TOXICOLOGY AND APPLIED PHARMACOLOGY
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2025
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IF 3.4
Yi Cai,Liduan Huang,Yanhong Hou,Peiwen Pang,Ying Zhou,Xuan Zhang,Yiyin Long,Huajian Li,Halimulati Muhetaer,Man Zhang,Bo Wu
Andrographolide, a diterpene compound derived from the medicinal plant Andrographis paniculata , possesses anti-inflammatory, antioxidant, antitumor, and antiviral properties. Injectable formulations containing andrographolide, such as Potassium Sodium Dehydroandrographolide Succinate for Injection (PSDS), are widely used in clinical practice to treat various diseases, including upper respiratory tract infections. However, clinical reports have highlighted that andrographolide-based herbal injections may induce acute kidney injury and other renal adverse effects, thereby restricting its clinical application. Despite these concerns, the molecular mechanisms underlying andrographolide-induced nephrotoxicity remain poorly understood. In this study, we demonstrated that andrographolide induces inflammation and fibrosis in renal tubular epithelial cells and mouse kidneys. Notably, we identified for the first time that andrographolide promotes cellular senescence in renal tubular epithelial cells and mouse kidneys while downregulating the expression and enzymatic activity of SIRT3. Mechanistic investigations revealed that andrographolide mediates kidney injury and senescence through inhibition of the SIRT3/p53 signaling pathway. Furthermore, andrographolide was found to disrupt the interaction between SIRT3 and p53, resulting in increased acetylation of p53 and upregulation of its downstream target genes involved in inflammation, fibrosis, and senescence. These findings elucidate the molecular mechanisms of andrographolide-induced nephrotoxicity and provide a scientific basis for developing strategies to reduce its toxic effects.
研究领域:
药理学
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分子生物学
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毒理学
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产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2025
·
IF 6.3
Shushu Jiang,Cheng Wang,Yin Dong,Long Chen,Menghao Shi,Fengxiao Zhang,Zhaohui Wang,Minglu Liang
Numerous studies have documented erucin's anticancer and vasodilatory properties, yet its impact on pathological cardiac hypertrophy remains to be fully understood. This study aimed to explore the therapeutic potential of erucin in cardiac hypertrophy induced by pressure overload. Cardiac hypertrophy was induced in mice by transverse aortic constriction (TAC) surgery, and in neonatal rat cardiomyocytes via phenylephrine (PE) treatment. Cardiac function and remodeling were evaluated using echocardiography, histological assessment, and molecular analyses. Mitochondrial function was assessed by measuring mitochondrial respiration, ATP concentration, the NAD+/NADH ratio, and reactive oxygen species (ROS) levels. Molecular docking was performed to identify erucin's downstream effector. Nrf2 and Sirt3 were silenced using siRNAs, and their activities were inhibited with ML385 and 3-TYP, respectively. Here, we found that erucin improved cardiac function and remodeling in TAC-induced hypertrophic mice, mitigated PE-induced cell hypertrophy, and restored mitochondrial function. Molecular docking analysis identified Nrf2 as a target protein of erucin. Erucin increased Nrf2 protein levels and activated the Nrf2 signaling pathway, which in turn promoted Sirt3 transcription. This effect was blocked by silencing Nrf2 or using ML385. Additionally, silencing Nrf2 and Sirt3 or using ML385 and 3-TYP abolished erucin's protective effects. This study is the first to demonstrate that erucin protects against cardiac hypertrophy by improving mitochondrial function through the activation of the Nrf2-Sirt3 pathway. Erucin may emerge as a promising therapeutic candidate for treating cardiac hypertrophy.
研究领域:
心血管生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2025
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IF 5.9
Guoliang Liu,Tao Zhang,Shunmeng Qian,Xiaoshuang Zhang,Hongxiang Lou,Peihong Fan
Mitochondria play a crucial role in cellular processes such as growth, differentiation, and energy conversion. Dysfunctional mitochondria have been implicated in Alzheimer's disease (AD), making mitochondrial improvement a promising therapeutic approach. SIRT3, a mitochondrial deacetylase, modulates mitochondrial function by deacetylating associated proteins. This study aimed to enhance the activity of honokiol, a natural SIRT3 modulator, and improve mitochondrial function for neuroprotective activity, using mitochondria targeting strategy. We synthesized mitochondrial targeting peptide conjugates using XJB as a carrier and found that honokiol conjugates exhibited lower toxicity and higher activity on neuronal injury models in vitro and i n vivo ( Zebrafish model) at lower concentrations compared to honokiol. The neuroprotective mechanism may involve the activation of cellular autophagy-related pathways, promotion of SIRT3 pathway activation, and up-regulation of mitochondrial fusion-associated protein Mfn-1 expression under damaged conditions. This study offers a promising approach for developing anti-Alzheimer's disease (AD) natural product derivatives based on SIRT3 regulation.
研究领域:
药理学
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神经科学
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生物化学
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DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
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2025
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IF 7.7
Wenxian Chen,Tongzhu Jin,Yilin Xie,Changsheng Zhong,Huiying Gao,Lei Zhang,Jin Ju,Ting Cheng,Mengyang Li,Huifang Wang,Zhenbo Yang,Qin Deng,Zhimin Du,Haihai Liang
Background and Purpose Emerging evidence indicated that the excessive lipid droplets (LDs) accumulation and lipotoxicity play a significant role in the development of diabetic cardiomyopathy (DCM), yet the regulatory mechanisms governing the function of cardiac LDs are still unknown. Lipophagy has been shown to be involved in the maintenance of LDs homeostasis. The objective of this study was to explore the mechanism of lipophagy in cardiomyocytes and investigate whether berberine could mitigate DCM by modulating this pathway. Experimental Approach Bioinformatics analysis identified disorders of lipid metabolism and autophagy in DCM. To carry out further research, db/db mice were utilized. Furthermore, H9C2 cells treated with palmitic acid were employed as a model to explore the molecular mechanisms involved in myocardial lipotoxicity. Key Results The results showed that lipophagy was impaired in DCM. Mechanistically, sirtuin 3 (SIRT3) was demonstrated to regulate lipophagy in cardiomyocytes. SIRT3 was down-regulated in DCM. Conversely, activation of SIRT3 by the activator nicotinamide riboside (NR) could promote lipophagy to alleviate PA-induced lipotoxicity in H9C2 cells. Moreover, berberine administration markedly mitigated diabetes-induced cardiac dysfunction and hypertrophy in db/db mice, which dependent on SIRT3-mediated lipophagy. Conclusion and Implications Collectively, SIRT3 could moderate cardiac lipotoxicity in DCM by promoting lipophagy, suggesting that the regulation of SIRT3-mediated lipophagy may be a promising strategy for treating DCM. The findings indicate that the therapeutic potential of berberine for DCM is associated with lipophagy.
研究领域:
心血管医学
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代谢生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
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2023
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IF 7.9
Yi Cai,Shisheng Jiang,Chaoming Huang,Ao Shen,Xuan Zhang,Wanling Yang,Yichuan Xiao,Shuhan Gao,Rong Du,Guodong Zheng,Tingdong Yan,Chunpeng (Craig) Wan
Background The conserved sirtuin protein sirtuin 3 (SIRT3) is a vital protective protein for cardiac hypertrophy. Inhibition of SIRT3 accelerated the development of heart hypertrophy. On the other hand, myocardial hypertrophy was prevented by overexpressing SIRT3. SIRT3 has been proposed as a potential therapeutic target for managing or averting heart hypertrophy. Baicalin, a flavonoid extracted from the Scutellaria baicalensis plant, has anti-cardiovascular properties, including protection against cardiac hypertrophy. However, the molecular mechanism of the anti-hypertrophic effect of baicalin is not well known. Purpose In this study, we aim to investigate the effect of baicalin on cardiac hypertrophy and explored its underlying molecular mechanisms. Study-design/methods Abdominal aortic constriction (AAC)-induced mouse cardiac hypertrophy and angiotensin II (Ang II)-induced cardiomyocyte hypertrophy models were established. After baicalin treatment, cardiac hypertrophy was monitored by detecting the expression of hypertrophic genes and cell surface area. Echocardiogram was performed to check the heart function in vivo . Moreover, the protein expression of the SIRT3-dependent pathway was detected by Western blotting. Results In this work, we demonstrated that baicalin might suppress the cell surface area and the expression of the Ang II -induced myosin heavy chain β (β-MHC), brain natriuretic polypeptide (BNP), and atrial natriuretic factor (ANF). Additionally, it reduced the AAC rats' hypertrophic impact. We also found that baicalin prevents cardiac hypertrophy by regulating SIRT3/LKB1/AMPK signaling pathway. Moreover, we showed that baicalin upregulated the SIRT3 protein expression by inhibiting proteasome and by the activation of 20 S proteasome subunit beta type-5 (PSMB5). Conclusion These results offer the first proof that baicalin inhibits cardiac hypertrophy due to its effect on the SIRT3-dependent signaling pathway, indicating its potential for treating cardiac hypertrophy and heart failure. The present study provides a preliminary experimental basis for the clinical application of baicalin and baicalin-like compounds.
研究领域:
心脏病学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Siyuan Liu,Jincheng Lv,Peng Peng,Xianshu Song,Pengyu Dai,Fangle Liu,Yufeng Yao,Chenchen Zhu,Chaozhan Lin
Ethnopharmacological relevance Recurrent or persistent respiratory tract infection may progress to chronic pneumonia or other debilitating sequelae in the absence of appropriate therapeutic interventions, seriously compromising the patients' quality of life. LianZhiXiaoYan Formula (LZXYF), a Chinese prescription composed of Chinese medical herbs Andrographis herba (ChuanXinLian) and Radix helicteris (ShanZhiMa), possesses efficiency of clearing heat and detoxifying, and shown a good therapeutic effect on respiratory infectious diseases, but its mechanism of action is not clear. Aim of the study Aim to evaluate the therapeutic efficacy of LZXYF in treatment of CP and investigate its molecular and physiological mechanisms. Materials and methods The therapeutic effects of LZXYF on CP was evaluated in an LPS-induced murine model by assessing the pulmonary function, lung histopathology, and biochemical indicators. To explore the mechanism of LZXYF, the lung metabolomics and the components of LZXYF distributed in lung were analyzed by UHPLC-Q-TOF-MS/MS. The impact of LZXYF on SIRT3-SDH-SCUNR1 pathway was investigated using RT-qPCR and Western blot, and the interaction between LZXYF and SIRT3 was verified via CETSA. LPS-induced LLC cell and succinate-induced RAW264.7 cell were employed to investigate the effect and mechanism of LZXYF on metabolic reprogramming and inflammation regulation, with selective inhibition of SIRT3 and SUCNR1, respectively. Results LZXYF treatment improved pulmonary function as demonstrated by increased Tidal volume, enhanced Minute ventilation, elevated Peak expiratory flow rate, and reduced Timed inspiration ( P < 0.05). Moreover, histopathological analysis revealed that LZXYF treatment attenuated emphysema and airway remodeling, concomitant with reduced the levels of TGF-β and HYP ( P < 0.01). Metabolomics demonstrated that LZXYF treatment restored 38 dysregulated metabolites in CP mice, primarily involving tryptophan, histidine, lysine and arginine metabolic pathways. Correlation analysis of 16 lung-distributed components and the 38 differential metabolites further indicated that LZXYF alleviated CP through SIRT3 signaling pathway mediated metabolic reprogramming. We further demonstrated that LZXYF could up-regulate SIRT3 to enhance the activities of SDH ( P < 0.01), a metabolic enzyme in TCA cycle, thereby regulating metabolic reprogramming and inhibiting the activation of SUCNR1 to prevent succinate-induced inflammation responses ( P < 0.01). Furthermore, we elucidated that the active components of LZXYF exerted ameliorated effects by up-regulating SIRT3 expression in LPS or 3-TYP induced LLC cell metabolic reprogramming, which revealed SIRT3 as a critical molecular target for LZXYF to improve metabolic reprogramming and suppress inflammatory responses induced by succinate. Conclusion LXZYF could ameliorate CP through up-regulating SIRT3, which enhances TCA cycle and suppresses succinate-mediated inflammation. This study provides new insight into the therapeutic potential of LZXYF for CP treatment.
研究领域:
呼吸病学
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中药药理学
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代谢生物学
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炎症免疫学
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分子药理学
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产品关联
DOI
PubMed
高影响因子
Regenerative Biomaterials
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2023
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IF 6.7
Hua Xi,Hou Mingzhuang,Deng Lei,Lv Nanning,Xu Yong,Zhu Xuesong,Yang Huilin,Shi Qin,Liu Hao,He Fan
The scarcity of native periosteum poses a significant clinical barrier in the repair of critical-sized bone defects. The challenge of enhancing regenerative potential in bone healing is further compounded by oxidative stress at the fracture site. However, the introduction of artificial periosteum has demonstrated its ability to promote bone regeneration through the provision of appropriate mechanical support and controlled release of pro-osteogenic factors. In this study, a polylactic acid (PLLA)/hyaluronic acid (HA)-based nanofibrous membrane was fabricated using the coaxial electrospinning technique. The incorporation of irisin into the core-shell structure of PLLA/HA nanofibers (PLLA/HA@Irisin) achieved its sustained release. In vitro experiments demonstrated that the PLLA/HA@Irisin membranes exhibited favorable biocompatibility. The osteogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs) was improved by PLLA/HA@Irisin, as evidenced by a significant increase in alkaline phosphatase (ALP) activity and matrix mineralization. Mechanistically, PLLA/HA@Irisin significantly enhanced the mitochondrial function of BMMSCs via the activation of the sirtuin 3 antioxidant pathway. To assess the therapeutic effectiveness, PLLA/HA@Irisin membranes were implanted in situ into critical-sized calvarial defects in rats. The results at four and eight weeks post-surgery indicated that the implantation of PLLA/HA@Irisin exhibited superior efficacy in promoting vascularized bone formation, as demonstrated by the enhancement of bone matrix synthesis and the development of new blood vessels. The results of our study indicate that the electrospun PLLA/HA@Irisin nanofibers possess characteristics of a biomimetic periosteum, showing potential for effectively treating critical-sized bone defects by improving the mitochondrial function and maintaining redox homeostasis of BMMSCs.
研究领域:
组织工程
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再生医学
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生物材料科学
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产品关联
DOI
PubMed
高影响因子
SKIN RESEARCH AND TECHNOLOGY
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2023
·Vol. 29
·期 3
·e13303
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IF 2.2
Chunxia Gan,Titi Liu,Xiaorong Jia,Xueqin Huang,Xiangdong Qin,Xuanjun Wang,Jun Sheng,Huanhuan Xu
Background Skin photoaging is the damage caused by excessive exposure to ultraviolet (UV) irradiation. We investigated the effect of adenosine triphosphate (ATP) supplementation on UVB-induced photoaging in HaCaT cells and its potential molecular mechanism. Materials and methods The toxicity of ATP on HaCaT cells was examined by the MTT assay. The effects of ATP supplementation on the viability and apoptosis of HaCaT cells were determined by crystal-violet staining and flow cytometry, respectively. Cellular and mitochondrial ROS were stained using fluorescent dyes. Expression of Bax, B-cell lymphoma (Bcl)-2, sirtuin (SIRT)3, and superoxide dismutase (SOD)2 was measured via western blotting. Results ATP (1, 2 mM) exerted no toxic effect on the normal growth of HaCaT cells. UVB irradiation caused the apoptosis of HaCaT cells, and ATP supplementation inhibited the apoptosis induced by UVB significantly, as verified by expression of Bax and Bcl-2. UVB exposure resulted in accumulation of cellular and mitochondrial reactive oxygen species (ROS), but ATP supplementation suppressed these increases. Expression of SIRT3 and SOD2 was decreased upon exposure to UVB irradiation but, under ATP supplementation, expression of SIRT3 and SOD2 was reversed, which was consistent with the reduction in ROS level observed in ATP-treated HaCaT cells after exposure to UVB irradiation. Conclusions ATP supplementation can suppress UVB irradiation-induced photoaging in HaCaT cells via upregulation of expression of SIRT3 and SOD2.
研究领域:
细胞生物学
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分子生物学
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皮肤科
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产品关联
DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
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2020
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IF 3.391
Ruobing Wang,Yahui Liu,Xuguang Mi,Qingmin Chen,Peiqiang Jiang,Junjie Hou,Yifan Lin,Siqi Li,Bai Ji,Yanqiu Fang
Regorafenib , a multiple kinase inhibitor, is recently approved for treatment of patients with advanced hepatocellular carcinoma (HCC). Previous studies demonstrated that regorafenib was a mitochondrial toxicant, which associated with the impairment of mitochondria. Sirt3 is involved in the regulation of mitochondrial function in cancers. This study aimed to investigate the mechanism of Sirt3 involved in the mitochondrial dysfunction which associated with regorafenib treatment in liver cancer cells. We found regorafenib inhibited Sirt3 and p-ERK expression in HCC cells in a dose-dependent manner. Bioinformatics analysis showed that Sirt3 expression was down-regulated in liver cancer tissues and its low expression was correlated with worse overall survival (OS) in liver cancer patients. After transfected with Sirt3 overexpression plasmid, we found that Sirt3 sensitized liver cancer cells to regorafenib and resulted in much more apoptosis with a significant increase of ROS level. However, exogenous antioxidant could not weaken the apoptosis. Mitochondrial membrane potential assay indicated that Sirt3 overexpression accelerated the mitochondrial depolarization process induced by regorafenib and aggravated mitochondrial injury. Cellular oxygen consumption assay showed that mitochondrial dysfunction was caused by the damage of the electron transport chain . The results demonstrated that Sirt3 overexpression promoted the increase of ROS and apoptosis induced by regorafenib through the acceleration of mitochondrial dysfunction by impairing function of the electron transport chain in liver cancer cells. Our studies verified the functional role of Sirt3 in regorafenib treatment and suggested that regorafenib accompanied with Sirt3 activator as a novel treatment strategy for HCC.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
MOLECULES
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2022
·Vol. 27
·期 12
·3823
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IF 4.927
Meng Zhou,Yanpeng Dai,Yong Ma,Yi Yan,Min Hua,Qi Gao,Xue Geng,Qian Zhou
Acute kidney injury (AKI) induced by cisplatin (CP), a first-line anticancer drug for chemotherapy, is common. To date, there is an urgent need to find effective treatments to reduce the nephrotoxicity caused by CP. Meanwhile, the restoration of mitochondrial dysfunction shows potential to be used as an adjunct to conventional therapeutic strategies. This study found that liquiritigenin can ameliorate mitochondrial dysfunction and acute kidney injury induced by CP in mice. The intraperitoneal injection of 15 mg/kg body weight liquiritigenin for 2 days markedly protected against CP-induced mitochondrial dysfunction, restored renal tubule and mitochondrial morphology, decreased blood Scr and BUN levels, and decreased cell apoptosis. Furthermore, the elevated expression of SIRT3 induced by liquiritigenin, which can be upregulated by NRF2, was confirmed in vivo and in vitro. The underlying protective mechanisms of liquiritigenin in CP-induced nephrotoxicity were then investigated. Molecular docking results showed that liquiritigenin has potent binding activities to KEAP1, GSK-3β and HRD1. Further results showed that liquiritigenin induced the nuclear translocation of NRF2 and increased the levels of mitochondrial bioenergetics-related protein such as PGC-1α, and TFAM, which are related to NRF2 activity and mitochondrial biogenesis. In addition, liquiritigenin was found to possibly reverse the decrease in BCL2/BAX ratio induced by CP in live cultured renal tubule epithelial cells. Collectively, these results indicated that liquiritigenin could be used as a potential nephroprotective agent to protect against cisplatin-induced acute kidney injury in a NRF2-dependent manner by improving mitochondria function.Keywords:liquiritigenin;NRF2;cisplatin;SIRT3;mitochondrial biogenesis
研究领域:
药理学
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毒理学
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分子生物学
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肾脏生理学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Xiaocui Jiang,Xiaoming Yu,Zhongyi Zhu,Yinjuan Lyu,Xinyu Jiang,Zihao Liu,Jigang Cao,Min Xiao
Ethnopharmacological relevance The effect of hyperuricemia (HUA) on testicular spermatogenesis cannot be ignored. The classical Chinese medicine compound Shenling Baizhu San (SLBZS) can reduce uric acid and improve testicular spermatogenesis, while researchers have not well explored the related pathology and pharmacodynamic mechanism have. Aims of study To investigate whether the dysfunction of testicular spermatogenesis caused by HUA and the therapeutic effect of SLBZS are related to testicular cell ferroptosis. Materials and methods C57BL/6 mice and C57BL/6 background Sirt3 -/- mice were induced by oxazinate potassium (OXO), and HUA spermatogenic dysfunction mice model were constructed and treated with SLBZS. Sperm quality detection and testicular histopathology served for evaluating the protective mechanism of SLBZS against testicular spermatogenesis in HUA mice. Biochemical detection, transmission electron microscopy, immunohistochemistry and immunofluorescence were used to evaluate ferroptosis level of testicular cells. Western blot analysis assisted in verifying the expression of the corresponding pathway proteins. Results The testes of mice with HUA spermatogenic dysfunction were subjected to OXO-induced oxidative stress and ferroptosis, and the Sirt3/Nrf2 pathway-related protein expressions were changed. SLBZS improved the testes of mice with HUA spermatogenic dysfunction in terms of their spermatogenic function, oxidative stress and ferroptosis, and promoted Sirt3/Nrf2 antioxidant pathway-related proteins to be expressed. The analysis of Sirt3 -/- mice was modeled and dosed, and it was found that SLBZS could not improve the spermatogenic function, oxidative stress and ferroptosis of Sirt3-deficient model mice’ testes. Conclusions OXO-induced spermatogenic dysfunction in HUA is associated with ferroptosis of testicular cells. SLBZS can be used for treating spermatogenic dysfunction in HUA possibly by activating Sirt3/Nrf2 signaling pathway, which inhibits ferroptosis due to oxidative stress.
研究领域:
药理学
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生殖医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Pharmaceuticals
·
2024
·Vol. 17
·期 10
·1288
·
IF 4.3
Chunhua Liu,Yu He,Mingjin Wang,Jia Sun,Jie Pan,Ting Liu,Yueting Li,Meng Zhou,Yong Huang,Yongjun Li,Yanmin Zhang,Yuan Lu
Background: Polygonum orientale L. (PO) has demonstrated notable efficacy in treating coronary heart disease. Previous research identified eight key active components in PO for cardiomyocyte protection, but the underlying mechanisms remained unclear; Methods: Network pharmacology and molecular docking were used to identify potential target proteins of PO’s active components. Experimental models assessed the cardioprotective effects and mechanisms; Results: Network analysis and molecular docking revealed that the active components exhibited the highest binding affinity with SOD2, indicating it as a key element in the cardiac protection of PO. In vivo, PO extract improved myocardial structure and function, and increased SOD2 protein levels. In vitro, the active components of PO (Mixture) mitigated oxidative stress and apoptosis, upregulating SIRT3 and decreasing acetylated SOD2, leading to increased SOD2 and reduced ROS levels. The observed effects were reversed by a SIRT3 inhibitor, indicating the involvement of the SIRT3/SOD2 signaling pathway; Conclusions: This comprehensive approach elucidated the critical mechanisms underlying the cardioprotective properties of PO’s bioactive constituents, highlighting the regulation of the SIRT3/SOD2 signaling pathway as a new mechanism for PO’s anti-cardiovascular disease effects, and suggesting the Mixture’s potential as a promising drug candidate.
研究领域:
药理学
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心血管病学
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网络药理学
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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）