PHYTOTHERAPY RESEARCH
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2025
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IF 6.3
Xiao-Man Ji,Xin-Xin Dong,Jia-Peng Li,Guang-Jie Tai,Shu Qiu,Wei Wei,Ceaser Wankumbu Silumbwe,Davaadagva Damdinjav,Joseph Nicolao Otieno,Xiao-Xue Li,Ming Xu
Vascular aging is a major contributor to age-related cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM) induced early arterial aging and excessive senescent cells (SCs) burden in vessels. Inhibiting cellular senescence or eliminating SCs could effectively improve aging-related CVDs. Fisetin, a flavonoid extracted from cotinus coggygria scop, has shown potential in alleviating aging by clearing SCs. This study investigated the unexplored mechanisms and efficacy of fisetin in alleviating T2DM-related aortic aging. The T2DM mouse model was induced using a high-fat diet and low-dose streptozotocin injection. Chronic fisetin treatment's protective effects against aortic aging were assessed via senescence-associated beta-galactosidase (SA-β-Gal) staining, histopathology, and vasomotor function. RNA-sequencing and western blotting identified relevant signaling pathways and protein expression. Fisetin's effects on SCs and senescence-associated secretory phenotype (SASP) factors were evaluated through cell viability, apoptosis, and co-culture assays. Docking simulations suggested fisetin as a potential Phosphoinositide 3-kinase (Pi3k) inhibitor. In vivo, chronic fisetin treatment reduced aortic SCs burden, alleviating T2DM-related and natural aortic aging. In vitro, fisetin selectively induced apoptosis of senescent endothelial cells via regulating the Pi3k-Protein Kinase B (Akt)-B-cell lymphoma (Bcl)-2/Bcl-xl pathway and suppressed SASP and its detrimental effects. Furthermore, fisetin combined with metformin therapy showed superior anti-aging effects on T2DM-related aortic aging compared to metformin monotherapy. In conclusion, chronic fisetin treatment alleviates T2DM-related aortic aging via clearing the SCs burden and abrogating the SASP factors. Fisetin combined with metformin therapy might be a potential therapeutic strategy for T2DM-related CVDs.
研究领域:
药理学
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心血管疾病
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分子生物学
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DOI
PubMed
高影响因子
Frontiers in Molecular Biosciences
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2026
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IF 4.4
Guozhen Ni,Ning Ma,Jian Xu
IntroductionApigenin (API) has been utilized in the treatment of atherosclerosis. Senescent macrophages exhibit a senescence-associated secretory phenotype (SASP), which plays a critical role in the progression of atherosclerosis. IL1A expression is thought to be involved in the transition of macrophages to the SASP phenotype. This study explored the effect of API on the atherosclerosis-related SASP in macrophages and the underlying mechanism.MethodsMacrophages were treated with different concentrations of API. The expression of DOT1-like histone lysine methyltransferase (DOT1L) was manipulated in macrophages. Stimulation with lipopolysaccharide (LPS) was conducted to induce the SASP. Macrophage senescence was detected by senescence-associated-β-galactosidase staining. The expressions of interleukin 1 α (IL1A), DOT1L, and markers related to senescence, the SASP, and inflammation in macrophages were assessed. Chromatin immunoprecipitation was performed to check DOT1L-mediated H3K79me2 enrichment at the promoter of IL1A.ResultsAPI treatment effectively reduced cellular senescence in LPS-exposed macrophages. Furthermore, it downregulated markers associated with senescence, SASP, and inflammation, while upregulating the anti-inflammatory cytokine IL-10. Moreover, LPS-induced DOT1L and H3K79me2 enrichment at the IL1A promoter, as well as DOT1L and IL1A upregulation in macrophages, were hindered by API. DOT1L overexpression counteracted API’s effects, including its ability to inhibit senescence, downregulate senescence/SASP/inflammation markers, upregulate IL-10, and prevent H3K79me2 and DOT1L binding at the IL1A promoter. DOT1L silencing reduced LPS-induced senescence, SASPs, and H3K79me2 enrichment in macrophages.ConclusionAPI inhibits DOT1L-mediated H3K79me2 enrichment to downregulate IL1A, thus reducing the SASP of macrophages.
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DOI
高影响因子
BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH
·
2025
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IF 1.5
Han Wang,Guan Mengtong,Liao Bo,Han Xiaoyu,Li Kaiting,Chen Qing,Guo Xiya,Niu Yajuan,Zhu Ying,Bai Dingqun
Cellular senescence is an important cause of age-related degenerative diseases, including osteoarthritis (OA). Chondrocyte senescence is crucial in OA onset and progression. As a non-invasive, safe, and widely used physical rehabilitation factor, the effect and mechanism of low intensity pulsed ultrasound (LIPUS) on chondrocyte senescence remain unclear. This study evaluated the inhibitory effect of LIPUS on OA chondrocyte senescence in vitro and in vivo. The effect of LIPUS on chondrocyte senescence was examined by RT-qPCR, enzyme-linked immunosorbent assay (ELISA), and western blotting. Changes in levels of reactive oxygen species (ROS) and γ-h2ax foci in senescent chondrocytes were detected using fluorescent staining. Chondrocyte senescence was evaluated by senescence-associated β-galactosidase (SA-β-gal) staining. The PI3K inhibitor LY294002 and the PI3K agonist 740Y-P were used to investigate whether PI3K/AKT/mTOR signalling was involved in the effect of LIPUS in senescent chondrocytes. Chondrocyte senescence and cartilage degeneration were analyzed in a destabilization of the medial meniscal (DMM) mouse model by immunohistochemistry, hematoxylin and eosin staining, and safranin-O/fast green staining. LIPUS inhibited the expression of the senescence-associated secretory phenotype (SASP) factors CCL4 and CCL2 and the senescence phenotype in doxorubicin-treated chondrocytes by inhibiting the PI3K/AKT/mTOR pathway. LIPUS alleviated chondrocyte senescence and attenuated OA progression in the DMM mice. These results demonstrated a novel role for LIPUS in inhibiting chondrocyte senescence and the SASP by modulating PI3K/AKT/mTOR signalling. Our findings expanded the clinical application of LIPUS and provide a new, non-invasive, and safe treatment approach to prevent and treat age-related degenerative joint disorders.
研究领域:
医学
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生物学
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DOI
PubMed
高影响因子
CELLULAR & MOLECULAR BIOLOGY LETTERS
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2026
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IF 12.2
Xiaoxuan Zhao,Yang Zhao,Yuepeng Jiang,Yiming Ma,Jing Ma,Hongli Zhao,Xiaoling Feng
Background Unexplained recurrent spontaneous abortion (URSA) is characterized by defective endometrial stromal cell decidualization, with cellular senescence emerging as a key contributor. However, the metabolic–epigenetic mechanisms linking glycolysis to senescence-driven decidualization failure remain unclear. This study elucidates how hexokinase 2 (HK2)-mediated glycolytic reprogramming promotes histone lactylation-dependent stromal senescence and decidualization impairment in URSA. Methods We employed multi-omics profiling (RNA-seq, metabolomics, and CUT&Tag) of primary stromal cells from patients with URSA and controls to map the histone H3K18 lactylation (H3K18la)–cut-like homeobox 1 (CUX1)–senescence-associated secretory phenotype (SASP) axis. Subsequently, this axis was validated both in vitro decidualization models and URSA murine models. Results Decidual tissues from patients with URSA exhibited stromal cell senescence and impaired decidualization. Mechanistically, HK2-driven glycolysis elevated lactate production, which in turn promoted H3K18la at the CUX1 promoter. CUX1 then directly activated the transcription of key SASP factors, thereby propagating the senescence state. Critically, CUX1 depletion or glycolysis inhibition rescued these senescence and decidualization deficiency in vitro. Furthermore, CUX1 knockdown in the URSA murine model reduced stromal senescence and improved decidualization. Conclusions Our findings define a novel HK2–H3K18la–CUX1–SASP signaling axis that drives URSA pathogenesis by linking metabolic reprogramming with epigenetic regulation. This work highlights CUX1 as a potential therapeutic target for correcting decidualization deficiency in URSA. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1186/s11658-026-00879-y.
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PubMed
高影响因子
Frontiers in Pharmacology
·
2024
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IF 4.4
Abdelmoaty Ahmed Attia Ahmed,Chen Jing,Zhang Kun,Wu Changhui,Li Ye,Li Peng,Xu Jianhua
Background: Ganoderma lucidum (G. lucidum) is a famous medicinal mushroom that has been reported to prevent and treat a variety of diseases. Different extractions from G. lucidum have been used to manage age-related diseases, including cancer. Nevertheless, the senolytic activity of G. lucidum against senescent cancer cells has not been investigated. Although cellular senescence causes tumor growth inhibition, senescent cells promote the growth of the neighboring tumor cells through paracrine effects. Therefore, the elimination of senescent cells is a new strategy for cancer treatment.Methods: In this study, senescence was triggered in HCC cells by the chemotherapeutic agent Adriamycin (ADR), and subsequently, cells were treated with TC to assess its senolytic activity.Results: We found for the first time that the triterpenoid complex (TC) from G. lucidum had senolytic effect, which could selectively eliminate adriamycin (ADR)-induced senescent cells (SCs) of hepatocellular carcinoma (HCC) cells via caspase-dependent and mitochondrial pathways-mediated apoptosis and reduce the levels of senescence markers, thereby inhibiting the progression of cancers caused by SCs. TC could block autophagy at the late stage in SCs, resulting in a significant activation of TC-induced apoptosis. Furthermore, TC inhibited the senescence-associated secretory phenotype (SASP) in SCs through the inhibition of NF-κB, TFEB, P38, ERK, and mTOR signaling pathways and reducing the number of SCs. Sequential administration of ADR and TC in vivo significantly reduced tumor growth and reversed the toxicity of ADR.Conclusion: A triterpenoid complex isolated from G. lucidum may serve as a novel senolytic agent against SCs, and its combination with chemotherapeutic agents may enhance their antitumor efficacy.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
AGING CELL
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2024
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IF 8
Xueling He,Chen Wang,Qianyu Zhang,Tong Yang,Qiuyan Guo,Yaxu Wang,Jiayue Guo,Pengjie Wang,Junzhe Zhang,Huan Tang,Yinhua Zhu,Jigang Wang
Cellular senescence plays a critical role in repeated ultraviolet (UV) exposure-induced skin photoaging. Currently, from the perspective of regulating senescent cells, potent compounds or reliable protein targets that could effectively prevent skin photoaging have not yet been reported. Herein, we demonstrated that chlorogenic acid (CGA) significantly inhibited UVA-induced senescence of human dermis skin fibroblasts (HDF) cells by screening the natural product library. The activity-based protein profiling (ABPP) result revealed that Enolase 1 (ENO1) is one of the direct targets of CGA in HDF cells. Further mechanism research indicated that CGA covalently binds to ENO1, and prevented UVA-induced cellular senescence by suppressing the activity of ENO1 protein to block the glycolytic pathway. Importantly, we found that CGA dose-dependently reduced the skin wrinkle score, alleviated skin pathological features and inhibited senescent characteristics in a photoaging mouse model. The proteomic analysis revealed that CGA treatment effectively inhibited senescence-associated secretory phenotype (SASP) secretion and glycolysis in skin samples of mice. Collectively, our study not only demonstrated that inhibiting cell senescence is an effective anti-skin photoaging strategy, but also revealed that ENO1 is a promising protein target to prevent photoaging.
研究领域:
药理学
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皮肤病学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Aging and Disease
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2024
·Vol. 16
·期 3
·1652
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IF 7
Cheng Zhuang,Ruiqi Sun,Yuchen Zhang,Qing Zou,Jianxin Zhou,Naijun Dong,Xuyu Zhao,Wenjun Fu,Xiaoke Geng,Jiao Wang,Qian Li,Robert Chunhua Zhao
Rheumatoid arthritis (RA) is an autoimmune disease that affects the living quality of patients, especially the elderly population. RA-related morbidity and mortality increase significantly with age, while current clinical drugs for RA are far from satisfactory and may have serious side effects. Therefore, the development of new drugs with higher biosafety and efficacy is demanding. Black phosphorus nanosheets (BPNSs) have been widely studied because of their excellent biocompatibility. Here, we focus on the inherent bioactivity of BPNSs, report the potential of BPNSs as a therapeutic drug for RA and elucidate the underlying therapeutic mechanism. We find that BPNSs inhibit autophagy at an early stage via the AMPK-mTOR pathway, switch the energy metabolic pathway to oxidative phosphorylation, increase intracellular ATP levels, suppress apoptosis, reduce inflammation and oxidative stress, and down-regulate senescence-associated secretory phenotype (SASP)-related genes in rheumatoid arthritis synovial fibroblasts (RA-SFs). Further, BPNSs induce the apoptosis of macrophages and promote their transition from the M1 to the M2 phenotype by regulating related cytokines. Significantly, the administration of BPNSs can alleviate key pathological features of RA in mice, revealing great therapeutic potential. This study provides a novel option for treating RA, with BPNSs emerging as a promising therapeutic candidate.
研究领域:
纳米医学
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免疫学
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药理学
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细胞生物学
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生物医学工程
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风湿病学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2024
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IF 5.3
Meng Yang,Shengquan Wu,Qihui Dai,Weihong Qin,Yujie Zhang,Yiting Lei,Haochang Song,Tingting Zheng,Min Guan,Gonghua Huang,Xinguang Liu
Excessive lipid accumulation often occurs in the early stage of chronic kidney disease (CKD) which is prone to induce oxidative stress and mitochondrial damage, promoting the progression of kidney fibrosis. Andrographolide (AP), a multifunctional natural terpenoids derived from Andrographis paniculate , has been suggested to play beneficial roles in metabolic disorders-associated disease. Here, we reported that AP effectively counteracts tubule injury and interstitial fibrosis in mice fed with a long-term high-fat diet (HFD). AP treatment decreased HFD-induced lipid accumulation in kidney parenchyma and attenuated lipotoxicity-mediated oxidative stress and mitochondrial dysfunction, resulting in a marked decrease in tubular cell senescence. Importantly, AP inhibited senescence-associated secretory phenotype (SASP) secretion by senescent tubular cells, and in turn suppressed proliferation and activation of fibroblasts in a paracrine effect. Furthermore, we revealed that AP functions as an AMP-activated protein kinase (AMPK) activator to ameliorate renal lipid accumulation through coordinately modulating AMP-activated protein kinase AMPK target genes. By stimulation of AMPK activity, AP protects injured kidney against tubular cell senescence and fibroblast activation. These results suggest the potential therapeutic application of AP in the prevention and treatment of CKD, highlighting the promising drug strategy of targeting the lipotoxicity-mediated premature senescence in tubular cells.
研究领域:
肾病学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2025
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IF 11.5
Zhaoming Guo,Yi Zhang,Yuwei Gong,Guqing Li,Jiawei Pan,Danni Dou,Kun Ma,Changhao Cui,Yubo Liu,Xudong Zhu
Conventional cancer treatments often induce a sustained DNA damage response (DDR) in tumor cells, leading to therapy-induced senescence (TIS), characterized by permanent cell cycle arrest and resistance to apoptosis. These senescent cells secrete senescence-associated secretory phenotypes (SASP), which can promote tumor progression and create an immunosuppressive microenvironment. This study introduces a novel approach to enhance chemotherapy efficacy by using functionalized curcuma-derived extracellular vesicles (DR5-CNV/DOX) to target and eliminate senescent tumor cells and inhibit their SASP. Curcuma-derived extracellular vesicles (CNV) were loaded with the chemotherapeutic drug doxorubicin (DOX) and surface-modified with an antibody targeting death receptor 5 (DR5), which is overexpressed on senescent tumor cells. In vitro experiments demonstrated that DR5-CNV/DOX effectively targeted senescent tumor cells, promoting apoptosis and suppressing SASP production. In vivo studies confirmed the inhibition of epithelial-mesenchymal transition (EMT) initiation, angiogenesis, and modulation of the tumor immune microenvironment, enhancing chemotherapy efficacy and demonstrating promising biocompatibility. This study highlights the potential of plant-derived extracellular vesicles as a novel drug delivery system to overcome senescent tumor cells and their SASP.
研究领域:
肿瘤学
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药理学
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生物技术
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Small Structures
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2024
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IF 13.9
Wanbo Zhu,Quan Liu,Ziheng Zhang,Yingjie Wang,Jiawei Mei,Dongdong Xu,Jun Zhou,Zheng Su,Xianzuo Zhang,Chen Zhu,Jiaxing Wang,Junchen Zhu,Xiaochun Peng,Xianlong Zhang
Soft tissue injuries (STIs) are the most common cause of extremity pain and motion dysfunction. Persistent inflammatory activation of immune cells characterized by senescence-associated secretory phenotype (SASP) and mitochondrial stress are considered the primary causes of STIs, a pathological process also termed inflammaging. Meanwhile, scavenging excessive “cellular waste” in the inflammaging microenvironment and further activating tissue repair processes remain elusive. Herein, an anti-inflammaging photothermal hydrogel microneedle patch for treating STIs is developed. Taurine-loaded Prussian blue nanoparticles (Taurine@PB) are encapsulated in a methacrylate-based hyaluronic acid hydrogel (HAMA) and further fabricated into taurine@PB@HAMA@microneedles (TPH@MN) patches. The acidic microenvironment of chronic inflammation and mild photothermal effects promote taurine release and anti-inflammaging immunomodulation, inhibiting mitochondrial stress via the SIRT3-NF-κB axis to promote glycolytic metabolic microenvironment of neutrophils reprogramming toward oxidative phosphorylation metabolism. Furthermore, TPH@MN activates macrophage efferocytosis and initiates the process of tissue repair. In mouse models of chronic diabetic wounds and tibialis anterior (TA) muscle injury, TPH@MN inhibits SASP expression and promotes STIs healing through thermosensitized anti-inflammaging immunomodulation. In summary, TPH@MN circumvents the side effects of systemic administration, providing new translatable options in the treatment modalities for patients suffering from STIs worldwide.
研究领域:
生物医学工程
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药学
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免疫学
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组织工程
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DOI
高影响因子
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