MEDICAL SCIENCE MONITOR
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2018
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IF 1.894
Lingling Wang,Yan Yin,Gang Hou,Jian Kang,Qiuyue Wang
Background Cigarette smoking is a well-known risk factor in multiple chronic pulmonary diseases. This study aims to investigate the role of peroxisome proliferator-activated receptor (PPAR) γ in cigarette smoking-induced inflammation. Material/Methods Cigarette smoking extract (CSE) was employed to induce inflammation in bronchial epithelial cells (BECs). After CSE administration, several autophagy-related proteins (Beclin1, autophagy-related gene (ATG)5, ATG7, p62, and LC3) and PPARγ levels were examined by western blot. Subsequently, PPARγ agonists and antagonist were used to treat CSE-induced BECs, several inflammatory factors (interleukin (IL)-6, IL-8, inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX)-2) and autophagy-related proteins were detected to measure the inflammatory and autophagy levels. Then LC3 knockdown was performed to verify the role of autophagy in CSE-induced inflammation. Finally, the AMP-activated protein kinase (AMPK) and its downstream S6 kinase (S6K) were detected in CSE-stimulated BECs. Results CSE administration caused insufficient autophagy and the decrease of PPARγ in BECs. The PPARγ agonists ameliorate the CSE-induced inflammation and promote the autophagy development, evidenced by the changes of inflammatory factors and autophagy-related proteins. Loss-of-function experiments demonstrated that the PPARg played an anti-inflammatory role in an autophagy-dependent manner. In addition, CSE administration inactivated the AMPK signaling, which was restored by PPARγ agonists. The effects of PPARγ agonists on inflammation and autophagy could be abolished by AMPK inhibitor. Conclusions We demonstrated that PPARγ played a protective role in CSE-induced inflammation and autophagy by activating AMPK signaling in BECs, which may provide investigation basis for clinical therapy of chronic pulmonary diseases.
研究领域:
肺部疾病
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分子生物学
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细胞信号传导
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炎症研究
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DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
·
2022
·Vol. 48
·期 2
·625-640
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IF 4.414
Hui Yuzuo,Zhao Han,Shi Lei,Zhang Haitao
8-Methoxypsoralen (8-MOP) has anti-inflammatory, antioxidant and tissue-repairing abilities. Here, we probed the function and mechanism of 8-MOP in traumatic brain injury (TBI). The in - vivo TBI model was constructed in Sprague-Dawley (SD) rats using controlled cortical impact (CCI) surgery. In parallel, BV2 microglia and HT22 neurons were activated by lipopolysaccharide (LPS) to establish an in-vitro model. The modified neurological score (mNSS) and the Morris water maze experiment were employed to evaluate the rats’ neurological functions. The rats’ brain edema was assessed by the dry and wet method, and neuronal apoptosis in damaged brain tissues was monitored by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) and Nissl’s staining. Immunohistochemistry (IHC) was applied to verify Iba1-microglial activation in brain lesions of rats. The expression of inflammatory cytokines in BV2 microglia and HT22 neurons in the injured lesion of TBI rats was examined by the enzyme-linked immunosorbent assay (ELISA). The levels of iNOS, COX2, TLR4, PPARγ, STAT3, and NF-κB in brain lesions, BV2 microglia and HT22 neurons were compared by Western blot. As a result, 8-MOP administration reduced inflammation and LPS-induced neuronal damage in BV2 microglia. In vivo, 8-MOP treatment relieved neurological deficits in TBI rats, improved cognitive, learning and motor functions and mitigated brain edema and neuroinflammation induced by TBI. Furthermore, LPS or TBI activated the NF-κB and STAT3 pathways and repressed the PPARγ expression. However, 8-MOP treatment attenuated NF-κB and STAT3 phosphorylation and elevated PPARγ levels. Hence, 8-MOP exerts neuroprotective and anti-inflammatory effects in TBI rats by modulating the PPARγ/NF-κB pathway.
研究领域:
神经科学
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药理学
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炎症
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神经保护
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PubMed
高影响因子
Journal of Materials Chemistry B
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2024
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IF 6.1
Dong Mo,Wei Cui,Linxin Chen,Juanjuan Meng,Yuting Sun,Kaiyong Cai,Jixi Zhang,Jianrong Zhang,Kui Wang,Xiaohe Luo
Hepatic ischemia-reperfusion injury (IRI) is a common pathological process during hepatectomy and liver transplantation and the two primary reasons for hepatic IRI are reactive oxygen species (ROS)-mediated oxidative stress and excessive inflammatory responses. Herein, a novel antioxidant nanodrug (A-MPDA@Fe3O4@PVP) is prepared by employing L-arginine-doped mesoporous polydopamine (A-MPDA) nanoparticles as the carrier for deposition of ultra-small ferric oxide (Fe3O4) nanoparticles and further surface modification with polyvinylpyrrolidone (PVP). A-MPDA@Fe3O4@PVP not only effectively reduces the aggregation of ultra-small Fe3O4, but also simultaneously replicates the catalytic activity of catalase (CAT) and superoxide dismutase (SOD). A-MPDA@Fe3O4@PVP with good antioxidant activity can rapidly remove various toxic reactive oxygen species (ROS) and effectively regulate macrophage polarization in vitro. In the treatment of hepatic IRI, A-MPDA@Fe3O4@PVP effectively alleviates ROS-induced oxidative stress, reduces the expression of inflammatory factors, and prevents apoptosis of hepatocytes through immune regulation. A-MPDA@Fe3O4@PVP can further protect liver tissue by activating the PPARγ/NF-κB pathway. This multiplex antioxidant enzyme therapy can provide new references for the treatment of IRI in organ transplantation and other ROS-related injuries such as fibrosis, cirrhosis, and bacterial and hepatic viral infection.
研究领域:
药理学
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纳米技术
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肝病学
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免疫学
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病理生理学
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PubMed
高影响因子
Nutrients
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2016
·Vol. 8
·期 12
·799
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IF 3.759
Shu-Fang Xia,Guo-Wei Le,Peng Wang,Yu-Yu Qiu,Yu-Yu Jiang,Xue Tang
Myricetin is an effective antioxidant in the treatment of obesity and obesity-related metabolic disorders. The objective of this study was to explore the regressive effect of myricetin on pre-existing hepatic steatosis induced by high-fat diet (HFD). C57BL/6 mice were fed either a standard diet or a HFD for 12 weeks and then half of the mice were treated with myricetin (0.12% in the diet,w/w) while on their respective diets for further 12 weeks. Myricetin treatment significantly alleviated HFD-induced steatosis, decreased hepatic lipid accumulation and thiobarbituric acid reactive substance (TBARS) levels, and increased antioxidative enzyme activities, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities. Microarray analysis of hepatic gene expression profiles showed that myricetin significantly altered the expression profiles of 177 genes which were involved in 12 biological pathways, including the peroxisome proliferator activated receptor (PPAR) signaling pathway and peroxisome. Further research indicated that myricetin elevated hepatic nuclear Nrf2 translocation, increased the protein expression of heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1), reduced the protein expression of PPARγ, and normalized the expressions of genes that were involved in peroxisome and the PPAR signaling pathway. Our data indicated that myricetin might represent an effective therapeutic agent to treat HFD-induced hepatic steatosis via activating the Nrf2 pathway and the PPAR signaling pathway.Keywords:myricetin;hepatic steatosis;Nrf2;PPARγ;oxidative stress
研究领域:
药理学
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分子生物学
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营养学
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DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2026
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IF 3.2
Yuchen Zheng,Zijia Liu,Zijie Zhao,Chao Sheng,Wenzhuo Li,Duo Tang,Yunlu Ning,Renhang Zhou,Ao Li,Zhixiang Zhou
As an emerging contaminant, nanoplastics (NPs) are widespread in the food chain and environment, raising concerns about their potential toxicity. However, their effects on lipid metabolic homeostasis and the underlying mechanisms remain unclear. This study used polystyrene nanoplastics (PS-NPs), common in food packaging, to examine their impact on adipogenic differentiation and lipid synthesis. Our research results indicated that after 10 days of oral exposure, PS-NPs significantly accumulated in the adipose tissue of mice. Within the exposure concentration range of 1-100 μg/mL, PS-NPs significantly increased the expression of genes related to adipogenesis, accelerated mitotic clonal expansion (MCE) during early differentiation, and enhanced triglyceride (TG) accumulation in mouse 3T3-L1 preadipocytes, leading to adipogenic differentiation and lipogenesis. These effects were positively correlated with the exposure concentration. Protein quantification and immunofluorescence revealed that PS-NPs promoted the nuclear translocation of peroxisome proliferator-activated receptor γ (PPARγ). Molecular dynamics simulations confirmed that PS-NPs bind to the nuclear localization signal (NLS) region of PPARγ. These findings suggested a new molecular mechanism in which PS-NPs influence PPARγ′s subcellular localization through NPs-protein interactions, triggering adipogenic programs. This study provides valuable insights for the safety assessment and toxicology of nanoplastics.
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Lifeng Ding,Xiufei Teng,Wei Du,Yonghao Zhang,Baozhe Liu,Shang Piao
This study introduces CA@PDX HMs, an injectable sustained-release hydrogel system for osteoarthritis (OA) therapy designed to regulate the immunometabolic microenvironment via the AMPK/PPARγ signaling pathway. The hydrogel consists of Protectin DX (PDX)-loaded microspheres embedded within an OHA/CMC-ADH matrix and is fabricated using a microfluidic strategy to achieve high encapsulation efficiency and controlled drug release. PDX demonstrated anti-inflammatory effects by suppressing pro-inflammatory cytokines and promoting M2 macrophage polarization. In vitro, CA@PDX HMs reduced chondrocyte apoptosis and matrix degradation, restoring key cartilage components. In an ACLT-induced OA rat model, intra-articular administration of CA@PDX HMs markedly improved cartilage integrity, reduced OARSI scores, and enhanced IL-10 expression. Transcriptomic analysis revealed significant enrichment of the AMPK/PPARγ pathway, indicating coordinated regulation of metabolic and inflammatory processes. Mechanistic validation further confirmed activation of p-AMPK and PPARγ signaling, accompanied by suppression of inflammatory mediators and remodeling of the local immune microenvironment. These findings highlight the hydrogel's anti-inflammatory, anti-apoptotic, and matrix-protective effects, showcasing its potential as a promising localized treatment for OA with excellent biocompatibility and retention characteristics.
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PubMed
高影响因子
Frontiers in Pharmacology
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2026
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IF 5.4
Ling Ou,Qian Du,Jiayang Liu,Haiyan Tai,Yinghan Chai,Xiaoqiong Tan,Bing Li,Lirong Tan,Ying Cao,Tingting Zhu
Introduction The liver, as the central metabolic hub of the body, is highly susceptible to diet-induced injury. The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) highlights the urgent need for effective clinical interventions. Currently, there are no specific therapeutics for MASLD, and dietary patterns are closely associated with its pathogenesis, making the exploration of natural bioactive compounds a promising strategy. Methods In this study, we identified acetylshikonin (AS), a component derived from traditional Chinese medicine (TCM), as a core bioactive agent targeting MASLD via a cross-screening strategy of MASLD-related TCM formulas. Male mouse models of MASLD were induced by a high-fat and high-cholesterol (HFHC) diet or carbon tetrachloride (CCl4) and treated with AS (600 mg/kg, gavage) for six consecutive weeks. In vitro experiments were conducted on Hepa1-6 and HCCLM3 hepatocytes stimulated with palmitic acid/oleic acid (PA/OA, 1:2). Integrated network pharmacology, molecular docking, and thermal shift assays were applied to explore the underlying mechanism. Results In vivo results showed that AS markedly attenuated hepatic steatosis (assessed by triglyceride and total cholesterol levels) and liver fibrosis (evaluated by collagen deposition). In vitro, AS suppressed intracellular lipid accumulation (validated by Oil Red O staining and lipid quantification) and inflammatory responses (assessed by pro-inflammatory cytokine expression) in the stimulated hepatocytes. Mechanistically, AS downregulated the transcriptional expression of key genes involved in lipid metabolism (Pparγ and Srebp1c), inflammation (Tnfα and Ccl2), and fibrosis (Col1a1 and Acta2) pathways. Integrated analyses confirmed peroxisome proliferator-activated receptor γ (PPARγ) as the core direct target of AS. Western blotting demonstrated that AS reduced PPARγ protein expression, and its lipid-lowering effect was synergistically enhanced when combined with the PPARγ antagonist GW9662. Discussion This is the first study to definitively confirm that AS exerts therapeutic effects on diet-induced MASLD by targeting the PPARγ signaling pathway, thereby reducing hepatic lipid deposition, alleviating inflammation, and ameliorating liver fibrosis progression. Our findings provide novel experimental evidence supporting the use of natural products in MASLD treatment and lay a theoretical foundation for the application of AS in the health management of diet-related liver diseases.
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高影响因子
EMBO REPORTS
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2021
·Vol. 22
·期 5
·e52146
·
IF 8.807
Yushi Chen,Ruifan Wu,Wei Chen,Youhua Liu,Xing Liao,Botao Zeng,Guanqun Guo,Fangfang Lou,Yun Xiang,Yizhen Wang,Xinxia Wang
Obesity has become a major health problem that has rapidly prevailed over the past several decades worldwide. Curcumin, a natural polyphenolic compound present in turmeric, has been shown to have a protective effect on against obesity and metabolic diseases. However, its underlying mechanism remains largely unknown. Here, we show that the administration of curcumin significantly prevents HFD-induced obesity and decreases the fat mass of the subcutaneous inguinal WAT (iWAT) and visceral epididymal WAT (eWAT) in mice. Mechanistically, curcumin inhibits adipogenesis by reducing the expression of AlkB homolog 5 (ALKHB5), an m6A demethylase, which leads to higher m6A-modified TNF receptor-associated factor 4 (TRAF4) mRNA. TRAF4 mRNA with higher m6A level is recognized and bound by YTHDF1, leading to enhanced translation of TRAF4. TRAF4, acting as an E3 RING ubiquitin ligase, promotes degradation of adipocyte differentiation regulator PPARγ by a ubiquitin–proteasome pathway thereby inhibiting adipogenesis. Thus, m6A-dependent TRAF4 expression upregulation by ALKBH5 and YTHDF1 contributes to curcumin-induced obesity prevention. Our findings provide mechanistic insights into how m6A is involved in the anti-obesity effect of curcumin.
研究领域:
分子生物学
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代谢学
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营养学
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药理学
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PubMed
高影响因子
Journal of Environmental Sciences
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2026
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IF 6.5
Xiaoyan Li,Ying Cheng,Zhuling Xu,Runfeng Chang,Jin Yan,Zejun Wang,Xuedong Wang,Huili Wang,Qiuhui Qian
● AgNPs disrupted hepatic lipid metabolism and induced ferroptosis-related toxicity. ● AgNPs induced SCD1 upregulation associated with lipid dysregulation and ferroptosis. ● SCD1 may link lipid metabolism with PPARγ pathway and ferroptosis-related injury. ● AgNPs exposure was associated with insulin resistance– and T2DM-like alterations. Silver nanoparticles (AgNPs) are widely used nanomaterials, yet their potential metabolic and hepatic risks remain insufficiently understood. In this study, we investigated the toxicological effects of AgNPs in zebrafish and explored the potential involvement of a peroxisome proliferator-activated receptor γ (PPARγ)–stearoyl-CoA desaturase 1 (SCD1)–ferroptosis–related pathway associated with lipid metabolic disturbance and type 2 diabetes mellitus (T2DM)-like metabolic alterations. AgNPs exposure induced coordinated upregulation of PPARγ and SCD1 and downregulation of glutathione peroxidase 4 (GPX4), which were accompanied by hepatic lipid accumulation, oxidative stress, and ferroptosis-related responses in larvae, as indicated by elevated reactive oxygen species (ROS) and Fe 2+ levels, glutathione (GSH) depletion, and enhanced lipid peroxidation. These alterations persisted into adulthood and were accompanied by increased body and liver weight, dyslipidemia, hyperglycemia, and impaired insulin signaling, resembling T2DM-like phenotypes. Pharmacological inhibition further supported the involvement of this pathway: the ferroptosis inhibitor deferoxamine (DFO), the PPARγ antagonist 2-chloro-5-nitro-N-(pyridin-4-yl)benzamide (T0070907), and the SCD1 inhibitor 4-(2-chlorophenoxy)-N-[3-[(methylamino)carbonyl]phenyl]-1-piperidinecarboxamide (A939572) significantly alleviated AgNPs-associated hepatic injury. Mechanistic analyses suggest that SCD1, acting downstream of PPARγ, may function as a key mediator linking lipid metabolic dysregulation to ferroptosis. Collectively, these findings provide new insight into the metabolic toxicity associated with AgNPs exposure and contribute to improved ecological and biomedical safety assessment of engineered nanomaterials. Download: Download high-res image (382KB) Download: Download full-size image
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高影响因子
Cell Host & Microbe
·
2024
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IF 20.6
Ying-Xi Xu,Lu-Di Liu,Jiang-Yuan Zhu,Shan-Shan Zhu,Bing-Qi Ye,Jia-Lu Yang,Jing-Yi Huang,Zhi-Hao Huang,Yi You,Wen-Kang Li,Jia-Lin He,Min Xia,Yan Liu
Hyperuricemia induces inflammatory arthritis and accelerates the progression of renal and cardiovascular diseases. Gut microbiota has been linked to the development of hyperuricemia through unclear mechanisms. Here, we show that the abundance and centrality of Alistipes indistinctus are depleted in subjects with hyperuricemia. Integrative metagenomic and metabolomic analysis identified hippuric acid as the key microbial effector that mediates the uric-acid-lowering effect of A. indistinctus. Mechanistically, A. indistinctus-derived hippuric acid enhances the binding of peroxisome-proliferator-activated receptor γ (PPARγ) to the promoter of ATP-binding cassette subfamily G member 2 (ABCG2), which in turn boosts intestinal urate excretion. To facilitate this enhanced excretion, hippuric acid also promotes ABCG2 localization to the brush border membranes in a PDZ-domain-containing 1 (PDZK1)-dependent manner. These findings indicate that A. indistinctus and hippuric acid promote intestinal urate excretion and offer insights into microbiota-host crosstalk in the maintenance of uric acid homeostasis.
研究领域:
微生物学
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代谢组学
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药理学
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胃肠病学
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PubMed
高影响因子
Cell Metabolism
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2021
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IF 27.287
Guang-Nian Zhao,Zheng-Wei Tian,Tian Tian,Zhi-Peng Zhu,Wen-Jie Zhao,Han Tian,Xu Cheng,Feng-Jiao Hu,Man-Li Hu,Song Tian,Ting Ding,Siping Chen,Yan-Xiao Ji,Peng Zhang,Xiao-Jing Zhang,Zhi-Gang She,Yufeng Yuan,Wenping Chen,Lan Bai,Hongliang Li
Summary Obesity is characterized by the excessive accumulation of the white adipose tissue (WAT), but healthy expansion of WAT via adipocyte hyperplasia can offset the negative metabolic effects of obesity. Thus, identification of novel adipogenesis regulators that promote hyperplasia may lead to effective therapies for obesity-induced metabolic disorders. Using transcriptomic approaches, we identified transmembrane BAX inhibitor motif-containing 1 (TMBIM1) as an inhibitor of adipogenesis. Gain or loss of function of TMBIM1 in preadipocytes inhibited or promoted adipogenesis, respectively. In vivo , in response to caloric excess, adipocyte precursor (AP)-specific Tmbim1 knockout (KO) mice displayed WAT hyperplasia and improved systemic metabolic health, while overexpression of Tmbim1 in transgenic mice showed the opposite effects. Moreover, mature adipocyte-specific Tmbim1 KO did not affect WAT cellularity or nutrient homeostasis. Mechanistically, TMBIM1 binds to and promotes the autoubiquitination and degradation of NEDD4, which is an E3 ligase that stabilizes PPARγ. Our data show that TMBIM1 is a potent repressor of adipogenesis and a potential therapeutic target for obesity-related metabolic disease.
研究领域:
分子生物学
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代谢学
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肥胖研究
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细胞生物学
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DOI
PubMed
高影响因子
RSC Medicinal Chemistry
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2026
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IF 4.6
Shi-Ying Xu,Quan-Xing Liu,Yan Luo,Wu-He Wu,Qing Li,Shang-Gao Liao,Jun-Li Ao,Guo-Bo Xu
The broad biological activity of synthetic halogenated steroid derivatives has spurred considerable recent research. In this study, we synthesized and evaluated cytotoxicity against HepG2 cells for twenty-eight halogen-containing pregnenolone derivatives. Compound 20 exhibited the highest cytotoxicity, with an IC50 value of 1.490 ± 0.041 μM. It effectively inhibited cell proliferation, clone formation, and migration, as well as induced DNA damage in hepatocellular carcinoma cells. Flow cytometry revealed that compound 20 induced G0/G1 cell cycle arrest. Concurrently, experimental evidence from Hoechst 33258 staining, flow cytometry, and western blotting convincingly demonstrated that compound 20 robustly promotes apoptosis in HepG2 cells, marked by decreased expression of pro-survival proteins (caspase 3/8/9, Bcl-2) and increased expression of pro-apoptotic Bax. Network pharmacology identified PPARγ as a key potential target. Western blots using a PPARγ agonist (pioglitazone) and antagonist (T0070907) validated its crucial role in mediating compound 20-induced apoptosis in HepG2 cells. Complementary molecular modeling, including docking and molecular dynamics simulations, underscored the high binding affinity and stabilizing interaction between compound 20 and PPARγ. Furthermore, a CETSA assay provided additional support, confirming that compound 20 enhances PPARγ's thermal stability. Collectively, these findings strongly suggest that compound 20 inhibits HepG2 proliferation and promotes HepG2 apoptosis via PPARγ modulation, positioning it as a promising lead compound for hepatocellular carcinoma treatment.
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高影响因子
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