Human Cell
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2022
·Vol. 35
·期 5
·1424-1439
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IF 4.374
Liu Wen,Li Guojuan,Li Jing,Chen Wei
The long-term treatment of glucocorticoids is a common cause of osteoporosis (OP). This study concentrated on inquiring into the regulatory role and potential mechanisms of TRG-AS1 on dexamethasone (Dex)-induced OP in rats. We adopted Dex to treat rat osteoblasts and rats to simulate in-vitro and in-vivo OP models, respectively. Gain-of-function assays of TRG-AS1, miR-802 and CAB39 were constructed in rat osteoblasts to make certain the influence of TRG-AS1, miR-802 and CAB39 on differentiation, proliferation and apoptosis of rat osteoblasts. TRG-AS1 and CAB39 were down-regulated in the Dex-induced OP model in rats, in contrast to miR-802. Overexpression of TRG-AS1 restrained Dex-induced inhibition of osteogenic differentiation, promoted CAB39/AMPK/SIRT-1 and inhibited NF-κB, while overexpression of miR-802 bridled the inhibitory effect of TRG-AS1 on OP. miR-802 was targeted by TRG-AS1, and inhibited CAB39. Inhibition of either AMPK or SIRT-1 abated the osteogenic differentiation-promoting effect of CAB39. Animal experiments displayed that overexpressing TRG-AS1 alleviated Dex-induced OP in rats. In conclusion, up-regulation of TRG-AS1 protected against glucocorticoid-induced OP in rats by modulating the miR-802-mediated CAB39/AMPK/SIRT-1/NF-κB axis.
研究领域:
分子生物学
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药理学
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骨科
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2026
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IF 6.7
Wei Ye,Lei Wang,Ye Fan,Li Ma,Zaohong Chen,Jinmeng Zhang,Rong Zeng,Xiang Liu
Metabolic dysfunction-associated steatotic liver disease (MASLD) progression closely involves ferroptosis. Using high-fat diet-challenged mice and free fatty acid (FFA)-treated HepG2 cells, we demonstrate that oleanolic acid (OA) ameliorates MASLD and suppresses ferroptosis─an effect validated by the ferroptosis activator Erastin. Supported by network pharmacology, mechanistic analyses reveal that OA exerts synergistic efficacy via a dual-axis network. First, molecular docking, cellular thermal shift assay (CETSA), and molecular dynamics (MD) simulations confirm that OA directly binds PTGS2, mitigating lipid peroxidation and inflammatory mediator release. Second, OA activates the AMPK/ACC metabolic signaling pathway, inhibiting ACC through phosphorylation to correct lipid metabolism disorders, and its antiferroptotic effect can be blocked by AMPK inhibitors. This study first elucidates OA’s therapeutic mechanism against MASLD via “metabolic correction + oxidative inhibition,” outlining a novel strategy for targeting hepatic ferroptosis.
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PHYTOTHERAPY RESEARCH
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2026
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IF 8.1
Wen Jiang,Chen Ye,Ting Hu,Jichao Liang,Yong Chen
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over a quarter of the global adult population and is the primary cause of liver diseases worldwide. Costunolide (COS) is a sesquiterpene lactone that exhibits a range of biological activities and has significant hepatoprotective effects. However, the regulatory effects of COS on hepatic lipid metabolism and its potential molecular mechanisms remain poorly understood. This study aimed to examine the effects of COS on MASLD and to elucidate the underlying molecular mechanisms. The therapeutic effects of COS were assessed using a mouse model, fed a high-fat/high-fructose/high-cholesterol diet (HFHFrC) and primary hepatocytes treated with palmitic acid (PA) and oleic acid (OA). RNA sequencing (RNA-seq), quantitative PCR and western blotting were performed to explore the molecular mechanisms by which COS modulates hepatic lipid metabolism. Our findings indicated that COS effectively reduced lipid accumulation in the livers of mice fed a HFHFrC diet and lowered triglyceride (TG) content in hepatocytes induced by PA/OA. RNA-seq analysis, along with in vitro and in vivo experiments, demonstrated that COS activated ACC1 phosphorylation by promoting AMPK phosphorylation and inhibiting the expression of genes related to lipid synthesis. Co-treatment with the AMPK inhibitor, compound C abolished the lipid-lowering effect of COS. COS reduced the expression of genes related to lipid synthesis through the AMPK/ACC1 signalling pathway, thereby improving liver function, alleviating excessive lipid accumulation and ameliorating MASLD in both in vitro and in vivo models.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2026
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IF 5.6
Xiaohu Xi,Jiankuan Li,Yingjing Wang,Yan Ni,Jiangtao Zhou,Lingya Cao,Wei Wei,Jianping Gao
Background Dextran sulfate sodium-induced ulcerative colitis is featured by excessive intestinal inflammation and disrupted mucosal immune homeostasis. Codonopsis pilosula is the sovereign herb in Shenling Baizhu Formula for ulcerative colitis therapy, and Codonopsis pilosula polysaccharides are its key active components, while their immunomodulatory effects and molecular mechanisms in Shenling Baizhu Formula against ulcerative colitis remain elusive. This study explored the critical role of Codonopsis pilosula polysaccharides and the spermidine-AMPK-mediated mitophagy-cGAS-STING inflammatory axis in regulating intestinal inflammation and ameliorating ulcerative colitis. Methods A dextran sulfate sodium-induced ulcerative colitis mouse model was established to evaluate the indispensable role of Codonopsis pilosula polysaccharides in Shenling Baizhu Formula. Ultra-high performance liquid chromatography metabolomics and 16S ribosomal RNA sequencing were performed to identify key metabolites and gut microbiota. In vitro dextran sulfate sodium-induced ulcerative colitis cellular models (human colorectal adenocarcinoma Caco-2 and human normal colonic epithelial NCM460 cells) were constructed to validate the regulatory mechanism of spermidine on AMPK-mediated mitophagy, inflammatory balance and intestinal epithelial injury. Results Codonopsis pilosula polysaccharides were essential for the anti-ulcerative colitis efficacy of Shenling Baizhu Formula: removal of Codonopsis pilosula significantly aggravated colonic pathological lesions, intestinal inflammatory responses and oxidative stress in ulcerative colitis mice, whereas Codonopsis pilosula polysaccharides supplementation reversed these abnormal phenotypes ( P < 0.05). Metabolomics and microbiomics confirmed that Codonopsis pilosula polysaccharides exerted therapeutic effects via spermidine (a key metabolite in glutamate metabolism pathway) and Muribaculaceae. Critically, in vitro dual-cell experiments verified that spermidine activated AMPK-mediated mitophagy to directly inhibit the hyperactivation of cGAS-STING inflammatory axis, thereby restoring intestinal inflammatory homeostasis and alleviating epithelial cell injury in ulcerative colitis. Conclusion Codonopsis pilosula polysaccharides extracted from the sovereign herb Codonopsis pilosula in Shenling Baizhu Formula ameliorate dextran sulfate sodium-induced ulcerative colitis, and the core mechanism depends on spermidine-triggered AMPK-mediated mitophagy to suppress the cGAS-STING inflammatory signaling axis, which plays a pivotal role in regulating intestinal immunity and repairing mucosal epithelial damage.
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NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
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2022
·Vol. 395
·期 10
·1283-1295
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IF 3.195
Xiong Ziwei,Cui Yushun,Wu Jiahui,Shi Lingyu,Quan Wen,Yang Shilin,Feng Yulin
Pteris cretica L. var. nervosa is one of the most well-known Chinese medicines. Although it is widely used to treat jaundice hepatitis, the main ingredient for its treatment was not thoroughly explored until recently. Essentially, the purpose of this study is to find the monomer compound in Pteris cretica L. var. nervosa , which is most likely to be effective in treating liver injury. Through the model of LPS/D-gal-induced liver injury in mice, the best therapeutic site of the total extract was explored, the chemical components of the parts with the best therapeutic effect were separated, a total of 10 flavonoids were isolated, and the RAW264.7 cells induced by LPS were used as the experimental model to explore the preliminary anti-inflammatory activity of NO production in vitro. Finally, the anti-inflammatory activity and the highest content in this plant Luteolin-7-O-rutinoside (LUT) were selected, as the object of study in vivo. It was found that LUT could not only reduce alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, but also significantly reduce the release of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), and inhibit PI3K/AKT/AMPK/NF-κB pathway. In addition, LUT can increase levels of SOD and GSH to reduce oxidative stress. It has an obvious therapeutic effect on acute liver injury induced by LPS/D-gal in mice. Therefore, infer LUT is a functional substance in Pteris cretica L. var. nervosa. Graphical abstract
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JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Xiaolong Feng,Xinru Tao,Penghui Li,Jun Chen,Kaiyi Chen,Jinsheng Jiang,Yuan Cai,Yanmei Peng
Ethnopharmacological relevance Yuye Jiedu Granule (YYJD), a traditional herb preparation developed by Hunan Changde Sanjin Pharmaceutical Co., Ltd., has been used in clinical settings for many years to manage upper respiratory tract infections (URTI) attributed to exogenous wind-heat. Although its effectiveness is well recognized, the active constituents responsible for its effects and the molecular pathways involved are not clear yet. Aim of the study To identify the bioactive constituents of YYJD and elucidate its molecular mechanisms in treating URTI. Materials and methods Initially, the chemical composition of YYJD was analyzed using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) in combination with a molecular networking approach. Anti-inflammatory components within the formula were then identified using a UPLC-based separation system and a dual-luciferase reporter gene screening assay, followed by in vitro validation. Subsequently, an acute pneumonia model was developed using Pseudomonas aeruginosa infection to comprehensively assess the therapeutic efficacy of YYJD through integrated transcriptomic, metabolomic, and network pharmacology analyses. Finally, the underlying molecular mechanisms were experimentally confirmed. Results A total of 145 chemical constituents were identified in YYJD, among which 15 were found to inhibit NF-κB. In vivo studies demonstrated that YYJD notably decreased mortality, lung indices, and serum pro-inflammatory cytokines in P. aeruginosa -infected mice. Integrated multi-omics analysis highlighted adenosine monophosphate (AMP) as a central metabolite, with major bioactive compounds classified as organic acids, flavonoids, iridoid glycosides, and triterpenoid saponins . Nine pivotal targets and the AMPK-mTORC1/2-PI3K/Akt/NF-κB axis were identified as central to YYJD’s anti-URTI effects. Mechanistically, YYJD modulated the phosphorylation of GSK3β, Akt, IκBα, mTOR, and AMPK, along with the p65 expression. Conclusion This study presents the first in-depth analysis of YYJD’s chemical profile and elucidates its multi-target therapeutic mechanisms against URTI through AMPK-centered metabolic-inflammatory interplay. These results offer a stronger scientific foundation for the clinical use of YYJD and introduce a potential new approach for treating respiratory infections.
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EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2017
·
IF 3.756
Enfang Shan,Zhu Zhu,Shuangcheng He,Dongbao Chu,Dinghao Ge,Yunran Zhan,Wei Liu,Jian Yang,Jing Xiong
Type 2 diabetes mellitus (T2D) is a complex metabolic disorder requiring polypharmacy treatment in clinic, with metformin being widely used antihyperglycemic drug. However, the mechanisms of metformin as a perpetrator inducing potential drug-drug interactions and adverse drug reactions are scarcely known to date. Carboxylesterases (CESs) are major hydrolytic enzymes highly expressed in the liver, including mouse carboxylesterase 1d (Ces1d) and Ces1e. In the present study, experiments are designed to investigate the effects and mechanisms of metformin on Ces1d and Ces1e in vivo and in vitro. In results, metformin suppresses the expression and activity of Ces1d and Ces1e in a dose- and time-dependent manner. The decreased expression of nuclear receptor PXR and its target gene P-gp indicates the involvements of PXR in the suppressed expression of carboxylesterases by metformin. Furthermore, metformin significantly suppresses the phosphorylation of AMPK and JNK, and the suppression of carboxylesterases induced by metformin is repeatedly abolished by AMPK inhibitor Compound C and JNK inhibitor SP600125 . It implies that the activation of AMPK and JNK pathways mediates the suppression of carboxylesterases by metformin. The findings deserve further elucidation including clinical trials and have a potential to make contribution for the rational medication in the treatment of T2D patients.
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Chinese Journal of Natural Medicines
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2025
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IF 4.9
Qian Chen,Shuying Zhang,Xuanxi Jiang,Jie Liao,Xin Shao,Xin Peng,Zheng Wang,Xiaoyan Lu,Xiaohui Fan
Coptis chinensis Franch. and Panax ginseng C. A. Mey. are traditional herbal medicines with millennia of documented use and broad therapeutic applications, including anti-diabetic properties. However, the synergistic effect of total alkaloids from Coptis chinensis and total ginsenosides from Panax ginseng on type 2 diabetes mellitus (T2DM) and its underlying mechanism remain unclear. The research demonstrated that the optimal ratio of total alkaloids from Coptis chinensis and total ginsenosides from Panax ginseng was 4∶1, exhibiting maximal efficacy in improving insulin resistance and gluconeogenesis in primary mouse hepatocytes. This combination demonstrated significant synergistic effects in improving glucose tolerance, reducing fasting blood glucose (FBG), the weight ratio of epididymal white adipose tissue (eWAT), and the homeostasis model assessment of insulin resistance (HOMA-IR) in leptin receptor-deficient (db/db) mice. Subsequently, a T2DM liver-specific network was constructed based on RNA sequencing (RNA-seq) experiments and public databases by integrating transcriptional properties of disease-associated proteins and protein-protein interactions (PPIs). The network recovery index (NRI) score of the combined treatment group with a 4∶1 ratio exceeded that of groups treated with individual components. The research identified that activated adenosine 5’-monophosphate-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) signaling in the liver played a crucial role in the synergistic treatment of T2DM, as verified by western blot experiment in db/db mice. These findings demonstrate that the 4∶1 combination of total alkaloids from Coptis chinensis and total ginsenosides from Panax ginseng significantly improves insulin resistance and glucose and lipid metabolism disorders in db/db mice, surpassing the efficacy of individual treatments. The synergistic mechanism correlates with enhanced AMPK/ACC signaling pathway activity.
研究领域:
药理学
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植物学
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分子生物学
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系统生物学
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内分泌学
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转录组学
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民族药理学
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Food Science and Human Wellness
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2022
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IF 8.022
Peng Ma,Rongrong Huang,Yu Ou
Soy glycinin derived octapeptide (SGP8) is a peptide obtained from degradation of the soy glycinin, whose amino acid sequence is IAVPGEVA. To determine the effect of SGP8 on non-alcoholic fatty liver disease (NAFLD), steatosis HepG2 cells were induced by 1 mmol/L free fatty acid (FFA) and C57BL/6J mice were fed with methionine-choline deficient (MCD) diet for 3 weeks to establish NAFLD model. The results of oil red O staining and total cholesterol (TC)/triglyceride (TG) contents showed that SGP8 could significantly reduce the lipid content of steatosis HepG2 cells. In vivo , SGP8 lowered plasma alanine aminotransferase (ALT) and low density lipoprotein (LDL) content, normalized hepatic superoxide dismutase (SOD) and malondialdehyde (MDA) production, and reduced the severity of liver inflammation. The results of Western blotting showed that SGP8 increased expression of Sirtuin-1 (SIRT1) and phosphorylation level of AMP activated protein kinase (AMPK) in hepatocytes. Through activation of SIRT1/AMPK pathway, SGP8 downregulated the expression of sterol regulatory element binding protein 1c (SREBP-1c) and its target genes ACC and FAS expression levels, and increased the phosphorylation level of acetyl CoA carboxylase (ACC). Furthermore, SGP8 also upregulated the expression of transcription factor peroxisome proliferator activated receptor α (PPARα), which was regulated by SIRT1/AMPK pathway, and its target gene CPT1 level. In conclusion, SGP8 might improve NAFLD by activating the SIRT1/AMPK pathway. Our data suggest that SGP8 may act as a novel and potent therapeutic agent against NAFLD.
研究领域:
药理学
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分子生物学
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肝病学
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JOURNAL OF NANOBIOTECHNOLOGY
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2021
·Vol. 19
·期 1
·1-18
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IF 10.435
Luo Lihua,Qin Bing,Jiang Mengshi,Xie Lin,Luo Zhenyu,Guo Xuemeng,Zhang Junlei,Li Xiang,Zhu Chunqi,Du Yongzhong,Peng Ling,You Jian
Background Photothermal therapy (PTT) is a highly effective treatment for solid tumors and can induce long-term immune memory worked like an in situ vaccine. Nevertheless, PTT inevitably encounters photothermal resistance of tumor cells, which hinders therapeutic effect or even leads to tumor recurrence. Naïve CD8+ T cells are mainly metabolized by oxidative phosphorylation (OXPHOS), followed by aerobic glycolysis after activation. And the differentiate of effector CD8+ T cell (CD8+ T eff ) into central memory CD8+ T cell (CD8+ TCM) depends on fatty acid oxidation (FAO) to meet their metabolic requirements, which is regulated by adenosine monophosphate activated protein kinase (AMPK). In addition, the tumor microenvironment (TME) is severely immunosuppressive, conferring additional protection against the host immune response mediated by PTT. Methods Metformin (Met) down-regulates NADH/NADPH, promotes the FAO of CD8+ T cells by activating AMPK, increases the number of CD8+ TCM, which boosts the long-term immune memory of tumor-bearing mice treated with PTT. Here, a kind of PLGA microspheres co-encapsulated hollow gold nanoshells and Met (HAuNS-Met@MS) was constructed to inhibit the tumor progress. 2-Deoxyglucose (2DG), a glycolysis inhibitor for cancer starving therapy, can cause energy loss of tumor cells, reduce the heat stress response of tumor cell, and reverse its photothermal resistance. Moreover, 2DG prevents N-glycosylation of proteins that cause endoplasmic reticulum stress (ERS), further synergistically enhance PTT-induced tumor immunogenic cell death (ICD), and improve the effect of immunotherapy. So 2DG was also introduced and optimized here to solve the metabolic competition among tumor cells and immune cells in the TME. Results We utilized mild PTT effect of HAuNS to propose an in situ vaccine strategy based on the tumor itself. By targeting the metabolism of TME with different administration strategy of 2DG and perdurable action of Met, the thermotolerance of tumor cells was reversed, more CD8+ TCMs were produced and more effective anti-tumor was presented in this study. Conclusion The Step-by-Step starving-photothermal therapy could not only reverse the tumor thermotolerance, but also enhance the ICD and produce more CD8+ TCM during the treatment. Graphical Abstract
研究领域:
癌症治疗
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免疫学
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纳米技术
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代谢工程
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FOOD AND CHEMICAL TOXICOLOGY
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2020
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IF 4.679
Rili Hao,Xinyu Song,Feng Li,Xintong Tan,Dongxiao Sun-Waterhouse,Dapeng Li
Exposure to nonbiodegradable cadmium (Cd) causes many health problems including the damage to the nervous system. This study aimed to increase knowledge about its neurotoxic effects and the neuroprotective potential of caffeic acid phenethyl ester (CAPE, a polyphenol abundant in honeybee propolis). In mice, CAPE (10 μmol/kg/day body weight) attenuated significantly learning and memory deficits induced by CdCl 2 (1.5 mg/kg/day body weight). For the CdCl 2 -treated mice, CAPE increased crossing number in open field test, decreased the alternation in Y-maze test, and increased the latency time and error number in step down test. CAPE also inhibited CdCl 2 -initiated Aβ accumulation and activation of pro-inflammatory factors and microglia in the brains. Therefore, CAPE could be a food-derived neuroprotective agent against Cd-induced neurotoxicity and neurodegenerative disorders, through attenuating neuronal apoptosis and neuroinflammation via the AMPK/SIRT1 pathway and amyloid-tau-neuroinflammation axis.
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BIOMEDICINE & PHARMACOTHERAPY
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2026
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IF 7.5
Yannan Xiang,Tianyue Guan,Jun Wang,Shasha Zhang,Yusa Li,Jing Xia,Panpan Zhao,Lei Wang
This study explores the protective effects of Atraric Acid (AA) against chronic kidney disease (CKD) induced by a high-fat diet (HFD) and its underlying mechanisms. In vivo HFD-induced CKD mouse models and in vitro OA/PA-stimulated HK2 cells were treated with AA. AA improved kidney morphology, reduced fibrosis, lipid accumulation, and body weight. It also decreased serum TC, TG, HDL-C, Scr, BUN, and Cys-C levels, indicating improved renal function. AA alleviated oxidative stress, ROS accumulation, and inflammation, as confirmed by DHE staining, oxidative stress markers, and pro-inflammatory cytokine levels. Western blotting showed that AA activated Nrf2 and suppressed NF-κB signaling. AMPK inhibition experiments demonstrated that AA regulated Nrf2 and NF-κB via AMPKα phosphorylation. In conclusion, AA mitigates HFD-induced CKD by targeting AMPKα to regulate oxidative stress and inflammation.
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