Food & Function
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2022
·Vol. 13
·期 14
·7560-7571
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IF 6.317
Shuai Lu,Jinyi Zhou,Chen Yang,Xiaoxue Zhang,Yingying Shi,Jie Liu,Xintong Yan,Juanjuan Liang,Xianli Liu,Lan Luo,Da Zhou,Zhimin Yin
Aging is a natural process accompanied by inflammation and oxidative stress and is closely associated with age-related diseases. As a direct precursor of glutathione, γ-glutamylcysteine (γ-GC) possesses antioxidant and anti-inflammatory properties; however, whether γ-GC plays an important role in anti-aging remains unknown. Here, we investigated the protective effects and mechanisms of γ-GC in D-galactose (D-gal)-induced senescence in PC12 cells and aging mice. Our results showed that γ-GC treatment significantly reduced the percentage of senescence-associated-β-galactosidase (SA-β-Gal)-positive cells and inhibited D-gal-induced cell cycle arrest in PC12 cells. The results of Nissl and hematoxylin and eosin (H&E) staining in mouse brain showed that γ-GC treatment markedly reversed the damage in the hippocampus of D-gal-induced aging mice. Moreover, γ-GC increased the phosphorylation of AMP-activated protein kinase (AMPK) to promote the nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) while inhibiting the nuclear translocation of deleted in breast cancer 1 (DBC1), which leads to the activation of sirtuin 1 (SIRT1) and deacetylation of p53 in the nucleus. Therefore, γ-GC may be a potential therapeutic candidate compound for the prevention and treatment of age-related diseases.
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JOURNAL OF DRUG TARGETING
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2019
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IF 3.277
Yan Jiang,Hongjiao Du,Xue Liu,Xi Fu,Xiaodong Li,Qian Cao
There is increasing evidence that atherosclerosis is the significant risk factor for cardiovascular diseases, which are the leading causes of morbidity and mortality worldwide. Artemisinin is a natural endoperoxides quiterpene lactone compound in Artemisia annua L with vasculoprotective effects. The primary aim of this study was to investigate whether artemisinin could be conferred an anti-atherosclerotic effect in high-fat diet (HFD)-fed ApoE–/– mice and explore the possible mechanism. We found that treatment with artemisinin (50 and 100 mg/kg) effectively ameliorated atherosclerotic lesions, such as foam cell formation, hyperplasia and fibrosis in the aortic intima. Atherosclerotic mice treated with artemisinin showed reduced inflammation by up-regulating adenosine 5′-monophosphate (AMP) activated protein kinase (AMPK) activation and by down-regulating nuclear factor-κB (NF-κB) phosphorylation and nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome expression in the aortas. In addition, artemisinin was found to promote AMPK activity in macrophages and its anti-inflammatory effect was neutralised by AMPK silence using specific siRNA. In conclusion, we demonstrate that artemisinin may protect the aortas from atherosclerotic lesions by suppression of inflammatory reaction via AMPK/NF-κB/NLRP3 inflammasomes signalling in macrophages.
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Journal of Advanced Research
·
2024
·
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
·
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
·
2025
·
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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Journal of Ginseng Research
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2025
·
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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Journal of Advanced Research
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2025
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IF 13
Ximing Yang,Siyi Wang,Hanxiong Liu,Tuo Zhang,Shuzhen Cheng,Ming Du
Zinc deficiency is a global health issue that impairs immune function, growth, and energy metabolism. Although conventional zinc supplements have been developed, their effectiveness is limited by poor bioavailability and susceptibility to dietary inhibitors. In this study, a peptide-zinc complex (IE-Zn) derived from oysters was developed to enhance zinc uptake and address metabolic disruptions caused by deficiency. It was determined that Zn 2+ binds with high affinity to the IE peptide, promoting structural flexibility that facilitates zinc transport through both zinc ion transporters and oligopeptide transporters. In Caco-2 and IEC-6 cell models, IE-Zn was shown to significantly improve zinc absorption and retention compared to ZnSO 4 , driven by the upregulation of ZIP4 and PEPT1 transporters. In vivo studies in a zinc-deficient mouse model confirmed enhanced zinc absorption and distribution across serum, intestine, and liver. Moreover, IE-Zn restored energy homeostasis by activating the AMPK/PGC1-α/NRF-1/TFAM signaling pathway, promoting mitochondrial biogenesis and reducing oxidative stress. These findings suggest that IE-Zn is a superior zinc supplement with higher bioavailability and serves as a potent regulator of cellular energy metabolism, offering therapeutic potential for managing conditions related to zinc deficiency and mitochondrial dysfunction. This study lays the foundation for further exploration of peptide-mineral complexes as advanced nutritional supplements with broad applications. Subsequent studies will further investigate the absorption pathway and targeting of peptide-zinc complex. The hope is to provide potential preventive applications for people in need, including zinc deficiency and a range of diseases caused by zinc deficiency.
研究领域:
营养学
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分子生物学
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代谢研究
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Virulence
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2026
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IF 6.8
Xinxian Wang,Shurui Yang,Lichun Xie,Shanshan Qi,Libo Gao,Yongmei Li,Qian Li,Junlong Bi,Jianping Liu,Yongneng Li,Gefen Yin
Classical swine fever virus (CSFV) remains a major threat to the global swine industry, yet the involvement of host miRNAs in its pathogenic mechanisms is not fully understood. In this study, we demonstrate for the first time that miR-17-5p inhibits CSFV replication through an autophagy-dependent mechanism by targeting polycystin-2 (PKD2), a key calcium channel protein that regulates the AMPK/mTOR signaling pathway. Using the PK-15 cell model, we found that CSFV infection significantly upregulates miR-17-5p expression. Functional assays revealed that miR-17-5p exerts antiviral effects by directly binding to the 3’-UTR of PKD2, as confirmed by bioinformatics prediction and dual-luciferase reporter assays. Silencing of PKD2 recapitulated the antiviral effect of miR-17-5p overexpression, while PKD2 reconstitution restored viral replication by activating AMPK signaling and suppressing mTOR activity, thereby significantly enhancing autophagic flux – as evidenced by increased LC3-II/I ratio and decreased p62 levels. Mechanistically, PKD2 regulates intracellular calcium dynamics, modulating the AMPK/mTOR-autophagy axis to promote CSFV proliferation. This work uncovers a novel host antiviral mechanism in which a miRNA controls virus-induced autophagy via calcium signaling. To our knowledge, this is the first report to establish the pivotal role of miRNA-mediated calcium signaling modulation in flavivirus-host interactions. These findings provide a mechanistic framework and potential therapeutic targets for anti-CSFV interventions focused on PKD2 or autophagy regulation.
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Journal of Stroke & Cerebrovascular Diseases
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2026
·Vol. 35
·期 5
·108628
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IF 2.1
Zhihong Zhong,Shuhong Wang,Canxin Xu,Qingyun Liu,Xiao Chen,Dong Lin,Liuguan Bian
Background and purpose Intracerebral hemorrhage (ICH) is a devastating acute neurological condition with high mortality and disability. Induced pluripotent stem cell-derived neural progenitor cells (iPSC NPCs) have been shown to promote behavioral recovery by enhancing neural connectivity and providing trophic support. As the adenosine monophosphate-activated protein kinase (AMPK)/ mammalian target of rapamycin (mTOR) signaling pathway is a key regulator of autophagy in stroke, we investigated its role in the context of iPSC NPC transplantation for ICH. Materials and methods The therapeutic effects of iPSC NPC transplantation were evaluated in both in vivo and in vitro ICH models. We analyzed changes in the protein and mRNA expression, along with immunofluorescence, of key markers including glial fibrillary acidic protein (GFAP), AMPK, mTOR, sequestosome 1 (SQSTM1/ P62), and microtubule-associated protein 1 light chain 3 (LC3). Results Our findings demonstrate that iPSC NPCs secrete cytokines that mitigate brain injury and protect astrocytes from autophagy. Specifically, iPSC NPCs promoted astrocyte activation by inhibiting AMPK phosphorylation and promoting mTOR activation in both model systems. The anti-autophagic effect of iPSC NPCs on astrocytes was abolished by an mTOR inhibitor. Conversely, AMPK knockdown with siRNA promoted mTOR phosphorylation and suppressed autophagy in astrocytes. Conclusion This study identifies the interaction between AMPK and mTOR in astrocytes as a critical mechanism underlying the therapeutic benefits of iPSC-NPC transplantation, highlighting it as a promising target for ICH treatment.
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FITOTERAPIA
·
2026
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IF 2.9
Xia Zhang,Yuying Li,Chengfu Zhang,Huali Zhang,Jing Zhao,Dong Pei,Tingfu Jiang,Lichun Zhao,Qingli Qu
The therapeutic potential of Olea europaea L. leaf in hepatitis is recognized, yet its active constituents against metabolic dysfunction-associated steatohepatitis (MASH), a specific form of hepatitis driven by metabolic disturbances, remain poorly defined. This study integrated HPLC fingerprinting of Olea europaea L. leaf extracts (OLE) with chemometrics and bioactivity profiling to identify anti-MASH components. Bioactivity was assessed using a palmitic acid-induced steatohepatitis model in L02 cells. Spectrum–effect relationships derived from pearson correlation and partial least squares regression highlighted four putative active compounds, designated P7, P8, P10, and P11. HPLC-MS identified these as cynaroside (P7), apigenin-7-O-glucoside (P8), oleuroside (P10), and ligustroside (P11). Subsequent in vitro and in vivo evaluations in a zebrafish MASH model confirmed that P7, P8, and P10 exhibited significant anti-MASH activity. Notably, a robust synergism was observed between cynaroside and oleuroside, which their 1:1 M combination yielded a ZIP synergy score of 11.965 and a combination index (CI) of 0.3151, indicating strong synergy at lower doses. These results identify key anti-MASH constituents in OLE and provide a mechanistic basis for using multi-component OLE, highlighting a synergistic approach for MASH management.
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Frontiers in Nutrition
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2026
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IF 5.5
Hong Wang,Bingqi Huang,Wenhong Zhao,Gongliang Liu,Weidong Bai
Introduction Chinese olive ( Canarium album L.) is a rich source of phenolic compounds and has been suggested to exhibit distinct lipid-lowering bioactivities from those reported for Mediterranean olive polyphenols. Methods This study investigated the effects of polyphenol-rich Chinese olive extracts on sodium oleate-induced lipid accumulation in HepG2 cells. Results Treatment with extracts was associated with a significant reduction in intracellular total lipid and triglyceride levels in a concentration-dependent manner. RT-qPCR results revealed that extract treatment was accompanied by the downregulation of lipogenesis-related genes (SREBP-1c, ACC1, FASN, and DGAT2) and the upregulation of β -oxidation-associated genes (PGC-1α, PPARα, CPT-1A, and ACOX1). Western blot analysis showed that extract treatment was associated with AMPK phosphorylation, occurring concurrently with the observed lipid-associated changes. Furthermore, treatment with extracts was accompanied by decreased expression of miR-122 and miR-21, which correlated with the expression of their respective lipid-metabolism target genes. UPLC–MS/MS analysis identified 39 phenolic compounds in the extract, including methyl brevifolincarboxylate and ellagic acid derivatives, indicating a complex phenolic composition. Discussion These results demonstrate that attenuation of lipid accumulation by polyphenol-rich Chinese olive extracts in HepG2 cells is accompanied by AMPK phosphorylation and miRNA modulation. This finding supports the potential of Chinese olive extracts as a natural hepatoprotective ingredient for the development of functional foods and nutraceuticals.
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Food Bioscience
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2026
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IF 6.2
Yuxin Liu,Xinyu Cui,Luyun Cai,Weiliang Guan
Air exposure is the primary stressor during waterless transport of live shrimp, affects shrimp metabolism and is closely associated with quality deterioration, particularly the loss of umami taste. However, the regulatory pathways underlying air exposure induced changes in umami-related metabolites in shrimp muscle and their actual impact on flesh taste remain unclear. Here, we investigated adenosine monophosphate-activated protein kinase (AMPK)-regulated metabolic responses in Pacific white shrimp ( Penaeus vannamei ) during air exposure and assessed their implications for flesh taste. Air exposure increased cytosolic Ca 2+ and the adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio, indicating activation of upstream AMPK signals. AMPK responses were tissue- and time-dependent: liver kinase B1 (LKB1) and Ca 2+ /calmodulin-dependent protein kinase kinase (CaMKK) and AMPK transcription peaked earlier in muscle than in hepatopancreas. AMPK reached its maximum at 8 h in muscle but at 12 h in hepatopancreas, consistent with enhanced glycolysis to compensate for energy deficiency. In parallel, ATP degradation and protein catabolism promoted the accumulation of umami-related metabolites in muscle, including inosine monophosphate (IMP) and free amino acids. Electronic tongue and equivalent umami concentration (EUC) analyses showed that 4 h exposure produced the most favorable taste profile, with increased umami and sweetness and reduced bitterness. Overall, moderate air exposure was associated with enhanced umami development, accompanied by AMPK-associated metabolic remodeling. This study updates the understanding of air exposure effects on umami taste of shrimp muscle contributing to the optimization of waterless transportation practices of aquatic animals.
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