JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY
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2023
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IF 3.6
Xiaofei Ren,Kui Xu,Jianming Xu,Qiao Mei
Melatonin possesses potent hepatoprotective properties, but it remains to be elucidated whether melatonin has a therapeutic effect on monocrotaline (MCT)-induced hepatic sinusoidal obstruction syndrome (HSOS). In this study, male Sprague Dawley rats were intraperitoneally injected with melatonin or the same volume of vehicle at 0 and 24 h after MCT intragastric administration. Next, hematoxylin–eosin staining and electron microscopy were performed to evaluate the hepatic sinusoidal injury of rats. Endothelial cell marker RECA-1 was observed by immunohistochemistry. Hepatic oxidative stress was analyzed by detecting malondialdehyde, glutathione S-transferase, and reactive oxygen species. Assessment of liver function was carried out by analysis of serum aspartate aminotransferase, alanine aminotransferase, total bilirubin, and albumin levels. Real-time polymerase chain reaction and Western blot analysis were used to identify liver Sirtuin-3 (SIRT3) and active matrix metallopeptidase 9 (MMP-9) expression. Besides, liver sinusoidal endothelial cells (LSECs) were used for the in vitro functional verification experiment. Specifically, liver histology of the melatonin-treated groups showed that the pathological damages caused by MCT were significantly attenuated, total HSOS scores were decreased, and the elevation of serum hyaluronic acid observed in the model group was also reduced. Moreover, melatonin treatment also improved the survival of rats after partial hepatectomy. Administration of melatonin ameliorated MCT-induced LSECs injury, hepatic oxidative stress, and hepatic dysfunction. Furthermore, melatonin treatment increased SIRT3 expression while attenuating MMP-9 activity in liver tissues. Cell experiment also demonstrated that SIRT3 might mediate the protective effect of melatonin on LSECs. Collectively, our study provided the potential rationale for the application of melatonin for the prevention of MCT-induced HSOS.
研究领域:
药理学
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肝病学
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分子生物学
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细胞生物学
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PubMed
高影响因子
JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION
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2024
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IF 2
Zhen Qin,Qiang-qiang Chu,An-lan Ding,Chuan-Ying Li,Mao-yan Zhang
Sirtuin 3 involved in development of various diseases, but its role in inflammatory bowel disease is still unknown. We used inflammatory bowel disease biopsies, colitis animal model, and vitro cells RAW264.7 to study the role of Sirtuin 3 in the pathophysiology of inflammatory bowel disease. Sirtuin 3 negatively correlated with intestinal TNF-α. Sirt3 was less pronounced in pediatric and adult inflammatory bowel disease patients compared with corresponding control group. Sirtuin 3 activator Honokiol suppressed dextran sulfate sodium induced colonic manifestations, while Sirt3 inhibitor caused opposite results. Honokiol inhibited colonic oxidative stress by and reduced intestinal permeability. Honokiol repressed inflammatory response by reducing macrophage infiltration, pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 levels, and inhibiting activation of NF-κB p65 in the colitis mice. However, Sirt3 inhibitor amplified colonic oxidative stress and inflammatory response. In vitro study, Sirt3 inhibitor or siRNA Sirtuin 3 activated NF-κB p65 and enhanced TNF-α, IL-1β, and IL-6 secretion from LPS stimulated RAW264.7, while Honokiol remarkably attenuated these pro-inflammatory cytokines secretion. Finally, knockdown of Sirt3 in Caco-2 cells enhanced TNF-α induced intestinal barrier integrity injury. Sirtuin 3 negatively regulates inflammatory bowel disease progression via reducing colonic inflammation and oxidative stress. Sirtuin 3 is a promising therapeutic target in clinical application for inflammatory bowel disease therapy.
研究领域:
胃肠病学
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免疫学
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药理学
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分子生物学
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PubMed
高影响因子
Science Advances
·
2025
·Vol. 11
·期 30
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IF 12.5
Caifeng Deng,Liukang Yu,Xuan Zhao,Yuxiao Chen,Jiabin Mei,Jie Wei,Xiaoyuan Chen,Guanghua Lei,Chao Zeng
Osteoarthritis (OA) is a multifactorial disease characterized by joint inflammation and cartilage degeneration, with no disease-modifying drugs available. The vicious cycle between the inflammatory microenvironment (inflamed soil) and dysfunctional chondrocytes (degeneration-related seeds) drives the chronic progressive deterioration of OA. Here, we report a genetically engineered chondrocyte-mimetic nanoplatform (termed HKL-GECM@MPNPs) comprising a honokiol (HKL)–loaded mitochondrion-targeting nanoparticle core coated with an interleukin-1 receptor type 2 (IL-1R2)–overexpressing chondrocyte membrane. HKL-GECM@MPNPs fuse with OA chondrocytes, transferring IL-1R2 onto the plasma membrane and reprogramming the inflamed microenvironment through IL-1β blockade. Mitochondrion-targeting cores then directly deliver HKL to restore mitochondrial sirtuin-3 in OA chondrocytes, reprogramming the cells’ pathological phenotype. Intra-articular injection of HKL-GECM@MPNPs in OA mice reduces inflammation, alleviates joint pain, and mitigates cartilage damage through a synergistic effect. Moreover, HKL-GECM@MPNPs effectively reverse cartilage degeneration in human OA cartilage explants. This approach highlights the potential of HKL-GECM@MPNPs to combine IL-1β blockade and mitochondrial sirtuin-3 restoration as a promising strategy for OA treatment.
研究领域:
纳米医学
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生物工程
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免疫学
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分子生物学
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药理学
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风湿病学
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PubMed
高影响因子
ARCHIVES OF TOXICOLOGY
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2024
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IF 4.8
Yang Liu,Li Qiao,Wang Sa,Ji Yi,Ma Xinbo,Qin Ming,Gao Yanhui,Yang Yanmei
Skeletal fluorosis is a chronic metabolic bone disease caused by long-term excessive fluoride intake. Abnormal differentiation of osteoblasts plays an important role in disease progression. Research on the mechanism of fluoride-mediated bone differentiation is necessary for the prevention and treatment of skeletal fluorosis. In the present study, a rat model of fluorosis was established by exposing it to drinking water containing 50 mg/L F − . We found that fluoride promoted Runt-related transcription factor 2 (RUNX2) as well as superoxide dismutase 2 (SOD2) and sirtuin 3 (SIRT3) expression in osteoblasts of rat bone tissue. In vitro, we also found that 4 mg/L sodium fluoride promoted osteogenesis-related indicators as well as SOD2 and SIRT3 expression in MG-63 and Saos-2 cells. In addition, we unexpectedly discovered that fluoride suppressed the levels of reactive oxygen species (ROS) and mitochondrial reactive oxygen species (mtROS) in osteoblasts. When SOD2 or SIRT3 was inhibited in MG-63 cells, fluoride-decreased ROS and mtROS were alleviated, which in turn inhibited fluoride-promoted osteogenic differentiation. In conclusion, our results suggest that SIRT3/SOD2 mediates fluoride-promoted osteoblastic differentiation by down-regulating reactive oxygen species.
研究领域:
生物学
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生物化学
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毒理学
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骨骼生物学
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PubMed
高影响因子
Signal Transduction and Targeted Therapy
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2024
·Vol. 9
·期 1
·1-17
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IF 40.8
Peng Fu,Liao Minru,Jin Wenke,Liu Wei,Li Zixiang,Fan Zhichao,Zou Ling,Chen Siwei,Zhu Lingjuan,Zhao Qian,Zhan Gu,Ouyang Liang,Peng Cheng,Han Bo,Zhang Jin,Fu Leilei
Sirtuin 3 (SIRT3) is well known as a conserved nicotinamide adenine dinucleotide + (NAD + )-dependent deacetylase located in the mitochondria that may regulate oxidative stress, catabolism and ATP production. Accumulating evidence has recently revealed that SIRT3 plays its critical roles in cardiac fibrosis, myocardial fibrosis and even heart failure (HF), through its deacetylation modifications. Accordingly, discovery of SIRT3 activators and elucidating their underlying mechanisms of HF should be urgently needed. Herein, we identified a new small-molecule activator of SIRT3 (named 2-APQC) by the structure-based drug designing strategy. 2-APQC was shown to alleviate isoproterenol (ISO)-induced cardiac hypertrophy and myocardial fibrosis in vitro and in vivo rat models. Importantly, in SIRT3 knockout mice, 2-APQC could not relieve HF, suggesting that 2-APQC is dependent on SIRT3 for its protective role. Mechanically, 2-APQC was found to inhibit the mammalian target of rapamycin (mTOR)-p70 ribosomal protein S6 kinase (p70S6K), c-jun N-terminal kinase (JNK) and transforming growth factor-β (TGF-β)/ small mother against decapentaplegic 3 (Smad3) pathways to improve ISO-induced cardiac hypertrophy and myocardial fibrosis. Based upon RNA-seq analyses, we demonstrated that SIRT3-pyrroline-5-carboxylate reductase 1 (PYCR1) axis was closely assoiated with HF. By activating PYCR1, 2-APQC was shown to enhance mitochondrial proline metabolism, inhibited reactive oxygen species (ROS)-p38 mitogen activated protein kinase (p38MAPK) pathway and thereby protecting against ISO-induced mitochondrialoxidative damage. Moreover, activation of SIRT3 by 2-APQC could facilitate AMP-activated protein kinase (AMPK)-Parkin axis to inhibit ISO-induced necrosis. Together, our results demonstrate that 2-APQC is a targeted SIRT3 activator that alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis, which may provide a new clue on exploiting a promising drug candidate for the future HF therapeutics.
研究领域:
心血管药理学
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分子生物学
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细胞生理学
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DOI
高影响因子
Frontiers in Pharmacology
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2024
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IF 4.4
Jiemei Shi,Min Liu,Jiajie Zhao,Ye Tan,Chunhui Jiang
Introduction: Mitochondrial dysfunction and oxidative stress play important roles in diabetic retinal vascular injuries. Honokiol (HKL) is a small-molecule polyphenol that exhibits antioxidant effects and has a beneficial effect in diabetes. This study aimed to explore the potential ability of HKL to ameliorate vascular injury in diabetic retinopathy (DR) and its possible mechanisms of action.Methods: The effect of HKL was evaluated in vascular injury in an in vivo type 2 diabetic (db/db) mouse model. In vitro, retinal microvascular endothelial cells were treated with high glucose (HG) to simulate the pathological diabetic environment. Cell viability, expression of apoptosis-related proteins, cellular reactive oxygen species, mitochondrial membrane potential, and morphological changes in the mitochondria were examined.Results: The diabetic mice exhibited severe retinal vascular damage, including vascular leakage in vivo and capillary endothelial cell apoptosis in vitro. HKL reversed the retinal vascular leakage in the diabetic mice. In vitro, HKL improved retinal capillary endothelial cell viability, decreased apoptosis, and reversed the HG-induced increased cellular oxidative stress and mitochondrial fragmentation. The sirtuin 3 (SIRT3) inhibitor 3-TYP blocked all the in vivo and in vitro protective effects of HKL against diabetic retinal vascular leakage and capillary endothelium and eliminated the decrease in oxidative stress levels and reduction of mitochondrial fragmentation.Discussion: In conclusion, these findings suggest that HKL inhibits vascular injury in DR, which was likely achieved through SIRT3-mediated mitochondrial fusion. This study provides a potential new strategy for the treatment of DR.
研究领域:
药理学
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糖尿病学
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眼科学
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细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2025
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IF 12.6
Deng Yu,Jiang Xinyu,Che Zhenzhen,Shang Yaqi,Hu Mengting,Wang Wentian,Yu Weixian,Yang Bai,Liu Xinchan
Periodontitis is a chronic inflammatory disease strongly linked to the sustained accumulation of reactive oxygen species (ROS). Eliminating excessive ROS and modulating the periodontal microenvironment to suppress inflammation represents a promising therapeutic approach for the treatment of periodontitis. Fisetin (FIS) is a naturally occurring flavonoid known for its strong antioxidant and anti-inflammatory effects. However, its poor water solubility and low bioavailability limit its therapeutic efficacy. Carbon dots (CDs), as an emerging nanomaterial, offer advantages such as simple synthesis, good biocompatibility, and low cost. To overcome the limitations of FIS, this study synthesized fisetin-derived carbon dots (FIS-CDs) via a hydrothermal method. The resulting FIS-CDs exhibits excellent water solubility, favorable biocompatibility, and demonstrates excellent ROS-scavenging capability without the need for further modification. In vitro FIS-CDs significantly reduced intracellular ROS levels, alleviate oxidative stress, maintain mitochondrial homeostasis, and suppress the generation of inflammatory cytokines. Furthermore, FIS-CDs exhibit excellent osteogenic potential. In vivo experiments confirmed that FIS-CDs markedly alleviated periodontal inflammation and oxidative damage, suppressed alveolar bone loss, and promoted regeneration of periodontal tissues. Mechanistically, FIS-CDs facilitate the activation of mitophagy by downregulating the SUMOylation of sirtuin 3 (SIRT3). This modulation contributes to the restoration of mitochondrial function, which in turn mitigates cellular injury and limits the secretion of inflammatory mediators. Collectively, these findings underscore the therapeutic promise of FIS-CDs as a safe and effective nanomaterial for periodontitis treatment and suggest a novel molecular target for future drug development. Graphical abstract
研究领域:
纳米医学
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牙科学
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分子生物学
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氧化应激与抗氧化
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炎症性疾病
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DOI
PubMed
高影响因子
Biomaterials Research
·
2026
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IF 9.8
Yiqiong Yang,Rui Zuo,Yi Wang,Rumeng Liu,Yi Zhou,Jun Wang
Sepsis-induced acute kidney injury (AKI) is characterized by mitochondrial dysfunction and dysregulated inflammation, with a lack of effective therapies. Studies have found that down-regulation of Sirtuin 3 (Sirt3) expression in renal tubular epithelial cells is associated with mitochondrial imbalance, suggesting its potential as a therapeutic target. Based on this, the research team developed a targeted nanodelivery system: black phosphorus nanosheets loaded with a cortistatin agonist were encapsulated with macrophage membranes modified with (KKEEE)₃K peptides to specifically deliver Sirt3-activating components to the kidneys. This nanosystem demonstrated favorable stability and biocompatibility. Ex vivo experiments confirmed its ability to alleviate lipopolysaccharide-induced oxidative stress, apoptosis, and inflammation in HK-2 cells, while restoring mitochondrial function. Mechanistically, the nanomaterial regulates mitochondrial homeostasis by activating the Sirt3–YME1L1 deacetylation axis. This study provides a novel nano-therapeutic strategy for sepsis-induced AKI, combining targeting capability with metabolism regulation, and holds broad implications for the treatment of inflammatory organ damage.
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高影响因子
Drug Design Development and Therapy
·
2022
·
IF 4.319
Liang Wang,Qiushi Li,Haibo Yan,Guangjun Jiao,Hongliang Wang,Hai Chi,Hongming Zhou,Lu Chen,Yu Shan,Yunzhen Chen
Purpose Glucocorticoids are used for the treatment of inflammatory diseases, but glucocorticoid treatment is associated with bone damage. Resveratrol is a phytoalexin found in many plants, and we investigated its protective role on dexamethasone-induced dysfunction in MC3T3-E1 cells and primary osteoblasts.Materials and Methods MC3T3-E1 cells and primary osteoblasts were treated with dexamethasone in the presence/absence of different doses of resveratrol for 24 or 48 h. Then, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium (MTT) and lactate dehydrogenase (LDH) assays were used to evaluate cell viability. Apoptosis was analyzed by a flow cytometry. An alkaline phosphatase (ALP) activity assay and Alizarin Red S staining were used to study osteoblast differentiation. Expression of osteoblast-related genes was measured by real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The AMP-activated protein kinase (AMPK) signaling pathway and mitochondrial expression of superoxide dismutase were evaluated by Western blotting. Intracellular reactive oxygen species (ROS), adenosine triphosphate (ATP) content, mitochondrial-complex activity, and mitochondrial DNA content were measured to evaluate mitochondrial function.Results Resveratrol induced the proliferation and inhibited apoptosis of osteoblasts in the presence of dexamethasone. Resveratrol increased the ALP activity and mineralization of osteoblasts. Resveratrol also attenuated dexamethasone-induced inhibition of mRNA expression of osteogenesis maker genes, including bone morphogenetic protein-2, osteoprotegerin, runt-related transcription factor-2, and bone Gla protein. Resveratrol alleviated dexamethasone-induced mitochondrial dysfunction. Resveratrol strongly stimulated expression of peroxisome proliferator–activated receptor-γ coactivator 1α and sirtuin-3 genes, as well as their downstream target gene superoxide dismutase-2. Resveratrol induced phosphorylation of AMPK and acetyl-CoA carboxylase (ACC). Blockade of AMPK signaling using compound C reversed the protective effects of resveratrol against dexamethasone.Conclusion Resveratrol showed protective effects against dexamethasone-induced dysfunction of osteoblasts by activating AMPK signaling.
研究领域:
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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骨骼健康
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产品关联
DOI
PubMed
高影响因子
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