PHYTOMEDICINE
·
2019
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IF 4.18
Dan Chen,Ya-Xian Wu,Yu-bao Qiu,Bin-bin Wan,Gang Liu,Jun-liang Chen,Mu-dan Lu,Qing-feng Pang
Background Hypoxia is commonly existed in tumors and lead to cancer cell chemo/radio-resistance. It is well-recognized that tumor hypoxia is a major challenge for the treatment of various solid tumors . Hyperoside (quercetin-3-O-galactoside, Hy) possesses antioxidant effects and has been reported to protect against hypoxia/reoxygenation induced injury in cardiomyocytes . Therefore, Hy may be attractive compound applicable to hypoxia-related diseases . Purpose This study was designed to determine the role of Hy in hypoxia-induced proliferation of non-small cell lung cancer cells and the underlying mechanism. Study Design and Methods A549, a human non-small cell lung cancer (NSCLC) cell line, was used in the present study. 1% O 2 was used to mimic the in vivo hypoxic condition of NSCLC. The potential mechanisms of Hy on hypoxia-induced A549 survival and proliferation, as well as the involvement of AMPK/HO-1 pathway were studied via CCK-8 assay, EdU staining, flow cytometry, qRT-PCR and western blot . Results We showed that pretreatment with Hy suppressed hypoxia-induced A549 survival and proliferation in dose-dependent manner. In terms of mechanism, hypoxia-treated A549 showed the lower AMPK phosphorylation and the reduced HO-1 expression, which were reversed by Hy pretreatment. Both AMPK inhibitor (Compound C) and HO-1 activity inhibitor (Zinc protoporphyrin IX) abolished Hy-evoked A549 cell death under hypoxia stimuli. Of note, Ferrous iron contributed to Hy-induced A549 cell death under hypoxia, while Hy had no effect on lipid peroxidation under hypoxia. Conclusion Taken together, our results highlighted the beneficial role of Hy against hypoxia-induced A549 survival and proliferation through ferrous accumulation via AMPK/HO-1 axis.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2018
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IF 3.412
Rui Chen,Yang Cui,Xuelian Zhang,Yanghai Zhang,Mingyue Chen,Tong Zhou,Xianyong Lan,Wuzi Dong,Chuanying Pan
Chlorpyrifos (CPF) is the most frequently applied insecticide. Aside from effects on the neuronal cholinergic system, previous studies suggested a potential relationship between CPF exposure and male infertility; however, the molecular mechanism remains elusive. The aim of this study was to investigate the toxic effect of CPF on testicular cells and the potential mechanism via in vitro and in vivo experiments. The cytotoxic effects of CPF on mouse-derived spermatogonial cell lines (GC-1), Sertoli cell lines (TM4) and Leydig cell lines (TM3) were assessed by a CCK-8 assay, flow cytometry, a TUNEL assay, quantitative RT-PCR, and Western blotting. Exposure to CPF (10–50 μM) for 12 or 24 h resulted in significant death in all three testicular cell lines. The number of TUNEL-positive apoptotic cells were dose-dependent and increased with raised CPF concentrations. Further investigation indicated that CPF induced cell-cycle arrest and then promoted cell apoptosis. Additionally, CPF increased reactive-oxygen-species (ROS) production and lipid peroxidation (MDA) and reduced mitochondrial-membrane potential. The mechanism of cell apoptosis induced by CPF involved an increase in phosphorylated-AMP-activated-protein-kinase (p-AMPK) levels in the tested cells. In vivo, the expression of steroid-hormone-biosynthesis-related genes in testis, spleen, and lung in F0 and F1 mice were downregulated when there was intraperitoneal injection or dietary supplementation of CPF. This study provides a potential molecular mechanism of CPF-induced toxicity in testicular cells and a theoretical basis for future treatment of male infertility.
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Journal of Functional Foods
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2025
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IF 4
Hanju Fan,Meng Yan,Yongshuai Jing,Ziyan Li,Yaqian He,Zhiwei Li,Junna Song,Lanfang Wu
Crataegus pinnatifida is the dried fruit of Crataegus pinnatifida . Crataegus pinnatifida polysaccharides (CPPs) eluted with water as the mobile phase (CPPs-H-1) is one of the important active components. CPPs-H-1 has anti-oxidation and blood lipid regulation activities in vitro. Therefore, we investigated the effects of CPPs-H-1 on nonalcoholic fatty liver disease (NAFLD) in C57/BL6J mice. As a result, CPPs-H-1 inhibited the rapid growth of body weight and alleviated the liver injury caused by high-fat diets, significantly reducing the liver index and blood lipid levels in the model group, inhibiting the production of inflammation and cytokines, and inhibiting oxidative stress. CPPs-H-1 also enhanced intestinal barrier function. At the phylum level, CPPs-H-1 reduced the ratio of Firmicutes to Bacteroides (F/B) and regulated the content of short-chain fatty acids (SCFAs). The CPPs-H-1 may regulate intestinal flora composition, and improve intestinal barrier function, ultimately delaying the progression of NAFLD in mice. Also, CPPs-H-1 improved NAFLD progression by enhancing the Amp-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor α (PPARα) signaling pathway to enhance fatty acid oxidation. All these results confirm that CPPs-H-1 plays a multi-pathway and multi-target role in the improvement of NAFLD.
研究领域:
营养学
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分子生物学
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药理学
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高影响因子
ADVANCED FUNCTIONAL MATERIALS
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2025
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IF 19
Linghui Song,Panpan Chen,Baimei Shi,Aihua Qu,Chuanlai Xu,Hua Kuang,Maozhong Sun
Autophagy is a key regulator in a diverse range of human diseases. Here, chiral copper sulfide (CuS) nanoparticles (NPs) modified with penicillamine are fabricated, which exhibited a circular dichroism (CD) spectrum between 300 and 1000 nm and a fluorescence peak at 680 nm. The experimental data showed that D -CuS NPs exhibited chirality-dependent autophagy induction, outperforming L -CuS NPs, and targeted breast cancer cells with 228.4 times higher affinity for CD81 receptor. The mechanism is revealed that chiral NPs specifically bound to CD81 receptor to open mechanosensitive calcium channels and motivated the calmodulin-dependent protein kinase kinase β (CaMKKβ)/AMPK pathway, which enhanced Atg1/Unc-51-like autophagy activating kinase 1 (ULK1) activity to promote autophagy. In vivo experiments confirmed the selective accumulation of D -CuS NPs in tumors, induction of autophagy, and successful treatment of the tumor. Therefore, chiral CuS NPs show great potential for modulating biological processes and improving tumor treatment.
研究领域:
纳米医学
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肿瘤学
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分子生物学
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细胞自噬
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生物材料
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转化医学
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Journal of Advanced Research
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2024
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IF 11.4
Sijia Lu,Quanxin Jiang,Peihui Zhou,Limin Yin,Ning Wang,Junting Xu,Qiqi Qian,Mijia Tao,Hanrui Yin,Liu Han,Yunqing Gu,Fei Gao,Junli Liu,Suzhen Chen
Introduction Promoting adipose thermogenesis is considered as a promising therapeutic intervention in obesity. However, endeavors to develop anti-obesity medications by targeting the canonical thermogenesis regulatory pathway, particularly β3-adrenergic receptor (β3-AR)-dependent mechanism, have failed due to the off-target effects of β3-AR agonists, exacerbating the risk of cardiovascular disease. Hyperforin (HPF), a natural compound extracted from the traditional herbal St. John’s Wort, binds to Dihydrolipoamide s-acetyltransferase (Dlat) and exerts effective anti-obesity properties through promoting adipose thermogenesis. Objectives The objective of this study was to investigate the oral efficacy and pharmacokinetics profile of HPF, and explore the detailed mechanism by which Dlat modulates HPF-mediated adipose thermogenesis. Methods To assess the anti-obesity efficacy of orally administered HPF in vivo , Dlat heterozygous knockout (Dlat +/- ) mice and wild-type (WT) mice, both fed a high-fat diet (HFD), underwent a validation process that involved the use of metabolic cages, NMR analysis, and infrared imaging. Sprague Dawley rats were employed to determine the pharmacokinetic parameters of HPF. Seahorse assays, JC-1 staining, qPCR, and immunoblotting were performed to evaluate cellular thermogenic efficacy of HPF and Dlat in vitro . Results Our study uncovered a non-canonical thermogenesis pathway involving Dlat, transient receptor potential vanilloid 3 (Trpv3, a calcium channel) and AMPK. Dlat interacted with Trpv3 to activate it, resulting in an increase in intracellular calcium (Ca 2+ ) and the activation of Camkkβ. Camkkβ then stimulated AMPK, leading to elevated Ucp1 expression and initiating adipose thermogenesis. HPF promoted thermogenesis in adipose tissues through enhancing the Dlat-Trpv3 interaction independently of β3-AR, causing minimal cardiac side effects. Notably, HPF’s thermogenic effects were reduced in Dlat +/- mice. Moreover, HPF exerted favorable oral bioavailability, a relatively long half-life, and extensive distribution within adipose tissues. Conclusion In summary, our study demonstrates that HPF targets a novel mechanism for promoting adipose thermogenesis and exhibits potent and safe anti-obesity efficacy.
研究领域:
药理学
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分子生物学
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代谢
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JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Luoning Zhang,Tianyun Han,Rui Qian,Yao Xiao,Wen Zhu,Linshen Xie
Ethnopharmacological relevance Cadmium (Cd) can first damage the kidney, leading to renal tubular dysfunction and irreversible renal damage. Ganoderma lucidum is a traditional Chinese herb that can enhances kidney qi and is extensively used in the management of renal diseases. As a new type of high-quality Ganoderma lucidum , Ganoderma leucocontextum (GL) has been shown to have antioxidant, anti-apoptotic, and anti-inflammatory properties, demonstrating significant potential for application in the treatment of cadmium-toxic nephropathy Aim of the study This study intends to investigate the impact and mechanism of GL extract on cadmium-toxic nephropathy Materials and methods A mouse Cd-toxic nephropathy model was established by intragastric administration of cadmium chloride for 4 weeks. Serum was collected for renal function index detection, and renal tissue was collected for Cd content, histopathology, oxidative stress index, apoptosis, and autophagy index detection to evaluate the damage of renal function and the intervention effect of the extract. The chemical ingredients of the extracts were detected by ultra-high liquid chromatography coupled with mass spectrometry detection (UPLC-MS/MS), and the total antioxidant capacity was determined. The targets and pathways of interest were derived from the integration of transcriptomic and network pharmacology results. Western blot (WB) and quantitative real-time PCR (qPCR) were used for subsequent validation. Results GL extract effectively improved kidney damage caused by Cd-toxic nephropathy, especially the GL ethanol extract (GLE). Compared with the model group, the intervention group exhibited a significant reduction in serum creatinine (Scr) and blood urea nitrogen (BUN) levels, an enhancement in histopathological integrity, a notable decrease in malondialdehyde levels, a significant increase in glutathione levels and superoxide dismutase activity, as well as a marked elevation in the ratios of Bcl-2/Bax and LC3BⅡ/LC3BⅠ. Expression of Cleaved Caspase-3 and P62 protein was markedly reduced. Comprehensive network pharmacology and transcriptomic analysis showed that the AMPK signaling pathway is a crucial pathway, and PPARα is an important target and downstream regulator of the AMPK pathway. WB and qPCR analyses showed that the activation of AMPK, SIRT1, PGC-1α, and PPARα in the kidney tissue of mice in the model group was markedly diminished, whereas it was dramatically elevated following GLE intervention Conclusions GL extract can effectively ameliorate kidney damage caused by Cd accumulation, most likely through the AMPK/SIRT1/PGC-1α/PPARα signaling pathway.
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IBRO Neuroscience Reports
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2025
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IF 2.9
Wei Nong,Xiaoli Chen,Yixin Chen,Xueping Feng,Wen Kong,Rui Chi,Li Yan,Zhiquan Wei
Extracellular β-amyloid protein (Aβ) plaques are prominent pathological feature of Alzheimer's disease (AD). Aβ oligomers and plaques induce sustained microglial activation via the adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/interferon regulatory factor 5 (IRF5) signaling pathway. This microglial activation-mediated neuroinflammation can accelerate neuronal cell senescence. Consequently, the regulation of the AMPK/mTOR/IRF5 pathway presents a potential therapeutic target for AD, as it may inhibit neuroinflammation and delay neuronal cell senescence. Mangiferin, a bioactive natural polyphenol extracted from the leaves of Mangifera indica Linn ., has garnered significant attention for its anti-inflammatory properties. However, it remains unclear whether mangiferin can modulate the AMPK/mTOR/IRF5 pathway to inhibit microglial activation-mediated neuroinflammation and delay neuronal cell senescence. This study employed both cellular and animal models of neuronal cell senescence to explore the effects of mangiferin on the regulation of the AMPK/mTOR/IRF5 pathway, aiming to inhibit neuroinflammation and delay neuronal cell senescence in vitro and in vivo . Specifically, SH-SY5Y neuroblastoma cells were subjected to a neuroinflammatory microenvironment induced by Aβ1–42-mediated HMC3 microglial activation to induce neuronal cell senescence in vitro . Additionally, SAMP8 accelerated aging mice were utilized as an aging animal model. The results indicate that mangiferin significantly enhances AMPK phosphorylation in microglial cells, inhibits mTOR activation, and downregulates IRF5 expression. These effects collectively suppress microglial activation and markedly reduce the production of pro-inflammatory cytokines by activated microglia. Consequently, there is a decrease in the proportion of neurons arrested in the G0/G1 phase and a reduction in the number of senescence-associated β-galactosidase (SA-β-gal) positive neurons. Furthermore, mangiferin significantly decreases the expression of neuronal cell senescence markers P16Ink4a and P21Cip1. Collectively, these findings suggest that mangiferin effectively regulates the AMPK/mTOR/IRF5 pathway, inhibits neuroinflammation mediated by microglial activation, and delays neuronal cell senescence. This study underscores the potential of mangiferin for the treatment of neuroinflammation and neurodegenerative diseases.
研究领域:
神经生物学
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药理学
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老年医学
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高影响因子
Journal of Ginseng Research
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2025
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IF 5.6
Weimin Wang,Kaixuan Zhou,Zengshuai Fu,Yucheng Huang,Jianjun Deng,Daidi Fan,Haixia Yang
Background Alcohol-induced liver injury contributes to various liver diseases, with dietary interventions of ginsenosides being a promising solution. Ginsenosides, the major active compounds of Panax ginseng Meyer , are divided into protopanaxadiol (PPD) and protopanaxatriol (PPT) based on C-3 or C-6 glycosylation, which have anti-inflammatory and antioxidant effects, but structure-activity relationships remain unclear. Methods Using C57BL/C mice with alcohol-induced liver injury, we evaluated Rg5 and F4 effects on liver function, inflammation, lipid deposition, apoptosis, alcohol metabolism, and lipid synthesis. Results Rg5 (60 mg/kg) demonstrated significantly superior efficacy to F4 in alleviating alcohol-induced liver injury, reducing lipid deposition through 33.9% and 25.8% decreases in serum triglyceride (TG) and total cholesterol (TC) levels versus the F4 group. Additionally, Rg5 attenuated hepatic apoptosis by reducing BAX and cleaved-CASPASE-3 protein expression by 26.3% and 28.4% compared to F4. Rg5 enhanced alcohol metabolism through activation of alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH), thereby restoring AMP-activated protein kinase (AMPK) phosphorylation by 26.1% while reducing sterol regulatory element-binding protein 1 (SREBP-1) expression by 27.8% (compared to F4), with efficacy approaching that of positive control silymarin. Molecular docking revealed that the C-6 sugar moiety of F4 induced hydrogen bond donor repulsion, increasing hydrogen bond length and weakening binding stability with ADH, ALDH and AMPK, providing a structural basis for Rg5's superior hepatoprotective activity. Conclusion These findings highlight the critical influence of glycosylation position on hepatoprotective activity of ginsenosides, and provide insights into the structural modification of ginsenosides, which could contribute to the treatment of alcohol-related liver disease.
研究领域:
药理学
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生物化学
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药物化学
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分子生物学
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营养学
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BRAIN RESEARCH BULLETIN
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2022
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IF 3.715
Bihui Song,Wenhao Zhou
Amarogentin (AMA), a secoiridoid glycoside that is mainly derived from SwertiaandGentiana roots, has been confirmed to exhibit antioxidative, tumor-suppressive and anti-diabetic properties. This research intends to investigate the protective effect of AMA against sepsis-induced brain injury and its mechanism. NSC-34 and HT22 cells were treated with lipopolysaccharide (LPS) to induce an in-vitro sepsis model and then treated with varying concentrations (1, 5, 10 µM) of AMA. Cell proliferation and apoptosis were evaluated. The intensity of inflammation and oxidative stress were assessed by different methods. The AMPK/SIRT1/NF-κB pathway expression was determined by WB . An in-vitro sepsis model was set up with cecal ligation and puncture (CLP) in adult C57/BL6J mice, and different concentrations (25, 50, 100 mg/kg) of AMA were applied for treatment. Neurological function was evaluated using the modified neurological severity scores (mNSS), and the brain tissue damage was measured using hematoxylin-eosin (H&E) staining and Nissl staining. Tissue apoptosis was tested using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Then, the AMPK inhibitor Compound C (CC) was administered to confirm AMA-mediated mechanism. Our finding illustrated that AMA mitigated LPS-induced neuronal damage, inflammation and oxidative stress, activated the AMPK/SIRT1 pathway and choked NF-κB phosphorylation. Furthermore, AMA improved neurological functions of sepsis mice by reliving neuroinflammation and oxidative stress. Inhibition of AMPK attenuated the protective effect of AMA on neurons or the mice’s brain tissues. In conclusion, AMA protected against sepsis-induced brain injury by modulating the AMPK/SIRT1/NF-κB pathway.
研究领域:
药理学
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神经科学
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炎症研究
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分子生物学
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高影响因子
Frontiers in Pharmacology
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2022
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IF 5.988
Zhou Fei,Ding Mingning,Gu Yiqing,Fan Guifang,Liu Chuanyang,Li Yijie,Sun Rong,Wu Jianzhi,Li Jianchao,Xue Xiaoyong,Li Hongjuan,Li Xiaojiaoyang
Nonalcoholic fatty liver disease (NAFLD), manifested as the aberrant accumulation of lipids in hepatocytes and inflammation, has become an important cause of advanced liver diseases and hepatic malignancies worldwide. However, no effective therapy has been approved yet. Aurantio-obtusin (AO) is a main bioactive compound isolated from Cassia semen that has been identified with multiple pharmacological activities, including improving adiposity and insulin resistance. However, the ameliorating effects of AO on diet-induced NAFLD and underlying mechanisms remained poorly elucidated. Our results demonstrated that AO significantly alleviated high-fat diet and glucose-fructose water (HFSW)-induced hepatic steatosis in mice and oleic acid and palmitic acid (OAPA)-induced lipid accumulation in hepatocytes. Remarkably, AO was found to distinctly promote autophagy flux and influence the degradation of lipid droplets by inducing AMPK phosphorylation. Additionally, the induction of AMPK triggered TFEB activation and promoted fatty acid oxidation (FAO) by activating PPARα and ACOX1 and decreasing the expression of genes involved in lipid biosynthesis. Meanwhile, the lipid-lowing effect of AO was significantly prevented by the pretreatment with inhibitors of autophagy, PPARα or ACOX1, respectively. Collectively, our study suggests that AO ameliorates hepatic steatosis via AMPK/autophagy- and AMPK/TFEB-mediated suppression of lipid accumulation, which opens new opportunities for pharmacological treatment of NAFLD and associated complications.
研究领域:
药理学
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肝病学
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代谢疾病
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AAPS Journal
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2017
·Vol. 19
·期 6
·1703-1714
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IF 3.423
Cao Mingnan,Wang Huixia,Guo Limei,Yang Simin,Liu Chun,Khor Tin Oo,Yu Siwang,Kong Ah-Ng
Oxidative stress is an important pathogenic factor in various hepatic diseases. Nuclear factor-erythroid 2-related factor-2 (Nrf2), which coordinates the expression of an array of antioxidant and detoxifying genes, has been proposed as a potential target for prevention and treatment of liver disease. Dibenzoylmethane (DBM) is a minor ingredient in licorice that activates Nrf2 and prevents various cancers and oxidative damage. In the present study, the mechanisms by which DBM activates Nrf2 signaling were delineated, and its protective effect against carbon tetrachloride (CCl 4 )-induced liver injury was examined. DBM potently induced the expression of HO-1 in cells and in the livers of mice, but this induction was diminished in Nrf2-deficient mice and cells. Overexpression of Nrf2 enhanced DBM-induced HO-1 expression, while overexpression of a dominant-negative fragment of Nrf2 inhibited this induction. DBM treatment resulted in dissociation from Keap1 and nuclear translocation of Nrf2. Moreover, DBM activated Akt/protein kinase B, mitogen-activated protein kinases, and AMP-activated protein kinase and increased intracellular calcium levels. Inhibition of JNK, AMPK, or intracellular calcium signaling significantly suppressed the induction of HO-1 expression by DBM. Finally, DBM treatment significantly inhibited CCl 4 -induced acute liver injury in wild-type but not in Nrf2-deficient mice. Taken together, our results revealed the mechanisms by which DBM activates Nrf2 and induces HO-1 expression, and provide molecular basis for the design and development of DBM and its derivatives for prevention or treatment of liver diseases by targeting Nrf2.
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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毒理学
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2026
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IF 6.6
Xinying Zhao,Xiangrong Zhou,Keying Li,Qiuchen Wu,Yuqin Sha,Zhuoyi Xie,Ping Zeng,Zhipeng Qi,Qiao Niu,Wei Li,Weiyi Song
Lanthanum (La), one of the most widely used rare earth elements (REEs), is inevitably released into the environment, raising concerns about its potential health risks. Epidemiological evidence has linked La exposure to liver injury, but the mechanisms underlying chronic hepatotoxicity remain poorly understood. Here, zebrafish were exposed to environmentally relevant concentrations of LaCl 3 (0.1 and 1 μM) from 2 hours post-fertilization (hpf) to 120 days post-fertilization (dpf), and integrated histological, biochemical, metabolomic, and transcriptomic analyses to examine LaCl 3 -induced hepatic responses. We found that chronic LaCl 3 exposure caused marked hepatic steatosis and liver injury in male zebrafish, and these effects persisted after a 30-day depuration period. Multi-omics analyses revealed that LaCl 3 drives glycolysis-dependent metabolic reprogramming, which subsequently suppresses the AMPK-ULK1-LC3B axis, thereby impairing lipophagy and leading to abnormal lipid droplet accumulation. In HepG2 cells, pharmacological inhibition of glycolysis with 2-DG or activation of AMPK with AICAR effectively restored AMPK-ULK1-LC3B signaling and attenuated LaCl 3 -induced lipid accumulation. Collectively, our findings provide a previously underrecognized mechanism underlying LaCl 3 -disrupted hepatic lipid homeostasis, offering novel insights into REEs-related hepatotoxicity and supporting environmental health risk assessment.
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