INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
·
2023
·Vol. 64
·期 3
·16-16
·
IF 4.4
Lili Lian,Zhenmin Le,Zhenzhen Wang,Ying-ao Chen,Xiaodong Jiao,Hang Qi,J. Fielding Hejtmancik,Xiaoyin Ma,Qinxiang Zheng,Yueping Ren
Purpose:To determine whether SIRT1 regulates high glucose (HG)–induced inflammation and cataract formation through modulating TXNIP/NLRP3 inflammasome activation in human lens epithelial cells (HLECs) and rat lenses.Methods:HG stress from 25 to 150 mM was imposed on HLECs, with treatments using small interfering RNAs (siRNAs) targeting NLRP3, TXNIP, and SIRT1, as well as a lentiviral vector (LV) for SIRT1. Rat lenses were cultivated with HG media, with or without the addition of NLRP3 inhibitor MCC950 or SIRT1 agonist SRT1720. High mannitol groups were applied as the osmotic controls. Real-time PCR, Western blots, and immunofluorescent staining evaluated the mRNA and protein levels of SIRT1, TXNIP, NLRP3, ASC, and IL-1β. Reactive oxygen species (ROS) generation, cell viability, and death were also assessed.Results:HG stress induced a decline in SIRT1 expression and caused TXNIP/NLRP3 inflammasome activation in a concentration-dependent manner in HLECs, which was not observed in the high mannitol–treated groups. Knocking down NLRP3 or TXNIP inhibited NLRP3 inflammasome-induced IL-1β p17 secretion under HG stress. Transfections of si-SIRT1 and LV-SIRT1 exerted inverse effects on NLRP3 inflammasome activation, suggesting that SIRT1 acts as an upstream regulator of TXNIP/NLRP3 activity. HG stress induced lens opacity and cataract formation in cultivated rat lenses, which was prevented by MCC950 or SRT1720 treatment, with concomitant reductions in ROS production and TXNIP/NLRP3/IL-1β expression levels.Conclusions:The TXNIP/NLRP3 inflammasome pathway promotes HG-induced inflammation and HLEC pyroptosis, which is negatively regulated by SIRT1. This suggests viable strategies for treating diabetic cataract.
研究领域:
眼科学
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细胞生物学
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糖尿病
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炎症
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分子生物学
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DOI
PubMed
高影响因子
TALANTA
·
2024
·
IF 5.6
Xinlin Chen,Lihong Hong,Ying Wu,Yucheng Gu,Jianguang Luo,Lingyi Kong
Sirtuin1 (SIRT1), an NAD + -dependent histone deacetylase, plays a crucial role in regulating molecular signaling pathways. Recently, inhibition of SIRT1 rather than its activation shows the therapeutic potential for central nervous system disorder, however, the discovered SIRT1 inhibitors remains limited. In this work, a dual recognition-based strategy was developed to screen SIRT1 inhibitors from natural resources in situ . This approach utilized a Ni-modified metal-organic framework (Ni@Tyr@UiO-66-NH 2 ) along with cell lysate containing an engineered His-tagged SIRT1 protein, eliminating the need for purified proteins, pure compounds, and protein immobilization. The high-performance Ni@Tyr@UiO-66-NH 2 was synthesized by modifying the surface of UiO-66-NH 2 with Ni 2+ ions to specifically capture His-tagged SIRT1 while persevering its enzyme activity. By employing dual recognition, in which Ni@Tyr@UiO-66-NH 2 recognized SIRT1 and SIRT1 recognized its ligands, the process of identifying SIRT1 inhibitors from complex matrix was vastly streamlined. The developed method allowed the efficient discovery of 16 natural SIRT1 inhibitors from Chinese herbs. Among them, 6 compounds were fully characterized, and suffruticosol A was found to have an excellent IC 50 value of 0.95 ± 0.12 μM. Overall, an innovative dual recognition-based strategy was proposed to efficiently identify SIRT1 inhibitors in this study, offering scientific clues for the development of drugs targeting CNS disorders.
研究领域:
生物化学
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药物开发
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分子生物学
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DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2021
·Vol. 24
·期 6
·1-9
·
IF 2.952
Juanjuan Huang,Xianfeng Chen,Aihua Xie
Formononetin has proven to be anti‑inflammatory and able to alleviate symptoms of certain allergic diseases. The present study aimed to determine and elucidate the potential effects of formononetin in allergic rhinitis. JME/CF15 cells were pretreated with formononetin at different doses, followed by stimulation with IL‑13. Cell Counting Kit‑8 assay was performed to determine the cytotoxicity of formononetin. The expression levels of inflammation‑related proteins, histamine, IgE, TNF‑α, IL‑1β, IL‑6, granulocyte‑macrophage colony‑stimulating factor and eotaxin in IL‑13‑stimulated JME/CF15 cells were detected using ELISAs. The expression levels of phosphorylated‑NF‑κB p65, NF‑κB p65 and cyclooxygenase‑2 (Cox‑2) were analyzed using western blotting. Reverse transcription‑quantitative PCR, western blotting and immunofluorescence were performed to measure the levels of mucin 5AC oligomeric mucus/gel‑forming. Expression levels of sirtuin 1 (SIRT1) and nuclear erythroid factor 2‑related factor 2 (Nrf2) proteins were also measured using western blotting. The results of the present study revealed that formononetin exerted no cytotoxic effect on the viability of JME/CF15 cells. Following stimulation of JME/CF15 cells with IL‑13, formononetin suppressed the upregulated expression levels of proinflammatory cytokines. IL‑13‑induced formation of mucus was also attenuated by formononetin treatment. Furthermore, it was found that the SIRT1/Nrf2 signaling pathway was activated in formononetin‑treated JME/CF15 cells, whereas treatment with the SIRT1 inhibitor, EX527, reversed the effects of formononetin on IL‑13‑induced inflammation and mucus formation in JME/CF15 cells. In conclusion, the findings of the current study indicated that formononetin may activate the SIRT1/Nrf2 signaling pathway, thereby inhibiting IL‑13‑induced inflammation and mucus formation in JME/CF15 cells. These results suggested that formononetin may represent a promising agent for the treatment of allergic rhinitis.
研究领域:
免疫学
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药理学
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细胞生物学
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过敏
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DOI
PubMed
高影响因子
Food & Function
·
2022
·Vol. 13
·期 14
·7560-7571
·
IF 6.317
Shuai Lu,Jinyi Zhou,Chen Yang,Xiaoxue Zhang,Yingying Shi,Jie Liu,Xintong Yan,Juanjuan Liang,Xianli Liu,Lan Luo,Da Zhou,Zhimin Yin
Aging is a natural process accompanied by inflammation and oxidative stress and is closely associated with age-related diseases. As a direct precursor of glutathione, γ-glutamylcysteine (γ-GC) possesses antioxidant and anti-inflammatory properties; however, whether γ-GC plays an important role in anti-aging remains unknown. Here, we investigated the protective effects and mechanisms of γ-GC in D-galactose (D-gal)-induced senescence in PC12 cells and aging mice. Our results showed that γ-GC treatment significantly reduced the percentage of senescence-associated-β-galactosidase (SA-β-Gal)-positive cells and inhibited D-gal-induced cell cycle arrest in PC12 cells. The results of Nissl and hematoxylin and eosin (H&E) staining in mouse brain showed that γ-GC treatment markedly reversed the damage in the hippocampus of D-gal-induced aging mice. Moreover, γ-GC increased the phosphorylation of AMP-activated protein kinase (AMPK) to promote the nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) while inhibiting the nuclear translocation of deleted in breast cancer 1 (DBC1), which leads to the activation of sirtuin 1 (SIRT1) and deacetylation of p53 in the nucleus. Therefore, γ-GC may be a potential therapeutic candidate compound for the prevention and treatment of age-related diseases.
研究领域:
药理学
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衰老
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神经科学
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分子生物学
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DOI
PubMed
高影响因子
BMC Ophthalmology
·
2021
·Vol. 21
·期 1
·1-11
·
IF 2.209
Yu Mengdan,Zhang Lijun,Sun Shasha,Zhang Zhenhua
Background Diabetic retinopathy (DR) is a common and potentially devastating microvascular complication of diabetes mellitus (DM). The main features of DR are inflammation and oxidative damage. Gliquidone (GLI) is confirmed to be a hypoglycemic drug by oral administration. The current study is aimed to investigate the role and mechanism of GLI on the pathogenesis of DR.Methods High glucose (HG)-induced human retinal endothelial cells (HRECs) were used to explore the anti-inflammatory and anti-oxidant effects of GLI on DR in vitro. Streptozotocin (STZ)-induced DM rats were used to investigate the effects of GLI on retinal structures, inflammation, and oxidative stress. The levels of SIRT1/Notch1 pathway-related proteins were determined by western blotting.Results GLI treatment promoted the viability and inhibited the apoptosis of HG-induced HRECs. Meanwhile, the levels of interleukin (IL)-6, IL-1β, tumour necrosis factor alpha and reactive oxygen species were suppressed, while both catalase and superoxide dismutase were elevated after GLI treatment in HG-induced HRECs. Furthermore, we found that Silencing information regulator 2 related enzyme 1 (SIRT1) silencing reversed the inhibiting effects of GLI on the levels of protein Notch1 and effector genes Hes1 and Hey2. Similar anti-inflammatory and anti-oxidant effects of GLI in STZ-induced DM rats were observed. Additionally, GLI administration also repressed vascular hyperpermeability in vivo.Conclusion GLI may be an effective agent to improve DR through repression of inflammation and oxidative stress via SIRT1/Notch1 pathway.
研究领域:
药理学
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内分泌学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
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2020
·Vol. 11
·期 12
·1-14
·
IF 6.304
Huang Xiaozhong,Shi Yujuan,Chen Hongjin,Le Rongrong,Gong Xiaohua,Xu Ke,Zhu Qihan,Shen Feixia,Chen Zimiao,Gu Xuemei,Chen Xiaojun,Chen Xiong
Diabetic nephropathy (DN) as a global health concern is closely related to inflammation and oxidation. Isoliquiritigenin (ISL), a natural flavonoid compound, has been demonstrated to inhibit inflammation in macrophages. Herein, we investigated the effect of ISL in protecting against the injury in STZ-induced type 1 DN and in high glucose-induced NRK-52E cells. In this study, it was revealed that the administration of ISL not only ameliorated renal fibrosis and apoptosis, but also induced the deterioration of renal function in diabetic mice. Mediated by MAPKs and Nrf-2 signaling pathways, respectively, upstream inflammatory response and oxidative stress were neutralized by ISL in vitro and in vivo. Moreover, as further revealed by the results of molecular docking, sirtuin 1 (SIRT1) binds to ISL directly, and the involvement of SIRT1 in ISL-mediated renoprotective effects was confirmed by studies using in vitro models of SIRT1 overexpression and knockdown. In summary, by reducing inflammation and oxidative stress, ISL has a significant pharmacological effect on the deterioration of DN. The benefits of ISL are associated with the direct binding to SIRT1, the inhibition of MAPK activation, and the induction of Nrf-2 signaling, suggesting the potential of ISL for DN treatment.
研究领域:
药理学
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糖尿病
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肾病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Hong Yang,Yong-xin Chen,Ke-gang Linghu,Peng-yan Ren,Yu-ting Yao,Feng Jiang,Guo-ping Wu,Ting-ting Chen,Ling Tao,Qian-yun Sun,Yue Li,Xiang-chun Shen
Background Type 2 diabetes mellitus (T2DM) is primarily attributed to impaired insulin secretion caused by β cell dysfunction. 1,8-Cineole is a key bioactive compound in the essential oil extracted from Fructus Alpiniae Zerumbet , which possesses anti-inflammatory and antioxidant properties. Nevertheless, it remains elusive about the protective effect and precise mechanisms of 1,8-Cineole against the β cell deterioration in DM. Purpose To investigate the effect of 1,8-Cineole on β cell dysfunction in T2DM and the potential mechanism of its action. Methods A mouse model of T2DM and a β cell model of high glucose induction were generated to analyze the pharmacological properties of 1,8-Cineole. Proteomic and network pharmacological analyses were conducted to identify the crucial pathways involved in T2DM. Resveratrol [a Sirtuin1 (Sirt1) agonist] and Sirt1 knockdown were used to ascertain the mechanism of 1,8-Cineole in T2DM. The binding affinity of 1,8-Cineole to Sirt1 was assessed with molecular docking, surface plasmon resonance, immunoprecipitation assay, and cellular thermal shift assay. Results First, dysregulated crucial pathways in T2DM were screened out, including redox imbalance and mitochondrial dysfunction. Subsequently, 1,8-Cineole was found to activate Sirt1 and nuclear factor E2-related factor 2 (Nrf2) to repress oxidative stress in both T2DM mice and high glucose-induced β cells, thereby relieving mitochondrial dysfunction and apoptosis. Furthermore, 1,8-Cineole specifically targeted Sirt1 and favored the direct interaction between Sirt1 and Nrf2, ultimately restoring β cell function. Conclusions Our findings provide the first evidence that 1,8-Cineole directly binds to Sirt1 protein and enhances its stability, therefore rectifying impaired oxidative homeostasis, and then suppressing mitochondrial dysfunction and apoptosis in T2DM, indicating that 1,8-Cineole may be a potential candidate drug for DM treatment.
研究领域:
药理学
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内分泌学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Shidong Cao,Senmiao Chen,Xilin Qiao,Yan Guo,Fang Liu,Zhishan Ding,Bo Jin
Background: Oxidative stress-induced endothelial cell death, such as apoptosis and autophagy, plays a critical role in ischemia-reperfusion injury. Protocatechualdehyde (PCA) is a major bioactive component of the traditional Chinese medicine Salvia miltiorrhiza Bunge (Lamiaceae), and it has been proved to be effective in the prevention and treatment of ischemic cardiovascular and cerebrovascular diseases. However, its role in oxidative stress-induced endothelial cell death and its underlying mechanisms remains unclear. This study aims to investigate the effects and mechanisms of PCA on endothelial cell apoptosis and autophagy induced by oxygen-glucose deprivation/reoxygenation (OGD/R) injury. Methods: After OGD/R induction, human umbilical vein endothelial cells (HUVECs) were treated with different concentrations of PCA. Cell viability, apoptosis, and autophagy were detected by Cell Counting Kit-8 assay, flow cytometry, and monodansylcadaverine assay, respectively. Western blot was applied to explore the effects of PCA on the expression levels of relevant protein factors. Results: The results show that PCA significantly promoted cell survival rate and cell proliferation and enhanced the antioxidant activity in OGD/R-induced HUVECs. PCA inhibited HUVECs apoptosis, as evidenced by decreased expression of cleaved-caspase-3, Bcl2-associated X (BAX), and increased expression of Bcl-2. PCA induced autophagy by reducing the expression of P62 while increasing the expression of Beclin-1 and LC3 II/I. Meanwhile, PCA enhanced the expression of Sirtuin 1 (SIRT1) and suppressed the expression of P53. When SIRT1 was inhibited by selisistat or SIRT1 small-interfering RNA, the anti-apoptotic and pro-autophagy abilities of PCA were attenuated. Conclusion: These results demonstrated that PCA rescued HUVECs from OGD/R-induced injury by promoting autophagy and inhibiting apoptosis through SIRT1 and could be developed as a potential therapeutic agent against ischemic diseases.
研究领域:
药理学
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细胞生物学
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神经科学
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心血管疾病
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
·
2025
·
IF 4.9
Heng Zhou,Yueming Long,Fangmei Yu,Chenhui Ji,Li Gui,Yunxia Lu
Resveratrol (RSV) ameliorates endothelial dysfunction (ED) primarily through sirtuin 1 (SIRT1). Increasing evidence shows pyroptosis as a novel mechanism in palmitic acid (PA)-induced ED. p66Shc is an adaptor protein involved in oxidative stress. However, whether RSV attenuates the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome via p66Shc remains elusive. This study aims to evaluate whether the anti-pyroptotic effect of RSV and the SIRT1 inhibitor EX527 are related to p66Shc. High-fat diet (HFD) induced obesity in mice, and RSV was administered intragastrically with 400mg/kg/d for 22 successive weeks. The serum levels of interleukin-1β (IL-1β) and IL-18 were analyzed, and the expression of related proteins were assayed with immunohistochemistry in the thoracic aorta. human umbilical vein endothelial cells (HUVECs) were induced by PA, then treated with RSV and EX527 respectively, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP) and expression of p66Shc, NLRP3, GSDMD and pyroptosis-related genes were assayed. RSV administration ameliorated endothelial cell pyroptosis by decreasing serum IL-1β and IL-18, the expression of NLRP3, p66Shc, and gasdermin D (GSDMD), and increasing the expression of SIRT1 in the HFD-treated thoracic aorta. PA promoted GSDMD-mediated endothelial cell pyroptosis by ROS production, LDH release, decreased MMP and SIRT1 expression, increased expression of p66Shc and activation of the NLRP3 inflammasome in a dose-dependent manner. RSV attenuated PA-induced pyroptosis, whereas EX527 reversed the antipyroptotic effect of RSV in PA-treated HUVECs. Our results suggested a new mechanism that RSV improves PA-induced pyroptosis in endothelial cells via the SIRT1-p66Shc-NLRP3 pathway.
研究领域:
药理学
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分子生物学
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心血管科学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2020
·
IF 3.943
Dan Li,Jiangping Xu,Yunyun Qin,Ningbo Cai,Yufang Cheng,Haitao Wang
Roflupram (ROF) is a novel phosphodiesterase 4 inhibitor. We previously found that ROF suppressed the production of pro-inflammatory factors in microglial cells; however, the underlying mechanisms are largely unknown. The present study aimed to elucidate the underlying molecular mechanisms of the anti-neuroinflammatory effects of ROF in lipopolysaccharide (LPS)-activated microglial cells and LPS-challenged mice. Treatment with ROF suppressed LPS-induced expression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α in BV-2 microglia cell line. Immunofluorescence and Western blotting analysis showed that ROF significantly inhibited the activation of microglia, as evidenced by decreased expression of ionized calcium binding adaptor molecule-1 (Iba1). Similar results were obtained in primary cultured microglial cells. ROF induced the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of Sirtuin 1 (Sirt1). Interestingly, the AMPK inhibitor, compound C, blocked the role of ROF in both the phosphorylation of AMPK and the expression of Sirt1 in BV-2 cells stimulated with LPS. More importantly, the Sirt1 inhibitor, EX527, abolished the inhibitory role of ROF on the production of pro-inflammatory factors, and reactivated BV-2 cells. In mice challenged with LPS, ROF improved cognition and decreased the levels of IL-6 and TNF-α in both the cortex and hippocampus. In contrast, EX527 weakened the effects of ROF on cognitive enhancement and reduction of pro-inflammatory factors in the cortex and hippocampus. Furthermore, EX527 blocked the inhibitory role of ROF in the activation of microglial cells in both the hippocampus and cortex. Taken together, our results indicated that ROF attenuated LPS-induced neuroinflammatory responses in microglia, and the AMPK/Sirt1 pathway is essential for the anti-inflammatory effects of ROF.
研究领域:
神经科学
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药理学
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免疫学
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产品关联
DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR BIOLOGY
·
2024
·Vol. 70
·期 2
·257-263
·
IF 1.5
Qingzhi Wan,Lisha Tang,Kaili Jin,Xuanyi Chen,Yinghuan Li,Xiaofeng Xu
Granulosa cells are somatic cells located inside follicles that play a crucial role in the growth and development of follicles. Quercetin and tanshinone are two key monomers in traditional Chinese medicine that have antioxidant and anti-aging properties. The KGN cell apoptosis model caused by triptolide (TP) was employed in this work to investigate granulosa cell death and medication rescue. Quercetin and tanshinone therapy suppressed KGN cell death and oxidation while also regulating the expression of critical apoptosis and oxidation-related markers such as B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax). Further research revealed that the effects of Quercetin and Tanshinone were accomplished via deacetylation of FOXO3A in the cytoplasm and mitochondria via the SIRT1/SIRT3-FOXO3a axis. In summary, Quercetin and tanshinone protect KGN cells from apoptosis by reducing mitochondrial apoptosis and oxidation via the SIRT1/SIRT3-FOXO3a axis.
研究领域:
药理学
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细胞生物学
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中医药
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生殖生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACOLOGICAL SCIENCES
·
2024
·
IF 3
Zhihang Zhang,Yalan Luo,Xijing Zhuang,Haifeng Gao,Qi Yang,Hailong Chen
Acute lung injury (ALI) is closely related to high mortality in severe acute pancreatitis (SAP). This study unveils the therapeutic effect and mechanism of miR-217-5p on SAP-associated ALI. The miR-217-5p RNA expression was significantly up-regulated in lipopolysaccharide (LPS)-stimulated primary rat alveolar epithelial type II cells (AEC II) and sodium taurocholate-treated pancreas and lung in SAP rats. miR-217 inhibition protected AEC II from LPS-induced damage by inhibiting apoptosis and reducing the TNF-α, IL-6, and ROS levels. miR-217 inhibition suppressed apoptosis and alleviated mitochondrial damage through mitochondria-mediated apoptotic pathway in vitro . Sirt1 is a direct target of miR-217-5p. Dual-luciferase reporter assay confirmed the binding of miR-217-5p to Sirt1 mRNA 3′-UTR. The rescue experiment identified that the anti-apoptotic, anti-inflammatory, and anti-oxidative effects of miR-217 inhibition were mediated by Sirt1 in vitro . Emodin (EMO) protected AEC II from LPS-induced damage and alleviated pancreatic and lung tissue injuries. EMO exerted similar effects as miR-217 inhibition in vitro and in vivo . The effects of EMO were abolished by miR-217 overexpression. In conclusion, miR-217-5p inhibition exerts protective effects on SAP-ALI in vitro and in vivo by repressing apoptosis, inflammation, and oxidative stress through Sirt1 activation. EMO protects against lung injuries in SAP-associated ALI rats through miR-217-5p/Sirt1 axis.
研究领域:
药理学
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分子生物学
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病理生理学
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内科学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）