine for the treatment of various ailments such as qi deficiency, temper deficiency, insomnia, and forgetfulness. Ginseng is commonly employed for replenishing qi and nourishing blood, fortifying the body and augmenting immunity; it has demonstrated efficacy in alleviating fatigue, enhancing memory, and retarding aging. Furthermore, it exhibits a notable ameliorative impact on age-related conditions including cardiovascular diseases and neurodegenerative disorders. One of its active constituents - ginsenoside Rg2 (G-Rg2) - exhibits potential therapeutic efficacy in addressing these ailments. AIM OF THE REVIEW The aim of this review is to explore the traditional efficacy of ginseng in anti-aging diseases and the modern pharmacological mechanism of its potential active substance G-Rg2, in order to provide strong theoretical support for further elucidating the mechanism of its anti-aging effect. METHODS This review provides a comprehensive analysis of the traditional efficacy of ginseng and the potential mechanisms underlying the anti-age-related disease properties of G-Rg2, based on an extensive literature review up to March 12, 2024, from PubMed, Web of Science, Scopus, Cochrane, and Google Scholar databases. Potential anti-aging mechanisms of G-Rg2 were predicted using network pharmacology and molecular docking analysis techniques. RESULTS In traditional Chinese medicine theory, ginseng has been shown to improve aging-related diseases with a variety of effects, including tonifying qi, strengthening the spleen and stomach, nourishing yin, regulating yin and yang, as well as calming the mind. Its potential active ingredient G-Rg2 has demonstrated significant therapeutic potential in age-related diseases, especially central nervous system and cardiovascular diseases. G-Rg2 exhibited a variety of pharmacological activities, including anti-apoptotic, anti-inflammatory and antioxidant effects. Meanwhile, the network pharmacological analyses and molecular docking results were consistent with the existing literature review, further validating the potential efficacy of G-Rg2 as an anti-aging agent. CONCLUSION The review firstly explores the ameliorative effects of ginseng on a wide range of age-related diseases based on TCM theories. Secondly, the article focuses on the remarkable significance and value demonstrated by G-Rg2 in age-related cardiovascular and neurodegenerative diseases. Consequently, G-Rg2 has broad prospects for development in intervening in aging and treating age-related health problems.
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Affiliation(s)
- Yu-Zhuo Zhang
- College of Chinese Medicinal Materials, Jilin Provincial International Joint Research Center for the Development and Utilization of Authentic Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China
| | - De-Yang Huo
- College of Chinese Medicinal Materials, Jilin Provincial International Joint Research Center for the Development and Utilization of Authentic Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China
| | - Zhi Liu
- College of Chinese Medicinal Materials, Jilin Provincial International Joint Research Center for the Development and Utilization of Authentic Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China
| | - Xin-Dian Li
- College of Chinese Medicinal Materials, Jilin Provincial International Joint Research Center for the Development and Utilization of Authentic Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China
| | - Zi Wang
- College of Chinese Medicinal Materials, Jilin Provincial International Joint Research Center for the Development and Utilization of Authentic Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China
| | - Wei Li
- College of Chinese Medicinal Materials, Jilin Provincial International Joint Research Center for the Development and Utilization of Authentic Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China; College of Life Sciences, Jilin Agricultural University, Changchun, 130118, China.
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Balaraman AK, Altamimi ASA, Babu MA, Goyal K, PadmaPriya G, Bansal P, Rajotiya S, Kumar MR, Rajput P, Imran M, Gupta G, Thangavelu L. The interplay of senescence and MMPs in myocardial infarction: implications for cardiac aging and therapeutics. Biogerontology 2025; 26:46. [PMID: 39832057 DOI: 10.1007/s10522-025-10190-6] [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: 11/18/2024] [Accepted: 01/04/2025] [Indexed: 01/22/2025]
Abstract
Aging is associated with a marked increase in cardiovascular diseases, such as myocardial infarction (MI). Cellular senescence is also a crucial factor in the development of age-related MI. Matrix metalloproteinases (MMPs) interaction with cellular senescence is a critical determinant of MI development and outcomes, most notably in the aged heart. After experiencing a heart attack, senescent cells exhibit a Senescence-Associated Secretory Phenotype (SASP) and are involved in tissue regeneration and chronic inflammation. MMPs are necessary for extracellular matrix proteolysis and have a biphasic effect, promoting early heart healing and detrimental change if overexpressed shortly. This review analyses the complex connection between senescence and MMPs in MI and how it influences elderly cardiac performance. Critical findings suggest that increasing cellular senescence in aged hearts elevates MMP activity and aggravates extended ventricular remodeling and dysfunction. Additionally, we explore potential therapeutics that address MMPs and senescence to enhance old MI patient myocardial performance and regeneration.
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Affiliation(s)
- Ashok Kumar Balaraman
- Research and Enterprise, University of Cyberjaya, Persiaran Bestari Cyber 11, Cyberjaya, Selangor, 63000, Malaysia
| | | | - M Arockia Babu
- Institute of Pharmaceutical Research, GLA University, Uttar Pradesh, Mathura, India
| | - Kavita Goyal
- Department of Biotechnology, Graphic Era (Deemed to Be University), Clement Town, Dehradun, 248002, India
| | - G PadmaPriya
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Pooja Bansal
- Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan, 303012, India
| | - Sumit Rajotiya
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, India
| | - M Ravi Kumar
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, 531162, India
| | - Pranchal Rajput
- Division of Research and Innovation, Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Mohd Imran
- Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, 91911, Rafha, Saudi Arabia
- Center for Health Research, Northern Border University, Arar, Saudi Arabia
| | - Gaurav Gupta
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Punjab, India
- Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Lakshmi Thangavelu
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
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马 运, 曹 玉, 韩 小. [Lupeol Alleviates Chondrocytes Senescence in Osteoarthritis by Regulating Autophagy via the Sirtuin 3/Mechanistic Target of Rapamycin Kinase Pathway]. SICHUAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF SICHUAN UNIVERSITY. MEDICAL SCIENCE EDITION 2025; 56:83-93. [PMID: 40109468 PMCID: PMC11914001 DOI: 10.12182/20250160503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Indexed: 03/22/2025]
Abstract
Objective To investigate the role of lupeol in mitigating chondrocyte senescence in osteoarthritis (OA) by regulating autophagy through the sirtuin 3 (SIRT3)/mechanistic target of rapamycin kinase (mTOR) pathway. Methods Knee articular chondrocytes from primary-generation mice were isolated and divided into different groups, including a control group, a lupeol group (given 2.5, 5, 10, 20, and 40 μmol/L lupeol), a tert-butyl hydrogen peroxide (TBHP) group (receiving 50 μmol/L TBHP), TBHP + lupeol group, TBHP + lupeol + chloroquine (CQ) group (receiving 20 μmol/L CQ, an autophagy inhibitor), TBHP + lupeol + si-NC group, and TBHP + lupeol + si-SIRT3 group. Cell proliferation, reactive oxygen species (ROS) levels, and apoptosis were determined by CCK-8, DCFH-DA probe, and flow cytometry. Cell senescence was evaluated by β-gal staining. Western blot was used to determine the expressions of SIRT3, mTOR, senescence marker proteins (p21 and p16), extracellular matrix (ECM) degradation-related proteins (aggrecan, collagen Ⅱ, ADAMTS5, and MMP13), and autophagy-related proteins (LC3BⅠ, LC3BⅡ, and P62). RT-qPCR was used to determine the mRNA levels of senescence-associated secretory phenotypes (SASP), including IL-6, Cxcl10, MCP1, and MMP3. The expression of LC3 was detected by immunofluorescence. Autophagosomes were observed by transmission electron microscopy. A total of 30 male wild-type C57BL/6 mice were divided into different groups (n = 10), including a Sham group, an OA group, and an OA + lupeol group receiving 50 mg/(kg·d) lupeol via gastric gavage. Cartilage damage was evaluated by safranin O-fast green staining. Results Based on the results of cell viability assay, 20 μmol/L lupeol treatment for 24 h was identified as the optimal intervention concentration and duration. Compared with that in the TBHP group, cell viability was elevated in the TBHP + lupeol group (P < 0.05); ROS production, the proportion of β-gal-positive cells, the protein expression levels of p21 and p16, and the mRNA levels of SASP were decreased (P < 0.05); the protein levels of aggrecan and collagen Ⅱ were elevated and the protein levels of ADAMTS5 and MMP13 were decreased (P < 0.05); apoptosis was reduced (P < 0.05); P62 protein levels were reduced and the LC3BⅡ/LC3BⅠ ratio, the intensity of LC3B fluorescence spots, and the number of autophagosomes were increased (P < 0.05); the expression level of SIRT3 was elevated and the level of mTOR phosphorylation was reduced (P < 0.05) in the TBHP+Lupeol group. CQ treatment effectively abolished the promotion effects of lupeol on cell viability and autophagy, and the inhibitory effects of lupeol on ROS level, cell senescence, ECM degradation, and apoptosis (P < 0.05). Silencing of SIRT3 reversed the inhibitory effect of lupeol on mTOR phosphorylation level and the promotion effect of lupeol on autophagy (P < 0.05). In the in vivo experiment, compared with the OA group, the OA + lupeol group showed reduced cartilage degeneration and lower scores for the Osteoarthritis Research Society International grading system (P < 0.05). The OA + lupeol group also showed up-regulated SIRT3 expression, reduced mTOR phosphorylation level, increased LC3BⅡ/LC3BⅠ ratio, reduced MMP13 protein level, and reduced mRNA level of SASP (P < 0.05). Conclusion Lupeol alleviates chondrocyte senescence in osteoarthritis by regulating autophagy through the SIRT3/mTOR pathway.
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Affiliation(s)
- 运锋 马
- 河南省中医药(河南中医药大学第二附属医院) 骨病一科 (郑州 450002)Department of Osteopathics, Henan Province Hospital of Traditional Chinese Medicine (The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine), Zhengzhou 450002, China
| | - 玉净 曹
- 河南省中医药(河南中医药大学第二附属医院) 骨病一科 (郑州 450002)Department of Osteopathics, Henan Province Hospital of Traditional Chinese Medicine (The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine), Zhengzhou 450002, China
| | - 小飞 韩
- 河南省中医药(河南中医药大学第二附属医院) 骨病一科 (郑州 450002)Department of Osteopathics, Henan Province Hospital of Traditional Chinese Medicine (The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine), Zhengzhou 450002, China
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Wei F, Yang W, Wang H, Song S, Ji Y, Chen Z, Zhuang Y, Dai J, Shen H. Reactive oxygen species-scavenging biomaterials for neural regenerative medicine. Biomater Sci 2025; 13:343-363. [PMID: 39620279 DOI: 10.1039/d4bm01221f] [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: 12/11/2024]
Abstract
Reactive oxygen species (ROS) are natural by-products of oxygen metabolism. As signaling molecules, ROS can regulate various physiological processes in the body. However excessive ROS may be a major cause of inflammatory diseases. In the field of neurological diseases, ROS cause neuronal apoptosis and neurodegeneration, which severely impede neuroregeneration. Currently, ROS-scavenging biomaterials are considered as a promising therapeutic strategy for neurological injuries due to their ability to scavenge excessive ROS at defects and modulate the oxidative stress microenvironment. This review provides an overview of the generation and sources of ROS, briefly describes the dangers of generating excessive ROS in nervous system diseases, and highlights the importance of scavenging excessive ROS for neuroregeneration. We have classified ROS-scavenging biomaterials into three categories based on the different mechanisms of ROS clearance. The applications of ROS-responsive biomaterials for neurological diseases, such as spinal cord injury, brain injury, and peripheral nerve injury, are also discussed. Our review contributes to the development of ROS-scavenging biomaterials in the field of neural regeneration.
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Affiliation(s)
- Feng Wei
- Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China.
- Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine Suzhou Institute of Nano-Tech and Nano-Bionics Chinese Academy of Sciences, Suzhou 215123, China.
- School of Nano Technology and Nano Bionics, University of Science and Technology of China, Hefei 230026, China
| | - Wen Yang
- Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine Suzhou Institute of Nano-Tech and Nano-Bionics Chinese Academy of Sciences, Suzhou 215123, China.
| | - Huiru Wang
- Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine Suzhou Institute of Nano-Tech and Nano-Bionics Chinese Academy of Sciences, Suzhou 215123, China.
- School of Nano Technology and Nano Bionics, University of Science and Technology of China, Hefei 230026, China
| | - Saijie Song
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Yuxuan Ji
- Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine Suzhou Institute of Nano-Tech and Nano-Bionics Chinese Academy of Sciences, Suzhou 215123, China.
- School of Nano Technology and Nano Bionics, University of Science and Technology of China, Hefei 230026, China
| | - Zhong Chen
- Department of Spine Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Yan Zhuang
- Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine Suzhou Institute of Nano-Tech and Nano-Bionics Chinese Academy of Sciences, Suzhou 215123, China.
| | - Jianwu Dai
- Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China.
- Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine Suzhou Institute of Nano-Tech and Nano-Bionics Chinese Academy of Sciences, Suzhou 215123, China.
- State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology Chinese Academy of Sciences, Beijing 100101, China
| | - He Shen
- Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China.
- Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine Suzhou Institute of Nano-Tech and Nano-Bionics Chinese Academy of Sciences, Suzhou 215123, China.
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Plum M, Beier JP, Ruhl T. Delayed cutaneous wound healing in young and old female mice is associated with differential growth factor release but not inflammatory cytokine secretion. Biogerontology 2025; 26:37. [PMID: 39775106 PMCID: PMC11711145 DOI: 10.1007/s10522-024-10179-7] [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: 11/20/2024] [Accepted: 12/26/2024] [Indexed: 01/11/2025]
Abstract
The capacity for tissue repair during wound healing declines with age. A chronic low but systemic inflammatory status, often called "inflammaging", is considered a key factor that contributes to impaired tissue regeneration. This phenomenon has been substantiated by an increased number of immune cells in wound-tissue of old mice. Although immune cells coordinate an inflammatory response by their secretome the composition of the wound milieu has not been examined. In young (2 months) and old (18 months) female mice, excision wounds were induced using a punch biopsy device, i.e., the healing progress occurred through secondary intention. The closure rate was analyzed for 7 days. At days 1, 3 and 7 post-surgery, wound specimen were investigated for immunohistochemical detection of granulocytes, M1-macrophages and mesenchymal stem cells of the skin. The concentrations of inflammatory cytokines and regenerative growth factors were determined in tissue homogenates by ELISA. The carbonyl assay was used to determine protein oxidation. In old mice, the wound closure was delayed between days 1 and 3 post-surgery, as was the peak of immune cell infiltration. There was no age effect on the concentration of inflammatory cytokines, but wounds of young animals contained higher number of mesenchymal stem cells and increased levels of growth factors. Protein oxidation was increased with age. The present study suggests that a reduced regenerative capacity rather than an enhanced inflammatory score affected the tissue regeneration process in old mice.
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Affiliation(s)
- Melissa Plum
- Department of Plastic Surgery, Hand Surgery-Burn Center, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Justus P Beier
- Department of Plastic Surgery, Hand Surgery-Burn Center, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Tim Ruhl
- Department of Plastic Surgery, Hand Surgery-Burn Center, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.
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Sato M, Torigoe D, Kinoshita Y, Cyuman M, Toda C, Sato M, Ikeda K, Kadomatsu T, Horiguchi H, Morinaga J, Fukami H, Sugizaki T, Miyata K, Kusaba R, Okadome Y, Matsunaga E, Node K, Oike Y. Long-term intake of Tamogi-take mushroom (Pleurotus cornucopiae) mitigates age-related cardiovascular dysfunction and extends healthy life expectancy. NPJ AGING 2025; 11:1. [PMID: 39779757 PMCID: PMC11711650 DOI: 10.1038/s41514-024-00191-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 12/20/2024] [Indexed: 01/11/2025]
Abstract
Age-related declines in cardiac function and exercise tolerance interfere with healthy living and decrease healthy life expectancy in older individuals. Tamogi-take mushrooms (Pleurotus cornucopiae) are known to contain high levels of Ergothioneine (EGT), an antioxidant with potential health benefits. In this study, we assessed the possibility that long-term consumption of Tamogi-take mushrooms might attenuate age-related decline in cardiac and vascular endothelial function in mice. We found that long-term intake of Tamogi-take mushrooms significantly maintained cardiac and vascular endothelial function and improved exercise tolerance in mice. Long-term mushroom consumption also increased levels of Nrf2 (Nuclear factor E2-related factor 2) protein in heart tissues and increased translation of HO-1 (Heme Oxygenase 1) proteins, which have antioxidant effects in heart and aortic tissues. Finally, long-term Tamogi-take mushroom consumption inhibited ROS accumulation with aging and reduced expression of inflammatory biomarkers. We conclude that ingestion of Tamogi-take mushrooms could serve as a dietary intervention to promote cardiovascular health, support healthy aging and slow the progression of age-related diseases.
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Affiliation(s)
- Michio Sato
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan
- Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
- Department of Cardiovascular Medicine, School of Medicine, Saga University, Saga, Japan
- Division of Kumamoto Mouse Clinic (KMC), Kumamoto University, Kumamoto, Japan
| | - Daisuke Torigoe
- Division of Laboratory Animal Science, Institute of Resource Development and Analysis (IRDA), Kumamoto University, Kumamoto, Japan
| | - Yuya Kinoshita
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan
| | - Momoka Cyuman
- Division of Laboratory Animal Science, Institute of Resource Development and Analysis (IRDA), Kumamoto University, Kumamoto, Japan
| | - Chitoku Toda
- Department of Neuroscience for Metabolic Control, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Masaru Sato
- Laboratory of Biomolecule Analysis, Department of Applied Genomics, Kazusa DNA Research Institute, Chiba, Japan
| | - Kazutaka Ikeda
- Laboratory of Biomolecule Analysis, Department of Applied Genomics, Kazusa DNA Research Institute, Chiba, Japan
- Laboratory of Omics and Informatics, Department of Molecular and Chemical Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
| | | | - Haruki Horiguchi
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan
- Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
- Department of Aging and Geriatric Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Jun Morinaga
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan
- Department of Disease Genome Epidemiology, Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kumamoto, Japan
| | - Hirotaka Fukami
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan
| | - Taichi Sugizaki
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan
| | - Keishi Miyata
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan
| | - Ryoko Kusaba
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan
| | - Yusuke Okadome
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan
| | - Eiji Matsunaga
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan
| | - Koichi Node
- Department of Cardiovascular Medicine, School of Medicine, Saga University, Saga, Japan
| | - Yuichi Oike
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan.
- Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
- Division of Laboratory Animal Science, Institute of Resource Development and Analysis (IRDA), Kumamoto University, Kumamoto, Japan.
- Department of Aging and Geriatric Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
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Zeng Y, Buonfiglio F, Li J, Pfeiffer N, Gericke A. Mechanisms Underlying Vascular Inflammaging: Current Insights and Potential Treatment Approaches. Aging Dis 2025:AD.2024.0922. [PMID: 39812546 DOI: 10.14336/ad.2024.0922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 10/18/2024] [Indexed: 01/16/2025] Open
Abstract
Inflammaging refers to chronic, low-grade inflammation that becomes more common with age and plays a central role in the pathophysiology of various vascular diseases. Key inflammatory mediators involved in inflammaging contribute to endothelial dysfunction and accelerate the progression of atherosclerosis. In addition, specific pathological mechanisms and the role of inflammasomes have emerged as critical drivers of immune responses within the vasculature. A comprehensive understanding of these processes may lead to innovative treatment strategies that could significantly improve the management of age-related vascular diseases. Emerging therapeutic approaches, including cytokine inhibitors, senolytics, and specialized pro-resolving mediators, aim to counteract inflammaging and restore vascular health. This review seeks to provide an in-depth exploration of the molecular pathways underlying vascular inflammaging and highlight potential therapeutic interventions.
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Singh P, Venkatasubramanian R, Mahoney SA, Darrah MA, Ludwig KR, Zhang A, Kaneshiro K, Najera LE, Wimer L, Shanmugam MM, Morazan E, Trujillo M, Galligan J, Sarpong R, Seals DR, Kapahi P, Clayton ZS. Methylglyoxal-induced glycation stress promotes aortic stiffening: Putative mechanistic roles of oxidative stress and cellular senescence. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.06.631561. [PMID: 39829921 PMCID: PMC11741384 DOI: 10.1101/2025.01.06.631561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Background Here, we assessed the role of the advanced glycation end-product (AGE) precursor methylglyoxal (MGO) and its non-crosslinking AGE MGO-derived hydroimidazolone (MGH)-1 in aortic stiffening and explored the potential of a glycation stress-lowering compound (Gly-Low) to mitigate these effects. Methods Young (3-6 month) C57BL/6 mice were supplemented with MGO (in water) and Gly-Low (in chow). Aortic stiffness was assessed in vivo via pulse wave velocity (PWV) and ex vivo through elastic modulus. Putative mechanisms underlying MGO- and MGH-1-induced aortic stiffening were explored using complementary experimental approaches in aortic tissue and cultured human aortic endothelial cells (HAECs). Moreover, aortic stiffness was assessed in old (24 month) mice after consumption of Gly-Low-enriched chow. Results MGO-induced glycation stress increased PWV in young mice by 21% (P<0.05 vs. control), which was prevented with Gly-Low (P=0.93 vs. control). Ex vivo, MGO increased aortic elastic modulus 2-fold (P<0.05), superoxide production by ∼40% (P<0.05), and MGH-1 expression by 50% (P<0.05), which were all mitigated by Gly-Low. Chronic MGO exposure elevated biomarkers of cellular senescence in HAECs, comparable to a known senescence inducer Doxorubicin, an effect partially blocked by Gly-Low. Moreover, elevated aortic elastic modulus induced by Doxorubicin (P<0.05 vs. control) was prevented with Gly-Low (P=0.71 vs. control). Aortic RNA sequencing implicated preservation of endogenous cellular detoxification pathways with Gly-Low following exposure to MGH-1. Old mice supplemented with Gly-Low had lower PWV (P<0.05) relative to old control mice. Conclusions MGO-induced glycation stress contributes to aortic stiffening and glycation stress lowering compounds hold promise for mitigating these effects. What Is New? This study provides the first comprehensive line of evidence that methylglyoxal (MGO)-induced glycation stress directly contributes to aortic stiffening and does so through mechanisms involving oxidative stress and cellular senescence. Using complementary in vivo , ex vivo , and in vitro experimental models, we establish that MGO-mediated glycation stress independently induces aortic stiffening. Furthermore, we demonstrate that the glycation-lowering compound, Gly-Low, mitigates MGO-induced aortic stiffening by mitigating excessive oxidative stress and cellular senescence, and can lower aortic stiffness in old mice. Mechanistically, activation of the detoxification enzyme, glyoxalase-1 (Glo-1), is a novel pathway by which Gly-Low mediates its therapeutic effects on aortic stiffening. Lastly, we show that Gly-Low holds promise for lowering aortic stiffness in old age. What Is Relevant? Aortic stiffening is a major risk factor for cardiovascular diseases (CVD) and a significant predictor of CV-related morbidity and mortality. Yet, the underlying mechanisms driving this process remain incompletely understood. This study identifies MGO-derived glycation stress as a critical and modifiable factor contributing to aortic stiffening through pathways involving excessive oxidative stress and cellular senescence. By establishing the efficacy of Gly-Low in mitigating these effects, our findings underscore the importance of targeting glycation stress in the context of aging, and likely in other settings of glycation stress, to improve arterial health and reduce CVD risk. Clinical/Pathophysiological Implications These findings have significant clinical implications, as they demonstrate that glycation stress is a viable and modifiable therapeutic target for the prevention and treatment of aortic stiffening. Gly-Low offers a promising therapeutic approach to ameliorate glycation stress- and age-related aortic stiffening, by directly targeting excess glycation stress, oxidative stress, and cellular senescence. Additionally, the involvement of the Glo-1 detoxification pathway suggests a specific molecular target for future interventions aimed at improving arterial health and mitigating the progression of CVD.
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Eswaran S, Bhat S, Upadhya D, Mascarenhas R, Kabekkodu SP. Biological functions of extracellular vesicle double C2-like domain beta in cervical cancer. Sci Rep 2025; 15:477. [PMID: 39747389 PMCID: PMC11695970 DOI: 10.1038/s41598-024-84643-2] [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: 07/01/2024] [Accepted: 12/25/2024] [Indexed: 01/04/2025] Open
Abstract
Double C-2 Like Domain Beta (DOC2B) located at 17q13.3 prevents metastasis by senescence induction and epithelial to mesenchymal transition inhibition in cervical cancer (CC). The extracellular vesicle (EV) mediated trafficking of DOC2B and its impact on tumor suppressive activity are not investigated in CC. Using a retroviral method, we first ectopically expressed DOC2B in SiHa, which do not normally express DOC2B. DOC2B-SiHa and vector-SiHa EVs were co-incubated separately with recipient cell and subjected to various cellular and biochemical experiments. For the first time, we demonstrated that DOC2B localizes to EVs, and its transfer to EV may require intracellular calcium. Co-culture of SiHa and HeLa cells with DOC2B-SiHa derived EVs induced morphological changes and suppressed their growth and migration, possibly by induction of G0/G1 to S phase arrest and anoikis. DOC2B-SiHa EVs elevated intracellular reactive oxygen species (ROS) and calcium levels and promoted lipid droplet accumulation and lipid peroxidation rate in recipient cells. DOC2B-SiHa EVs reduced active AKT1 and ERK1/2 levels and EMT marker expression and enhanced cellular senescence and cytotoxic effects of cisplatin. Re-expression of DOC2B significantly altered the global metabolite profile of EVs. Finally, we demonstrated that intracellular calcium chelation significantly reduces DOC2B localization to EVs and impacts its tumor-suppressive properties. Altogether, EV-mediated DOC2B transfer may reduce the aggressive behavior of CC cells.
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Affiliation(s)
- Sangavi Eswaran
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Samatha Bhat
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
- Manipal Center for Biotherapeutics Research, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Dinesh Upadhya
- Centre for Molecular Neurosciences, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Roshan Mascarenhas
- Newcastle University Medicine Malaysia (NUMed), 79200, Johor Bahru, Malaysia
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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Faisal Hayat M, Bibi M, Batool M, Eman R, Hamdi H, Umar Ijaz M. Ameliorative Potential of Sudachitin Against Paraquat Induced Renal Toxicity in Rats Via Regulating Nrf2/Keap1 Pathway: An Inflammatory, Apoptotic and Histopathological Assessment. Chem Biodivers 2025; 22:e202401656. [PMID: 39307685 DOI: 10.1002/cbdv.202401656] [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: 07/09/2024] [Accepted: 09/20/2024] [Indexed: 11/13/2024]
Abstract
Paraquat (PQ) is a noxious herbicide which is well known for its adverse effects on vital organs including kidneys. Sudachitin (SCN) is a plant derived flavone that is obtained from Citrus sudachi and demonstrates a range of pharmacological potentials. This investigation was executed to assess the protective effects of SCN to counteract PQ instigated renal damage in albino rats (Rattus norvegicus). Twenty-four rats were apportioned in 4 different groups i. e., control group, PQ (5 mg/kg) intoxicated group, PQ (5 mg/kg)+SCN (20 mg/kg) cotreated group and SCN (20 mg/kg) only administrated group. Our findings revealed that exposure to PQ reduced the expressions of Nrf2 (nuclear factor erythroid 2-related factor 2) and its cytoprotective genes while escalating the expression of keap1. Furthermore, PQ intoxication reduced the activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GSR), heme-oxygenase-1 (HO-1) and glutathione (GSH) contents while increasing the levels of malondialdehyde (MDA) and reactive oxygen species (ROS). Moreover, PQ exposure significantly increased the levels of neutrophil gelatinous-associated lipocalin (NGAL), urea, kidney injury molecule-1(KIM-1) as well as creatine while reducing creatine clearance. Additionally, PQ upregulated the levels of inflammatory markers including interleukin-6 (IL-6), tumor necrosis- α (TNF- α), nuclear factor- κB (NF-κB), interleukin 1beta (IL-1β), and cyclo-oxygenase-2 (COX-2). Moreover, PQ administration upregulated the expression of Bax (Bcl-2-associated X protein) and (cysteine-aspartic acid protease) Caspase-3 while downregulating the expressions of (B-cell lymphoma 2 protein) Bcl-2. Besides, PQ exposure prompted various histopathological damages in renal tissues. Nonetheless, SCN substantially restored aforementioned alterations in the renal tissues owing to its anti-oxidative, anti-inflammatory and anti-apoptotic potential.
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Affiliation(s)
- Muhammad Faisal Hayat
- Department of Zoology, Wildlife and Fisheries, University of Agriculture, Faisalabad, 38040, Pakistan
| | - Marrium Bibi
- Department of Zoology, Wildlife and Fisheries, University of Agriculture, Faisalabad, 38040, Pakistan
| | - Moazama Batool
- Department of Zoology, Govt. College Women University, Sialkot, Pakistan
| | - Rimsha Eman
- Department of Zoology, Wildlife and Fisheries, University of Agriculture, Faisalabad, 38040, Pakistan
| | - Hamida Hamdi
- Department of Biology, College of Science, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia
| | - Muhammad Umar Ijaz
- Department of Zoology, Wildlife and Fisheries, University of Agriculture, Faisalabad, 38040, Pakistan
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Fukui K. Introduction to serial articles: New findings on the relationship between aging and oxidative stress. J Clin Biochem Nutr 2025; 76:1-2. [PMID: 39896156 PMCID: PMC11782778 DOI: 10.3164/jcbn.24-intro] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 11/14/2024] [Indexed: 02/04/2025] Open
Affiliation(s)
- Koji Fukui
- Shibaura Institute of Technology, Fukasaku 307, Minuma-ku, Saitama 337-8570, Japan
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Maupin EA, Adams KL. Cellular Senescence in Glial Cells: Implications for Multiple Sclerosis. J Neurochem 2025; 169:e16301. [PMID: 39831743 PMCID: PMC11745082 DOI: 10.1111/jnc.16301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 12/16/2024] [Accepted: 12/19/2024] [Indexed: 01/22/2025]
Abstract
Aging is the most common risk factor for Multiple Sclerosis (MS) disease progression. Cellular senescence, the irreversible state of cell cycle arrest, is the main driver of aging and has been found to accumulate prematurely in neurodegenerative diseases, including Alzheimer's and Parkinson's disease. Cellular senescence in the central nervous system of MS patients has recently gained attention, with several studies providing evidence that demyelination induces cellular senescence, with common hallmarks of p16INK4A and p21 expression, oxidative stress, and senescence-associated secreted factors. Here we discuss the current evidence of cellular senescence in animal models of MS and different glial populations in the central nervous system, highlighting the major gaps in the field that still remain. As premature senescence in MS may exacerbate demyelination and inflammation, resulting in inhibition of myelin repair, it is critical to increase understanding of cellular senescence in vivo, the functional effects of senescence on glial cells, and the impact of removing senescent cells on remyelination and MS. This emerging field holds promise for opening new avenues of treatment for MS patients.
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Affiliation(s)
- Elizabeth A. Maupin
- Department of Biological SciencesUniversity of Notre DameNotre DameIndianaUSA
| | - Katrina L. Adams
- Department of Biological SciencesUniversity of Notre DameNotre DameIndianaUSA
- The Center for Stem Cells and Regenerative MedicineUniversity of Notre DameNotre DameIndianaUSA
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Luan J, Wang Q, Zheng W, He Y. The mTOR pathway is involved in the process of platelet-rich plasma improving intervertebral disc degeneration. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2025; 28:393-400. [PMID: 39906617 PMCID: PMC11790196 DOI: 10.22038/ijbms.2024.79218.17163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Abstract
Objectives Platelet-rich plasma (PRP) contains multiple growth hormones that may stimulate tissue repair. We aimed to assess PRP's efficacy and explore possible mechanisms using the intervertebral disc degeneration (IDD) model. Materials and Methods A total of 48 male Sprague-Dawley (SD) rats were randomly divided into three groups: sham, IDD+PBS, and IDD+PRP (n=16, respectively). IL-1β (10 ng/ml) was used to establish a humanized IDD model in human lumbar nucleus pulposus (NP) tissues from 36 patients with degenerative disc disease. These NP cells were randomly divided into three groups: sham, IDD+PBS, and IDD+PRP (n=12, respectively). RT-PCR and western blot were used to detect the expression of aggrecan, collagen II, IL-1β, IL-6, TNF-α, Bcl-2, cleaved-Caspase 3, Bax and Akt/mTOR/p70S6K signaling pathway. A related assay kit was used to detect MDA, SOD, and GSH. Results PRP affected the expression of aggrecan, collagen II, IL-1β, IL-6, TNF-α, MDA, SOD, GSH, Bcl-2, cleaved-Caspase 3, and Bax in IDD rats. Compared with the IDD+PBS group, the expression of p-mTOR, p-p70/S6K, and p-Akt was much lower in the rat IDD+PRP group (P<0.05). Similarly, with PRP treatment in the humanized IDD model, the expression of p-mTOR, p-p70/S6K, and p-Akt was also inhibited. Conclusion PRP may be a potential therapy for IDD via the mTOR signaling pathway in regulating and affecting extracellular matrix degradation, inflammatory factors, oxidative stress, and apoptosis.
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Affiliation(s)
- Jing Luan
- Department of Pain, Tianjin First Central Hospital, Tianjin, 300110, China
| | - Qi Wang
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin, 300110, China
| | - Wei Zheng
- Department of Pain, Tianjin First Central Hospital, Tianjin, 300110, China
| | - Yongjin He
- Department of Pain, Tianjin First Central Hospital, Tianjin, 300110, China
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Koch M, Ferrarese L, Ben-Yehuda Greenwald M, Werner S. Dose-dependent effects of Nrf2 on the epidermis in chronic skin inflammation. Dis Model Mech 2025; 18:dmm052126. [PMID: 39744884 PMCID: PMC11708820 DOI: 10.1242/dmm.052126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 11/27/2024] [Indexed: 01/11/2025] Open
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease, characterized by an impaired epidermal barrier and immunological alterations. The activity of the cytoprotective NRF2 transcription factor is reduced in the epidermis of AD patients. To determine the functional relevance of this deficiency, we used mice lacking fibroblast growth factor receptors 1 and 2 in keratinocytes (K5-R1/R2 mice), which exhibit several AD-like symptoms. Proteomics analysis of their epidermis revealed reduced Nrf2 activity. This was accompanied by an increase in DNA damage and in the number of senescent cells. Genetic deletion of Nrf2 in keratinocytes of these mice further promoted DNA damage and senescence, but time-limited pharmacological activation of Nrf2 in the skin had a mild protective effect. Surprisingly, long-term genetic activation of Nrf2 in keratinocytes of K5-R1/R2 mice caused strong hyperkeratosis, keratinocyte hyperproliferation, epidermal thickening, increased keratinocyte apoptosis and DNA damage, and altered immune cell composition. These results reveal a complex role of Nrf2 in the epidermis and show the necessity to optimize the duration and intensity of NRF2 activation for the treatment of epidermal alterations in patients with AD.
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Affiliation(s)
- Michael Koch
- Institute of Molecular Health Sciences, Department of Biology, ETH Zürich, 8093 Zürich, Switzerland
| | - Luca Ferrarese
- Institute of Molecular Health Sciences, Department of Biology, ETH Zürich, 8093 Zürich, Switzerland
| | | | - Sabine Werner
- Institute of Molecular Health Sciences, Department of Biology, ETH Zürich, 8093 Zürich, Switzerland
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Ahmed IA, Zamakshshari NH, Mikail MA, Bello I, Hossain MS. Garcinia flavonoids for healthy aging: Anti-senescence mechanisms and cosmeceutical applications in skin care. Fitoterapia 2025; 180:106282. [PMID: 39489352 DOI: 10.1016/j.fitote.2024.106282] [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: 06/16/2024] [Revised: 10/28/2024] [Accepted: 10/30/2024] [Indexed: 11/05/2024]
Abstract
Cellular senescence, the irreversible arrest of cell division, is a hallmark of aging and a key contributor to age-related disorders. Targeting senescent cells represents a promising therapeutic approach to combat these ailments. This review explores the potential of Garcinia species, a genus rich in flavonoids with established antioxidant and anti-inflammatory properties, as a source of natural anti-senescence agents. We investigate the intricate connections between aging, cellular senescence, and oxidative stress, highlighting the detrimental effects of free radicals on cellular health. Furthermore, we analyze the diverse array of flavonoids identified within Garcinia and their established cellular mechanisms. We critically evaluate the emerging evidence for the anti-senescence potential of flavonoids in general and the limited research on Garcinia flavonoids in this context. By identifying existing knowledge gaps and paving the way for future research, this review underscores the exciting potential of Garcinia flavonoids as natural anti-senescence agents. These agents hold promise for not only promoting healthy aging but also for the development of cosmeceutical products that combat the visible signs of aging.
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Affiliation(s)
- Idris Adewale Ahmed
- Department of Biotechnology, Faculty of Applied Science, Lincoln University College, 47301 Petaling Jaya, Selangor, Malaysia; Mimia Sdn. Bhd., Selangor, Malaysia.
| | - Nor Hisam Zamakshshari
- Department of Chemistry, Faculty of Resource Science and Technology, University Malaysia Sarawak, 94300 Kota Samarahan, Sarawak, Malaysia.
| | | | - Ibrahim Bello
- Agricultural and Biosystems Engineering, North Dakota State University, Fargo, USA.
| | - Md Sanower Hossain
- Centre for Sustainability of Mineral and Resource Recovery Technology (Pusat SMaRRT), University Malaysia Pahang Al-Sultan Abdullah, Kuantan 26300, Malaysia.
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Huang Y, Li X, Xu S, Zu D, Liu H, He H, Bao Q, He Y, Liang C, Shi Y, Cheng X, Teng Y, Ye Z. Polyvinyl chloride nanoplastics suppress homology-directed repair and promote oxidative stress to induce esophageal epithelial cellular senescence and cGAS-STING-mediated inflammation. Free Radic Biol Med 2025; 226:288-301. [PMID: 39515594 DOI: 10.1016/j.freeradbiomed.2024.11.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 11/04/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
Nanoplastics (NPs), which are characterized by plastic particles smaller than 1 μm, have emerged as pervasive environmental pollutants, raising concerns about their potential toxicity to living organisms. Numerous investigations have highlighted the tendency of NPs to accumulate in organs, resulting in toxic effects. Despite polyvinyl chloride (PVC) being one of the most prevalent NPs, its impact on the esophagus and the associated underlying mechanisms remain largely unknown. In this study, we investigated the impact of PVC NPs on the esophagus and found that PVC NPs exposure induces oxidative stress and elicits DNA damage responses. Further analysis revealed that PVC NPs inhibit the homology-directed repair (HDR) pathway by suppressing the expression of breast cancer susceptibility gene 2 (BRCA2) and growth factor receptor-bound protein 2 (GRB2), resulting in genomic instability. Additionally, the release of free DNA activates cGAS-STING and the downstream NF-κB signaling, elevating inflammatory factors and chemokines, which further leads to cellular senescence. In vivo experiments corroborated these findings, showing that PVC NPs induced oxidative stress, inflammation, and cellular senescence, subsequently impacting mouse behavior. This study contributes novel insights into the health risks associated with PVC NPs exposure and identifies potential therapeutic targets.
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Affiliation(s)
- Yixing Huang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, China; Zhejiang University School of Medicine, Hangzhou, 310058, China; Department of Otorhinolaryngology, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Xiao Li
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, China; The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Shengfeng Xu
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Dan Zu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, China; School of Life Sciences, Tianjin University, Tianjin, 300100, China
| | - Haidong Liu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China
| | - Hanyi He
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China
| | - Qimei Bao
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, China
| | - Yanhua He
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China
| | - Chen Liang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, China
| | - Yin Shi
- Department of Biochemistry, and Department of Pulmonology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Xiangdong Cheng
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
| | - Yaoshu Teng
- Department of Otorhinolaryngology, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
| | - Zu Ye
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China; Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, 530021, China; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, 530021, China.
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Li M, Liu Z, Cao X, Xiao W, Wang S, Zhao C, Zhao Y, Xie Y. [Gly14]-Humanin ameliorates high glucose-induced endothelial senescence via SIRT6. Sci Rep 2024; 14:30924. [PMID: 39730568 DOI: 10.1038/s41598-024-81878-x] [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: 06/02/2024] [Accepted: 11/29/2024] [Indexed: 12/29/2024] Open
Abstract
High glucose (HG) induced endothelial senescence is related to endothelial dysfunction and cardiovascular complications in diabetic patients. Humanin, a member of mitochondrial derived peptides (MDPs), is thought to contribute to aging-related cardiovascular protection. The goal of the study is to explore the pathogenesis of HG-induced endothelial senescence and potential anti-senescent effects of Humanin. Human umbilical vein endothelial cells (HUVECs) were exposed to glucose to induce senescence, determined by β-galactosidase staining and the expressions of p21, p53, and p16. A clinically relevant dose of HG (15 mM, HG) induced endothelial senescence after 72 h incubation without elevated apoptosis. HG-induced senescence was attributed to the induction of reactive oxygen species (ROS) caused by SIRT6 downregulation, as ROS inhibitor N-acetyl cysteine blocked HG-induced senescence, while inactivation of SIRT6 increased ROS levels and promoted senescence. Strikingly. pretreatment with [Gly14]-Humanin (HNG) antagonized the downregulation of SIRT6 in response to HG and alleviated ROS production and cell senescence. HG-induced reduction of SIRT6 results in ROS overproduction and endothelial senescence. Humanin protects against HG-induced endothelial senescence via SIRT6. This study provides new directions for biological products related to Humanin to be a potential candidate for the prevention of vascular aging in diabetes.
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Affiliation(s)
- Muqin Li
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
- Department of Endocrinology, The First People's Hospital of Lianyungang, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, 222061, JiangSu, China
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, 215004, China
| | - Zhihua Liu
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Xueqin Cao
- Department of Endocrinology, The Fourth Affiliated Hospital of Soochow University, Chongwen Road No. 9, Suzhou, 215000, Jiangsu, China
| | - Wenjin Xiao
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Shurong Wang
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Chengyuan Zhao
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
- Department of endocrinology, Taizhou school of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Nanjing Medical University, 366 Taihu Road, Taizhou, 225300, China
| | - Ying Zhao
- Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Soochow Medical College of Soochow University, Suzhou, 215123, China.
| | - Ying Xie
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
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50
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Tang Y, Zheng W, Chen J, Xie Y, Yang J, Wang Z, Qin H. Ameliorating Oxidative Stress-Aggravated Adipose Tissue Senescence by Sesamol in Aged Obese Mice via Nrf2/p38MAPK Signaling. PLANT FOODS FOR HUMAN NUTRITION (DORDRECHT, NETHERLANDS) 2024; 80:11. [PMID: 39680188 DOI: 10.1007/s11130-024-01249-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 10/29/2024] [Indexed: 12/17/2024]
Abstract
Adipocyte senescence is one of the major common features correlated with aging, which can also lead to obesity, and aggravated oxidative stress contributes to cell senescence. Sesamol, a lignan from plants found in sesame, has been proven to alleviate obesity. However, the effects and mechanisms of sesamol on adipose tissue senescence remain unclear. In the current research, we used an aged model of obesity by feeding old mice high-fat diet (HFD), and a senescent cell model by treating 3T3-L1 mature adipocytes with repeated exposure to hydrogen peroxide (H2O2). Both HFD induced aged obesity mice and H2O2 treated cells presented features associated with senescence. Additionally, obesity in aged mice accelerated the expression of adipose tissue senescence-associated markers. Notably, the presence of sesamol showed marked activation of Nrf2 and inhibition of p-p38MAPK, along with the suppression of oxidative stress (ROS, MDA, SOD), inflammatory factors (IL-6, TNFα) and cell cycle inhibitors (p53, p21, p16). A pretreatment of ML385, an inhibitor of Nrf2, reversed the effects induced by sesamol treatment. In conclusion, our results demonstrated that obesity contributed to deteriorated adipose tissue senescence during aging. Furthermore, sesamol, acted as an activator of Nrf2 and exerted negative impacts on the activation of p38MAPK, which were associated with amelioration of adipose senescence, thereby indicating it could be a potential nutritional intervention for preventing and treating aging-related disorders.
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Affiliation(s)
- Yongyan Tang
- Xiangya School of Public Health, Central South University, Changsha, China
- Tropical Disease and Chronic Disease Prevention and Control Institute, Hainan Provincial Center for Disease Control and Prevention, Haikou, China
| | - Wenya Zheng
- Xiangya School of Public Health, Central South University, Changsha, China
| | - Jingfang Chen
- Changsha Center for Disease Control and Prevention, Changsha, China
| | - Yan Xie
- Xiangya School of Public Health, Central South University, Changsha, China
| | - Jinxin Yang
- Xiangya School of Public Health, Central South University, Changsha, China
| | - Zhipeng Wang
- Xiangya School of Public Health, Central South University, Changsha, China
| | - Hong Qin
- Xiangya School of Public Health, Central South University, Changsha, China.
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