JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
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2020
·Vol. 75
·期 4
·321
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IF 2.598
Cao Qian,Du Hongjiao,Fu Xi,Duan Na,Liu Changhe,Li Xiaodong
Artemisinin is an endoperoxide sesquiterpene lactone from Artemisia annua L with multiple beneficial effects, including anti-inflammation, antioxidant, and vascular protection. Recent studies have found that inflammation along with autophagy deficiency in macrophages is the possible reason for foam cell accumulation in the intima, which leads to atherosclerotic plaque formation. The primary aims of this study were to explore the inhibiting effect of artemisinin on atherosclerosis in high-fat diet–fed ApoE −/− mice and investigate the probable mechanism. Artemisinin (50 and 100 mg/kg, intragastric administration) treatment effectively inhibited foamy macrophage transformation and decreased atherosclerotic plaque formation in atherosclerotic mice. Moreover, artemisinin promoted AMP-activated protein kinase (AMPK) activation, inhibited mammalian target of rapamycin (mTOR) and uncoordinated-51-like kinase 1 (ULK1) phosphorylation, and increased LC-3II accumulation and P62 degradation, thereby enhancing macrophage autophagy . Besides, the inhibiting effect of artemisinin on mTOR and ULK1 phosphorylation could be abrogated by AMPK knockdown, suggesting AMPK was the essential target of artemisinin on promoting macrophage autophagy . Our study indicated that artemisinin alleviated atherosclerotic lesions by accelerating macrophage autophagy through the AMPK/mTOR/ULK1 pathway.
研究领域:
药理学
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心血管疾病
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分子生物学
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PubMed
高影响因子
STRAHLENTHERAPIE UND ONKOLOGIE
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2023
·
IF 3.1
Huang Hui,Xue Jie,Xie Mei-Lin,Xie Tao
Purpose Osthole possesses anti-tumor activities. However, whether osthole can have a radiosensitization effect on hepatic cancer remains unclear. Here, an HCC-LM3 cells-inoculated subcutaneous transplanted tumor was adopted to explore the effect of osthole. Methods The tumor-bearing mice were treated with 100 mg/kg osthole for 12 days, 4 Gy irradiation twice, or their combination. The tumor volume and weight, lactic acid content, glycolytic enzyme activities, and protein expression of glycogen synthase kinase 3β (GSK-3β), p‑GSK-3β, mammalian target of rapamycin (mTOR), p‑mTOR, AMP-activated protein kinase (AMPK), p‑AMPK, glucose transporter 1/3, and pyruvate kinase M2 were determined. The GSK-3β-overexpressed HCC-LM3 or SK-Hep‑1 cell models were also adopted to verify the effects of osthole on expression of these proteins. Results The tumor volume and weight, lactic acid content, and glycolytic enzyme activities in tumor tissues were lower in the osthole + radiation group than in the radiation group. Moreover, osthole could reverse the radiation-induced increments of p‑GSK-3β/GSK-3β and p‑mTOR/mTOR protein ratios and the expression of glucose transporter 1/3 and pyruvate kinase M2 proteins in tumor tissues, and increase the protein ratio of p‑AMPK/AMPK. The effects of osthole on these glycolysis-related proteins were also observed in GSK-3β-overexpressed HCC-LM3 or SK-Hep‑1 cell models. Conclusion Osthole has a radiosensitizing effect on subcutaneous transplanted hepatocellular carcinoma, and its mechanism may be related to inhibition of GSK-3β/AMPK/mTOR pathway-controlled glycolysis.
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BIOMEDICINE & PHARMACOTHERAPY
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2023
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IF 7.5
Tao Long,Xue Chen,Yue Zhang,Yu-Jia Zhou,Yan-Ni He,Yun-Fei Zhu,Hai-Jun Fu,Lu Yu,Chong-Lin Yu,Betty Yuen-Kwan Law,Jian-Ming Wu,Da-Lian Qin,An-Guo Wu,Xiao-Gang Zhou
Enhancing the clearance of proteins associated with Alzheimer's disease (AD) emerges as a promising approach for AD therapeutics. This study explores the potential of Radix Stellariae , a traditional Chinese medicine, in treating AD. Utilizing transgenic C. elegans models of AD, we demonstrated that a 75% ethanol extract of Radix Stellariae (RSE) (at 50 µg/mL) effectively diminishes Aβ and Tau protein expression, and alleviates their induced impairments including paralysis, behavioral dysfunction, neurotoxicity, and ROS accumulation. Additionally, RSE enhances the stress resistance of C. elegans . Further investigations revealed that RSE promotes autophagy, a critical cellular process for protein degradation, in these models. We found that inhibiting autophagy-related genes negated the neuroprotective effects of RSE, suggesting a central role for autophagy in the actions of RSE. In PC-12 cells, we observed that RSE not only inhibited Aβ fibril formation but also promoted the degradation of AD-related proteins and reduced their cytotoxicity. Mechanistically, RSE was found to induce autophagy via modulating PI3K/AKT/mTOR and AMPK/mTOR signaling pathways. Importantly, inhibiting autophagy counteracted the beneficial effects of RSE on the clearance of AD-associated proteins. Moreover, we identified Dichotomine B, a β-carboline alkaloid, as a key active constituent of RSE in mitigating AD pathology in C. elegans at concentrations ranging from 50 to 1000 µM. Collectively, our study presents novel discoveries that RSE alleviates AD pathology and toxicity primarily by inducing autophagy, both in vivo and in vitro. These findings open up new avenues for exploring the therapeutic potential of RSE and its active component, Dichotomine B, in treating neurodegenerative diseases like AD.
研究领域:
神经科学
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药理学
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中药学
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细胞生物学
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分子生物学
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高影响因子
KAOHSIUNG JOURNAL OF MEDICAL SCIENCES
·
2021
·Vol. 38
·期 5
·457-468
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IF 2.744
Ting Yao,Jin-Mei Chen,Le-Er Shen,Yong-Sheng Yu,Zheng-Hao Tang,Guo-Qing Zang,Yi Zhang,Xiao-Hua Chen
Aging is characterized by inevitable organ function decline over time, with consequent body deterioration and increased susceptibility to death. Astragalus polysaccharide (APS) has been reported to have anti-oxidative, anti-apoptotic, and anti-inflammatory properties. We investigated the potential protective effects of APS on hydrogen peroxide (H 2 O 2 ) induced hepatocyte senescence and identified related mechanisms in L02, Huh7, and LM3 cell lines. Aged female C57BL/6 mice were given APS for 1 week by intraperitoneal injection, and APS provided the strongest protective effect against H 2 O 2 -induced damage at 100 μM. APS reduced the expression of cell senescence markers and alleviated pathological damage in aged mouse liver. APS treatment decreased oxidative stress, apoptosis, NOD-like receptor protein-3-mediated pyroptosis, and maintained mitochondrial homeostasis. Notably, the protective effect of APS was weakened in the presence of chloroquine. APS might enrich autophagy by activating AMP-activated protein kinase (AMPK) and inhibiting mammalian target of rapamycin (mTOR). In conclusion, APS reduced reactive oxygen species levels, inhibited apoptosis and pyroptosis, and promoted mitophagy via AMPK/mTOR pathway to alleviate hepatocyte senescence in vitro and in vivo.
研究领域:
药理学
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细胞生物学
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老年学
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PubMed
高影响因子
PHYTOTHERAPY RESEARCH
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2023
·Vol. 37
·期 4
·1377-1390
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IF 7.2
Xueyao Yang,Xin Zhao,Yanfei Liu,Yue Liu,Libo Liu,Ziyu An,Haoran Xing,Jinfan Tian,Xiantao Song
Studies demonstrated that Ginkgo biloba extract (GBE) played a cardioprotective role in diabetic conditions. Impaired autophagy is one of the mechanisms underlying diabetic cardiomyopathy (DCM). The effect of GBE on autophagy has been observed in several diseases; however, whether GBE can ameliorate DCM by regulating autophagy remains unclear. Here, we investigated the effect of GBE on DCM and the potential mechanisms regarding autophagy using a streptozotocin (STZ)-induced diabetic rat model and a high-glucose (HG)-stimulated H9C2 cell model. We demonstrated that GBE attenuated metabolic disturbances, improved cardiac function, and reduced myocardial pathological changes in diabetic rats. Impaired autophagy as well as dysregulation of the adenosine monophosphate-activated protein kinase/ mammalian target of the rapamycin (AMPK/mTOR) signaling pathway were observed in diabetic hearts, as evidenced by the reduced conversion of LC3B-I to LC3B-II along with excessive p62 accumulation, decreased AMPK phosphorylation, and increased mTOR phosphorylation, which could be reversed by GBE treatment. In vitro , GBE reduced the apoptosis induced by HG in H9C2 cells by activating AMPK and inhibiting mTOR to restore autophagy. However, this effect was inhibited by the AMPK inhibitor Compound C. In conclusion, the ameliorative effect of GBE on DCM might be dependent on the restoration of autophagy through modulation of the AMPK/mTOR pathway.
研究领域:
药理学
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心脏病学
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糖尿病
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细胞生物学
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高影响因子
JOURNAL OF CHEMICAL NEUROANATOMY
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2024
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IF 2.7
Lili Ma,Na Mi,Zhi Wang,Rui Bao,Jing Fang,Yajing Ren,Xiuzhi Xu,Hongjia Zhang,Ying Tang
Neuroinflammation associated with microglial activation plays a role in the development of Parkinson's disease (PD). The upregulation of interferon regulatory factor 8 (IRF8) in microglia following peripheral nerve injury has been observed to induce microglial activation. This suggests the potential therapeutic significance of IRF8 in PD. This research aims to explore the effects of IRF8 on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model and lipopolysaccharide (LPS)-induced neuroinflammation, along with its underlying mechanisms. The study examines the differential expression of IRF8 and its effects on neuropathological changes using a PD mouse model and a PD model established from BV2 cells in vitro . IRF8 was found to be prominently expressed in the substantia nigra pars compacta (SNpc) region of PD mice and LPS-stimulated BV2 cells, while the expression of tyrosine hydroxylase (TH) and dopamine (DA) content in the SNpc region of PD mice was notably reduced. MPTP treatment and LPS stimulation intensified microglial activation, inflammation, and activation of the AMPK/mTOR signaling pathway in vivo and in vitro , respectively. Upon IRF8 silencing in the PD mouse and cell models, the knockdown of IRF8 ameliorated MPTP-induced behavioral deficits, increased the counts of TH and Nissl-positive neurons and DA content, reduced the number of Iba-1-positive microglia, and reduced the content of inflammatory factors, possibly by inhibiting the AMPK/mTOR signaling pathway. Similar outcomes were observed in the PD cell model. In conclusion, the suppression of IRF8 alleviates neuroinflammation through regulating microglial activation in PD models in vivo and in vitro by the AMPK/mTOR signaling pathway.
研究领域:
神经科学
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药理学
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细胞生物学
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分子生物学
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高影响因子
Diabetes Metabolic Syndrome and Obesity-Targets and Therapy
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2021
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IF 3.168
Hong Liu,Quan Wang,Ge Shi,Wenqiang Yang,Yanmin Zhang,Weidong Chen,Sheng Wan,Fei Xiong,Zengsi Wang
Purpose The activation of autophagy has potential protective effect on diabetic nephropathy (DN) podocyte injury, and the AMPK/mTOR signaling pathway is an important regulatory pathway of autophagy. Emodin has been reported to effectively delay DN progression; however, the therapeutic mechanisms involved in vivo remain ambiguous. The present study aimed to elucidate the mechanism of emodin in improving renal tissue and podocyte injury in DN by regulating the AMPK/mTOR-autophagy signaling pathway. Methods All rats were divided into 4 groups: a Sham group, a Vehicle group, a low-dose emodin (LD-Emo) group (20 mg/kg/day) and a high-dose emodin (HD-Emo) group (40 mg/kg/day). The different doses of Emo and distilled water were daily administrated for 8 weeks after the induction of DN by the unilateral nephrectomy combined with intraperitoneal injections of streptozotocin (STZ). The rats' general status, blood glucose, biochemical parameters, urinary protein excretion, renal histological changes and cell apoptosis in renal tissue, as well as the key protein expressions in the AMPK/mTOR signaling pathway and apoptosis-related proteins were examined, respectively. Results Emodin ameliorated the general condition, kidney weight and urinary protein excretion of the rats, but has little influence on serum biochemical parameters and did not lower blood glucose; emodin attenuated renal fibrosis including the cell numbers, extracellular matrix rate and collagen area in glomerulus, simultaneously relieved podocyte foot process fusion, up-regulated the expression of nephrin protein and suppressed glomerular and tubular epithelial cell apoptosis. In addition, emodin can induce and enhance autophagy in podocytes including increased expression of LC3-II/I, Beclin-1, p-AMPK protein and decreased expression of p62, p-mTOR protein, as well as increased autophagosomes in podocytes. Conclusion We have demonstrated that emodin, as a natural regulator in vivo, reduced proteinuria and alleviated renal fibrosis without affecting hyperglycemia in DN rats. The potential mechanisms by which emodin exerts its renoprotective effects in vivo are through suppressing cell apoptosis and enhancing autophagy of podocytes via the AMPK/mTOR signaling pathway in the kidney.
研究领域:
药理学
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肾病学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Chunlai Wang,Xiao Xu,Haoyun Zhu,Dengyu Wu,Jianing Liang,Xiangxiang Wang,Ruoxi Song,Liangye Shen,Yuhang Hu,Dechang Wang,Haoru Zhu,Xinhui Cheng,Yu Qi
Ethnopharmacological relevance Effective activation of neuronal autophagy and clearance of amyloid-beta (Aβ) represents a promising therapeutic strategy in the treatment of Alzheimer's disease (AD). The Acori Tatarinowii Rhizoma-Curcumae Radix Herbal pair (ACHP), derived from the traditional Changpu Yujin Decoction, has a long history in Traditional Chinese Medicine for addressing conditions related to cognitive function. However, the precise mechanisms underlying its role in autophagic dysfunction-related dementia remain unclear. Aim of the study This study aims to investigate the neuroprotective effects of ACHP and the underlying mechanisms in AD. Materials and methods Analysis of prototype constituents in drug-containing serum was performed using UHPLC-Triple-TOF/MS. The neuroprotective effects of ACHP were evaluated in APP/PS1 mice using behavioral tests, including the Y-maze and Morris water maze. Transcriptomic analysis was conducted to identify potential neuroprotective pathways activated by ACHP. Neuronal damage and structural recovery were assessed through HE and Nissl staining. In addition, the anti-inflammatory and autophagy-regulating effects of ACHP were further investigated in N2a/APP cells. The molecular mechanisms were further elucidated using Western blot, immunofluorescence, ELISA, and qRT-PCR in both in vivo and in vitro models. Results Twenty-five compounds in ACHP-treated mouse serum were identified. ACHP improved spatial learning and memory performance, increased intracellular Ca 2+ levels and downregulated the expressions of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, while significantly promoting autophagy. ACHP increased CaMKKβ protein expression and activated the AMPK signaling pathway (elevated p-AMPK/AMPK ratio), as well as those of autophagy-related proteins, while improving neuronal morphology. Conclusion These findings indicate that ACHP alleviates neuro-inflammatory damage and cognitive impairment potentially through modulation of the Ca 2+ /CaMKKβ–AMPK–mTOR signaling pathway involved in autophagy.
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高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
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2026
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IF 8
Rucui Yu,Yan Zhang,Ruiying Wu,Jingwei Xu
Objective Mitochondrial dysfunction and dysregulated cell death are key drivers of diabetic kidney disease (DKD) progression. This study aimed to construct CD44-targeted chitosan (Cs) nanoparticles encapsulating ginsenoside Rg1 (CD44-Cs@Rg1) for targeted delivery, and to evaluate their ability to regulate autophagy, pyroptosis, and mitochondrial function in DKD. Methods CD44-Cs@Rg1 nanoparticles were synthesized using a covalent modification strategy. Their targeting uptake, effects on GSDMD-mediated pyroptosis, autophagic flux, and energy metabolism were systematically evaluated in renal tubular epithelial cells under high-glucose (HG) conditions and in DKD mouse models. Mitochondrial function was assessed by Western blotting, immunostaining, MitoSOX, JC-1, and ATP assays. Transcriptomic profiling and pharmacological interventions were applied to elucidate the involvement of the AMPK/mTOR signaling axis. Results CD44-Cs@Rg1 nanoparticles were efficiently internalized by renal tubular epithelial cells, significantly reducing pyroptosis while restoring autophagic flux through AMPK activation and mTOR inhibition. These effects improved mitochondrial membrane potential, reduced reactive oxygen species accumulation, and enhanced ATP production. In vivo , CD44-Cs@Rg1 treatment markedly ameliorated renal dysfunction and histopathological injury in DKD mice. Transcriptomic and protein-level analyses consistently revealed enrichment of pathways related to AMPK signaling, autophagy, and energy metabolism. Conclusion CD44-targeted Cs nanoparticles enable precise delivery of ginsenoside Rg1 to renal tubular cells in DKD, restoring mitochondrial homeostasis and regulating autophagy–pyroptosis balance via the AMPK/mTOR axis. This nanotherapeutic platform demonstrates strong translational potential for DKD treatment.
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高影响因子
Oncotarget
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2017
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IF 5.168
Ting Tao,Caimei He,Jun Deng,Yanjun Huang,Qiongli Su,Mei Peng,Meiling Yi,Kwame Oteng Darko,Hui Zou,Xiaoping Yang
Quercetin is a naturally existing compound and shows attractive anticancer properties for a variety of solid tumors including glioma, bladder cancer, hepatocellular carcinoma, breast cancer, hematological malignancies and prostate carcinoma. However, these anticancer properties have not been clinically approved due to unclear mechanistic information and its low bioactivity. In our previous study, we elucidated that quercetin activates AMPK pathway which is the major mechanism for its unique anticancer effect in bladder cancer. In the present study, we are trying to enhance its bioactivity by chemical modification using fluorination approach to prepare novel chemical entities, based on the principle of intermediate derivative method (IDM). The compound we obtained is named 8-trifluoromethyl-3,5,7,3′,4′-O-pentamethyl- quercetin (TFQ), characterized by NMR spectra and mass spectrum (MS). The results from MTT and cologenic assay in two human and one murine bladder cancer cell lines showed that TFQ exhibits more potent inhibition on the three bladder cancer cell lines than quercetin (Que) although this enhanced effects is not very dramatic. Furthermore, we found that the survival of normal bladder cells PEBC was not significantly suppressed by TFQ compared with Que. Western blot analysis showed that TFQ possess more potent AMPK activation than Que. The downstream of AMPK was further examined by western blot. TFQ treatment is able to inactivate mTOR signaling pathway with the regulation of mTOR, 4EBP1 and P70S6K. These results demonstrated that the fluorinated quercetin derivative TFQ inhibits bladder cancer cell growth through the AMPK/mTOR pathway. Altogether, our findings suggest that TFQ could serve as a new potential therapeutic agent for bladder cancer more effective than Que.
研究领域:
肿瘤学
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药理学
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化学生物学
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DOI
PubMed
高影响因子
Journal of Functional Foods
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2026
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IF 3.9
Yifan Zheng,Kunying Ding,Haojie Jin,Zhaorong Wang,Liujie Zheng,Zhengwei Fu,Yinhua Ni
Cellular senescence is a core hallmark of aging and a major risk factor for most chronic diseases. Natural products targeting senescent cells have garnered increasing attention for anti-senescence potential in aging-related disease intervention. Previous studies revealed that hydrolyzed chicken extract (HCE) exerts neuroprotective effects, but its role in senescent cell clearance and underlying mechanisms remains unclear. Here, we investigated the anti-senescent effects and mechanisms of HCE in D-galactose-induced senescent HT-22 hippocampal neurons, compared with the traditional essence of chicken (EC). HCE significantly enhanced cellular antioxidant capacity, reduced SA-β-gal positivity, restored cell cycle progression, inhibited senescence-associated secretory phenotype (SASP) secretion, and promoted autophagic flux, with a slightly stronger efficacy than EC. We further identified cyclo (Val-Pro), cyclo (His-Pro), and cyclo(Gly-Pro) as bioactive components, with cyclo(His-Pro) showing the strongest potency. Mechanistically, HCE and these cyclopeptides exerted effects via SIRT1/AMPK/mTOR-mediated autophagy, which was fully abolished by SIRT1 knockdown or targeted pathway inhibition.
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高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2019
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IF 3.17
Qi Wan,Hui Chen,Guirun Xiong,Rui Jiao,Yun Liu,Xiaolei Li,Yu Sun,Jingcheng Wang,Lianqi Yan
Intraarticular fibrosis following knee surgery is a troublesome complication and remains a challenging problem for clinicians. Artesunate (ART), a classical anti-malarial drug extracted from the Chinese medicinal herb Artemisia annua L, has been associated with some fibrosis-related diseases. However, its effect and underlying mechanism on knee arthrofibrosis are still obscure. In the present study, we found that ART induced cellular autophagy flux and inhibited cell proliferation in fibroblasts. Intriguingly, genetic depletion of Beclin-1 abolished ART-triggered cellular autophagy and further attenuated the inhibitory effect of ART on fibroblasts proliferation. Moreover, at molecular level, our results demonstrated that ART-induced autophagy activation was associated with the inhibition of mTOR signaling through PI3K/AKT/mTOR pathway and AMPK/mTOR pathway. In vivo, ART treatment triggered autophagy activation and alleviated the severity of surgery-induced knee arthrofibrosis. Taken together, we concluded that ART exhibited anti-proliferation efficacy in fibroblasts and alleviated the severity of knee arthrofibrosis in rabbits by inducing Beclin-1-mediated autophagy via inhibition of mTOR signaling. These findings indicated that ART might be a potential therapeutic agent for preventing the progression of surgery-induced intraarticular fibrosis of knee.
研究领域:
药理学
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骨科
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细胞生物学
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分子生物学
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PubMed
高影响因子
危险品化学品经营许可证（带存储）