Scientific Reports
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2023
·Vol. 13
·期 1
·1-13
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IF 4.6
Li Shaocong,He Qi,Chen Baihao,Zeng Jiaxu,Dou Xiangyun,Pan Zhaofeng,Xiao Jiacong,Li Miao,Wang Fanchen,Chen Chuyi,Lin Yuewei,Wang Xintian,Wang Haibin,Chen Jianfa
Iron homeostasis plays an essential role in joint health, while iron overload can cause damage and death of cartilage cells. Cardamonin (CAR) is a substance found in the fruit of the chasteberry plant and has anti-inflammatory and anti-tumor activities. We first administered iron dextran (500 mg/kg) intraperitoneally to establish an iron overload mouse model and surgically induced osteoarthritis. The extent of OA and iron deposition were assessed using Micro-ct, Safranin-O/fast green staining, H&E staining, and Prussian Blue 10 weeks later. We administered primary chondrocytes with Ferric Ammonium Citrate (FAC) to evaluate the chondrocyte changes. Chondrocytes were identified in vitro by toluidine blue staining, and chondrocyte viability was evaluated by CCK-8. The rate of apoptosis was determined by Annexin V-FITC/PI assay. The mechanism of action of CAR was verified by adding the SIRT1 inhibitor EX527, and the expression of SIRT1 and MAPK signaling pathways was detected by Western blot. Iron overload also promoted chondrocyte apoptosis, a process that was reversed by CAR. In addition, CAR reduced NLRP3 inflammasome production via the SIRT1-MAPK pathway, and the SIRT1 inhibitor EX527 inhibited the treatment of OA by CAR.CAR inhibited cartilage degeneration induced by iron overload both in vivo and in vitro. Besides, our study showed that iron overload not only inhibited type II collagen expression but also induced MMP expression by catalyzing the generation of NLRP3 inflammasome. Our results suggest that CAR can treat KOA by promoting SIRT1 expression and inhibiting p38MAPK pathway expression to reduce the production of NLRP3 inflammasome vesicles.
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BIOMEDICINE & PHARMACOTHERAPY
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2023
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IF 7.5
Yongjian Guo,Chengju Luo,Yuening Sun,Wenjing Guo,Ruitian Zhang,Xin Zhang,Xue Ke,Libin Wei
Mitochondria dynamically change their morphology via fusion and fission, a process called mitochondrial dynamics. Dysregulated mitochondrial dynamics respond rapidly to metabolic cues, and are linked to the initiation and progression of diverse human cancers. Metabolic adaptations significantly contribute to tumor development and escape from tissue homeostatic defenses. In this work, we identified oroxylin A (OA), a dual GLUT1/mitochondrial fusion inhibitor, which restricted glucose catabolism of hepatocellular carcinoma cells and simultaneously inhibited mitochondrial fusion by disturbing SIRT1/PDK2/PARL axis. Based the dual action of OA in metabolic regulation and mitochondrial dynamics, further results revealed that mitochondrial functional status and spare respiratory capacity (SRC) of cancer cells had a close correlation with mitochondrial metabolic plasticity, and played important roles in the susceptibility to cancer therapy aiming at glucose restriction. Cancer cells with healthy mitochondria and high SRC exhibit greater metabolic flexibility and higher resistance to GLUT1 inhibitors. This phenomenon is attributed to the fact that high SRC cells fuse mitochondria in response to glucose restriction, enhancing tolerance to energy deficiency, but undergo less mitochondrial oxidative stress compared to low SRC cells. Thus, inhibiting mitochondrial fusion breaks mitochondrial metabolic plasticity and increases cancer cell susceptibility to glucose restriction therapy. Collectively, these finding indicate that combining a GLUT1 inhibitor with a mitochondrial fusion inhibitor can work synergistically in cancer therapy and, more broadly, suggest that the incorporations of mitochondrial dynamics and metabolic regulation may become the targetable vulnerabilities bypassing the genotypic heterogeneity of multiple malignancies.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2021
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IF 4.932
Xinrui Li,Peiquan Yu,Yinghua Yu,Ting Xu,Jiao Liu,Yuan Cheng,Xia Yang,Xiaoying Cui,Cui Yin,Yi Liu
Hyperglycemia-induced neuroinflammation promotes the progression of diabetic encephalopathy. Hydrogen sulfide (H 2 S) exerts anti-inflammatory and neuroprotective activities against neurodegenerative diseases. However, the effects of H 2 S on hyperglycemia-induced neuroinflammation has not been investigated in neurons. Herein, by using HT-22 neuronal cells, we found that high glucose decreased the levels of endogenous H 2 S and its catalytic enzyme, cystathionine-β-synthase (CBS). The administration of sodium hydrosulfide (NaHS, a H 2 S donor) or S-adenosylmethionine (SAMe, an allosteric activator of CBS) restored high glucose-induced downregulation of CBS and H 2 S levels. Importantly, H 2 S ameliorated high glucose-induced inflammation in HT-22 cells, evidenced by NaHS or SAMe inhibited the pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) expression in HT-22 cells exposed to high glucose. Furthermore, NaHS or SAMe restored the SIRT1 level and the phosphorylation of mTOR and NF-κB p65 disturbed by high glucose in HT-22 cells, suggesting H 2 S reversed high glucose-induced alteration of SIRT1-mTOR/NF-κB signaling pathway. Our results demonstrated that exogenous H 2 S treatment or enhancing endogenous H 2 S synthesis prevents the inflammatory processes in the neurons with the exposure of high glucose. Therefore, increasing the H 2 S level using NaHS or SAMe might shed light on the prophylactic treatment of diabetic encephalopathy.
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Molecular Medicine Reports
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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.
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Frontiers in Pharmacology
·
2021
·
IF 5.811
Yin Zhihui,Geng Xinyue,Zhang Zhengyi,Wang Ying,Gao Xiaoyan
Neuronal mitochondrial oxidative stress induced by β-amyloid (Aβ) is an early event of Alzheimer’s disease (AD). Emerging evidence has shown that antioxidant therapy represents a promising therapeutic strategy for the treatment of AD. In this study, we investigated the antioxidant activity of rhein against Aβ1-42 oligomer-induced mitochondrial oxidative stress in primary neurons and proposed a potential antioxidant pathway involved. The results suggested that rhein significantly reduced reactive oxygen species (ROS) level, reversed the depletion of mitochondrial membrane potential, and protected neurons from oxidative stress-associated apoptosis. Moreover, further study indicated that rhein activated mitochondrial biogenesis accompanied by increased cytochrome C oxidase (CytOx) and superoxide dismutase (SOD) activities. CytOx on the respiratory chain inhibited the production of ROS from electron leakage and SOD helped to eliminate excess ROS. Finally, western blot analysis confirmed that rhein remarkedly increased the protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) together with its upstream deacetylase sirtuin 1 (SIRT1), and activated downstream transcription factor nuclear respiratory factor 1, promoting mitochondrial biogenesis. In conclusion, our results demonstrate that rhein activates mitochondrial biogenesis regulated by the SIRT1/PGC-1α pathway as an antioxidant defense system against Aβ1-42 oligomer-induced oxidative stress. These findings broaden our knowledge of improving mitochondrial biogenesis as an approach for relieving neuronal oxidative stress in AD.
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Aging-US
·
2019
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IF 5.515
Yin Ying,Cheng Jiang,Meiling Zhang,Jiye Jin,Shuyu Ge,Xiaodong Wang
Diabetic cardiomyopathy increases the risk of heart failure independent of coronary artery disease and hypertension. Phloretin (PHL) shows anti-inflammatory effects in macrophages. In this study, we explored the protective effects of PHL on high glucose (HG)-induced injury in diabetic cardiomyopathy in vivo and in vitro . Using streptozotocin-induced diabetic mouse model and incubating cardiac cells line under a HG environment, PHL were evaluated of the activities of anti-inflammation and anti-fibrosis. In the study, PHL treatment ameliorated cardiomyocyte inflammation injury, and reduced fibrosis in vivo and in vitro . PHL also improved cardiac biochemical criterions after 8 weeks of induction of diabetes in C57BL/6 mice. Molecular docking results indicated that silent information regulator 2 homolog 1 (SIRT1) bound to PHL directly and that SIRT1 expression was upregulated in the PHL-treated group in HG-induced H9C2 cells. Protective effect of PHL was been eliminated in silence SIRT1 H9C2 cells. Taken together, these results suggested that PHL suppressed HG-induced cardiomyocyte injury via restoring SIRT1 expression.
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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.
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PHYTOMEDICINE
·
2025
·
IF 8.3
Meiqi Wang,Beixuan Yang,Xin Li,Huanhuan Ma,Xia Ou,Zeren Dawa,Fangle Liu,Chenchen Zhu,Chaozhan Lin
Background Nonalcoholic fatty liver disease (NAFLD), which is characterized by the accumulation of fat in the liver, has emerged as a leading cause of chronic liver diseases and malignancies. However, there remains a scarcity of approved therapeutic interventions. Brunodelphinine A (BruA) is a diterpenoid alkaloid isolated from Delphinium brunonianum Royle. in our previous study. It was evaluated with strong activity of lipid-lowering. Nevertheless, its precise effects and mechanisms in the treatment of NAFLD remain unexplored. Purpose The present study aims to elucidate the effects of BruA against NAFLD and to investigate its potential pharmacological mechanism. Methods The lipid-lowering and anti-NAFLD effects of BruA were evaluated in the free fatty acid (FFA)-induced cell model and high-fat diet (HFD)-induced mice. Network pharology analysis combined with Non-targeted metabolomics study was used to explore the key mechanism of BruA. Furthermore, molecular docking and cellular thermal shift assay (CETSA) were used to simulate and verify the targeting activation of BruA on the NADPH oxidase 4 (NOX4). The core role of NOX4 in BruA in regulating nicotinamide adenine dinucleotide (NAD + )/Sirtuin 1 (SIRT1) and peroxisome proliferators-activated receptors (PPARs) signaling pathway to improve oxidative stress and lipid metabolic disorders was further focused, and such mechanism was evaluated in WT and NOX4 knockout mice or HepG2 cells. Results BruA dose-dependently reduced FFA-induced lipid accumulation and cell damage in vitro , and mitigated HFD-induced NAFLD in mice. At the metabolite level, BruA improved metabolic disorder in NAFLD mice focusing on the metabolism of arachidonic acid and linolenic acid, which has been considered as signs of oxidative stress, that positively correlated with NAFLD. BruA targeting inhibited NOX4 to mitigate reactive oxygen species (ROS)-mediated oxidative stress and prevent abnormal redox levels, thereby regulating NAD + /SIRT1 in protecting the liver from oxidative damage, and further affected downstream PPARs-related lipid metabolism regulation processes, thus alleviating hepatic lipid accumulation. Furthermore, NOX4 deficiency suppressed the protective effect of BruA in vitro and in vivo . Conclusion BruA improved oxidative stress and lipid metabolic disorders of NAFLD by regulating the NOX4-SIRT1-PPARs signaling axis in vivo and in vitro , and this regulation is targeting dependent on NOX4. For its mechanisms of antioxidant stress and lipid-lowering, there is great therapeutic potential for BruA in the treatment of period with elevated lipids and inflammation production in NAFLD.
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FREE RADICAL BIOLOGY AND MEDICINE
·
2025
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IF 8.2
Hailin Wang,Yueying Wang,Xin Li,Jiayang Ma,Zhiqi Hu,Qian Qu,Yong Miao
Hair graying and loss are significant indicators of aging, and oxidative stress plays an essential role in this progression. Ergothioneine (EGT), potent antioxidant from edible fungi and certain prokaryotes, regulates the antioxidant defense system. However, its anti-aging effects on hair follicles (HFs) are remain obscure. We used dermal papilla cells (DPCs) co-culture system, HFs organ culture system, aged mice and H 2 O 2 -induced gray hair mice to explore the antioxidative functions and mechanisms of EGT on HFs. Research demonstrated that EGT mitigated H 2 O 2 -induced DPCs damage, reduced the secretion of inflammatory factors (IL-6, IL-1β, and TNF-α) and enhanced the production of pigmentation promoting factors (SCF and SDF1) through the SIRT1/Nrf2 pathway in DPCs. In vitro experiments of co-culture system indicated that EGT-treated DPCs remarkably alleviated oxidative damages and promoted cell proliferation in A-375 and HaCaT. Furthermore, it increased tyrosinase activity, melanin content and the expression of key melanin synthesis genes in A-375. Meanwhile, it promoted the expression of K19 and K14 in HaCaT. In vivo experiments revealed that EGT exhibited excellent effects on reducing pigmentation disfunction and hair loss in aged mice and H 2 O 2 -induced gray hair mice. In the HFs organ culture, the EGT promoted hair growth and pigmentation via SIRT1/Nrf2 partly. Our research indicated that EGT had potent antioxidant and anti-aging functions for HFs. This not only provided new applications for EGT but also opened up new therapeutic avenues for hair aging.
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Nutrients
·
2020
·Vol. 12
·期 6
·1889
·
IF 4.546
Nancy Saji,Nidhish Francis,Lachlan J. Schwarz,Christopher L. Blanchard,Abishek B. Santhakumar
Oxidative stress is known to modulate insulin secretion and initiate gene alterations resulting in impairment of β-cell function and type 2 diabetes mellitus (T2DM). Rice bran (RB) phenolic extracts contain bioactive properties that may target metabolic pathways associated with the pathogenesis of T2DM. This study aimed to examine the effect of stabilized RB phenolic extracts on the expression of genes associated with β-cell function such as glucose transporter 2 (Glut2), pancreatic and duodenal homeobox 1 (Pdx1), sirtuin 1 (Sirt1), mitochondrial transcription factor A (Tfam), and insulin 1 (Ins1) in addition to evaluating its impact on glucose-stimulated insulin secretion. It was observed that treatment with different concentrations of RB phenolic extracts (25-250 µg/mL) significantly increased the expression ofGlut2,Pdx1,Sirt1, Tfam,andIns1genes and glucose-stimulated insulin secretion under both normal and high glucose conditions. RB phenolic extracts favourably modulated the expression of genes involved in β-cell dysfunction and insulin secretion via several mechanisms such as synergistic action of polyphenols targeting signalling molecules, decreasing free radical damage by its antioxidant activity, and stimulation of effectors or survival factors of insulin secretion.Keywords:rice bran;phenolic extracts;β-cell function;gene expression;insulin secretion
研究领域:
营养学
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分子生物学
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内分泌学
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药理学
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Food Frontiers
·
2025
·Vol. 7
·期 1
·e70204
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IF 6.9
Suwen Liu,Wenhong Jiang,Hanchen Li,Xuli Wang,Jiancheng Ma,Lina Dong
Lonicera caerulea berry polyphenols (LCBP) exhibit multiple physiological effects. In this study, we investigated the role of LCBP in reducing cholesterol accumulation in rats with type 2 diabetes mellitus (T2DM) and its underlying mechanism. LCBP reduced the content of neutral lipids in the aorta and decreased the plaque area by 47.3% ( p < 0.01) compared with that in the model group. LCBP also reduced the expression of CD11b and F4/80 in peritoneal macrophages. The cholesterol efflux rate in the LCBP group increased significantly by 61.2% ( p < 0.01). Western blotting and immunohistochemical experiments revealed that LCBP promoted cholesterol efflux via a dual mechanism of activating silent information regulator 1 (SIRT1) in macrophages in a high-glucose environment and the miR-33/SREBP2-ABCA1 pathway. SIRT1 activation enhanced the effects of LCBP on cholesterol regulation. Molecular dynamics simulation experiments revealed that the three main monomer components of LCBP—cyanidin-3-glucoside, catechin, and chlorogenic acid—could stably bind to the active site of SIRT1 and serve as key components in the regulation of cholesterol by this protein. This study provides new insights into the use of LCBP as a functional food additive for T2DM-related atherosclerosis.
研究领域:
营养生物化学
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分子生物学
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内分泌学
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心血管研究
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功能食品
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PHYTOMEDICINE
·
2026
·
IF 11.3
Yeqiu Xu,Junrui Jonathan Hai,Duan Sun,Yihan Yang,Chen Wang,Xinan Zhang,Huanli Xu,Yajin Liao,Xianjun Qu,Bo Han,Weishi Liang,Yong Hai
Background Distractive spinal cord injury (DSCI) is a severe complication of spinal deformity correction surgery, causing early disruption of the blood–spinal cord barrier (BSCB). However, the molecular mechanisms that translate mechanical stress into vascular endothelial dysfunction remain unclear, and effective pharmacological strategies targeting this process are lacking. Purpose This study aimed to investigate the therapeutic effects of sodium rutin (NaR), a water-soluble derivative of rutin, on BSCB disruption following DSCI, and to elucidate the underlying molecular mechanisms. Methods In vivo rat DSCI models and in vitro mechanical distraction models of spinal cord microvascular endothelial cells were employed. The therapeutic effects of oral NaR administration on locomotor function and BSCB permeability in rats following DSCI were systematically evaluated. Mechanistic investigations targeting the SIRT1/β-catenin axis and oxidative stress were conducted utilizing RNA sequencing, interventions with small interfering RNA and SIRT1 inhibitors, alongside standard molecular biology techniques. Results NaR treatment dose-dependently improved locomotor recovery in DSCI rats and significantly reduced BSCB permeability by restoring the expression of tight junction proteins. Mechanical distraction caused a significant downregulation of SIRT1 in endothelial cells. NaR treatment upregulated SIRT1 expression and promoted its nuclear-to-cytoplasmic translocation. This upregulation of SIRT1 was associated with significant inhibition of mitochondrial oxidative stress. Furthermore, oxidative stress was found to promote β-catenin phosphorylation and subsequent degradation via the ubiquitin-proteasome pathway. NaR stabilized β-catenin through SIRT1-mediated antioxidant effects, promoting its nuclear translocation and the downstream expression of tight junction genes. Consequently, by repairing the BSCB, NaR restricted the infiltration of immune cells (CD68 + macrophages/microglia and MPO + neutrophils) into the spinal parenchyma, thereby attenuating secondary neuroinflammation. Conclusion The SIRT1/β-catenin axis may serve as a critical mechanotransduction pathway regulating BSCB integrity. NaR protects the BSCB after DSCI by restoring SIRT1 activity, suppressing oxidative stress, and stabilizing β-catenin signaling. NaR may be a promising pharmacological strategy for the treatment of DSCI. In brief: Hai et al. identify a mechanism by which mechanical distraction disrupts the blood-spinal cord barrier through suppression of SIRT1 and oxidative destabilization of β-catenin. Oral sodium rutin restores barrier integrity, limits inflammation, and thus improves locomotor recovery, highlighting a vascular-targeted therapeutic strategy for distraction-induced spinal cord injury Download: Download high-res image (296KB) Download: Download full-size image
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