Brain Hemorrhages
·
2025
·
IF 1.4
Wenying Zhang,Wanyu Ma,Siying Ren,Likun Wang,Guofeng Wu
Intracerebral hemorrhage (ICH) is a severe stroke subtype with high mortality and disability. Cuproptosis is a regulatory cell death modality dependent on intracellular copper ion concentration, the role of which in ICH is unclear. Upon activation by ligand agonists, peroxisome proliferator-activated receptor-γ (PPARγ), can alleviate brain injury after ICH. To investigate the inhibitory effect of activating PPARγ on cuproptosis following ICH, we established the ICH model in vivo and in vitro and they were treated with the PPARγ agonist or antagonist after models being established successfully. Then, the copper ion concentration was measured by copper colorimetric assay and the expression of cuproptosis-related regulatory factors and copper transporter 1 was detected by western blotting and immunofluorescence staining (except in the cell level). We found that the increase in copper ion concentration following ICH leads to the disruption of copper homeostasis, inducing cuproptosis via copper toxicity. Activating PPARγ regulates the expression of cuproptosis-associated positive or negative regulatory factors and mitigates copper toxicity by inhibiting the influx of copper ions into the cell, thereby inhibiting cuproptosis. This study not only reveals the relationship between ICH and cuproptosis but also may provide new therapeutic strategies for improving the prognosis of patients with ICH.
研究领域:
神经科学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
Toxins
·
2021
·Vol. 13
·期 11
·802
·
IF 4.546
Qian-Wen Zheng,Xu-Fen Ding,Hui-Jun Cao,Qian-Zhi Ni,Bing Zhu,Ning Ma,Feng-Kun Zhang,Yi-Kang Wang,Sheng Xu,Tian-Wei Chen,Ji Xia,Xiao-Song Qiu,Dian-Zhen Yu,Dong Xie,Jing-Jing Li
Ochratoxin A(OTA) is considered to be one of the most important contaminants of food and feed worldwide. The liver is one of key target organs for OTA to exert its toxic effects. Due to current lifestyle and diet, nonalcoholic fatty liver disease (NAFLD) has been the most common liver disease. To examine the potential effect of OTA on hepatic lipid metabolism and NAFLD, C57BL/6 male mice received 1 mg/kg OTA by gavage daily. Compared with controls, OTA increased lipid deposition and TG accumulation in mouse livers. In vitro OTA treatment also promoted lipid droplets accumulation in primary hepatocytes and HepG2 cells. Mechanistically, OTA prevented PPARγ degradation by reducing the interaction between PPARγ and its E3 ligase SIAH2, which led to activation of PPARγ signaling pathway. Furthermore, downregulation or inhibition of CD36, a known of PPARγ, alleviated OTA-induced lipid droplets deposition and TG accumulation. Therefore, OTA induces hepatic steatosis via PPARγ-CD36 axis, suggesting that OTA has an impact on liver lipid metabolism and may contribute to the development of metabolic diseases.Keywords:fatty liver disease;lipid metabolism;OTA;PPARKey Contribution:The in vitro and in vivo study reveal that OTA induces hepatic steatosis via PPARγ-CD36 axis. OTA prevents PPARγ from ubiquitination-mediated degradation by reducing the expression of the E3 ligase SIAH2 and SIAH2-PPARγ interaction.
研究领域:
毒理学
·
肝病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2020
·
IF 6.793
Jiapeng Jie,Ling Ling,Yuguo Yi,Liang Tao,Xin Liao,Pingshi Gao,Qian Xu,Weigao Zhang,Yuxin Chen,Jianfa Zhang,Dan Weng
Tributyltin (TBT), a bioaccumulative and persistent environmental pollutant, has been proposed as a metabolism disruptor and obesogen through targeting peroxisome proliferator-activated receptor gamma (PPARγ) receptor pathway. However, it remains unknown whether this biological effect occurs in macrophage, a cell type which cooperates closely with hepatocytes and adipocytes to regulate lipid metabolism . This study for the first time investigated the effect of TBT on PPARγ pathway in macrophages. Our results indicated that nanomolar levels of TBT was able to strongly activate PPARγ in human macrophages. TBT treatment also markedly increased the intracellular lipid accumulation, and enhanced the expression of lipid metabolism-related genes in macrophages, while these effects were all significantly down-regulated in PPARγ-deficient macrophages, confirming the involvement of PPARγ in TBT-induced lipogenesis. Next, a mouse model that C57BL/6 mice were orally exposed to TBT with the doses (250 and 500 μg/kg body weight) lower than NOAEL (no observed adverse effect level) was used to further investigate the in vivo mechanisms. And the in vivo results were consistent with cellular assays, confirming the induction of PPARγ and the increased expression of lipogenesis-regulating and lipid metabolism-related genes by TBT in vivo. In conclusion, this study not only provided the first evidence that TBT stimulated lipogenesis, activated PPARγ and related genes in human macrophages, but also provided insight into the mechanism of TBT-induced metabolism disturbance and obesity through targeting PPARγ via both in vitro cellular assays and in vivo animal models.
研究领域:
毒理学
·
分子生物学
·
细胞生物学
·
环境科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2024
·
IF 4.8
Junfeng Li,Min Guo,Cuiping Yuan,Tiezhu Li,Jie Zhang,Li Ren
ABSTRACT Peroxisome proliferator-activated receptor γ (PPARγ) was a major transcription factor and performed an essential function in the regulation of lipid metabolism. Ellagic acid (EA) was a natural phytochemical extracted from berries and pomegranates, and research had demonstrated its ameliorative effects on lipid metabolism disorders. We intended to explore the interventional effect and mechanism of action of EA on hyperlipidemia. In vitro experiments revealed that EA could reduce lipid accumulation in HepG2 cells. EA was found to bind stably to PPARγ, suppressing its nuclear translocation as well as its luciferase activity. It could also down-regulate the expression of genes and proteins related to lipid metabolism upstream and downstream of PPARγ. To explore the impact of EA on hyperlipidemia in vivo from different levels and perspectives, we established hyperlipidemia mice and hyperlipidemia zebrafish models. Consistent with the in vitro results, in vivo experiments revealed that EA attenuated lipid accumulation in hyperlipidemia mice and reduced the levels of related inflammatory factors in their serum. EA also inhibited lipid accumulation by decreasing the expression of upstream and downstream lipid-associated genes of pparg in hyperlipidemia zebrafish. In conclusion, EA could effectively improve hyperlipidemia by regulating PPARγ.
研究领域:
药理学
·
分子生物学
·
营养学
✓ 已验证
产品关联
DOI
高影响因子
Journal of Orthopaedic Surgery and Research
·
2023
·Vol. 18
·期 1
·1-15
·
IF 2.6
Xue Xiang,Dai Tianming,Chen Junyan,Xu Yangyang,Yang Zhenyu,Huang Jian,Xu Wuyan,Li Siming,Meng Qingqi
Background Osteoarthritis (OA) is a prevalent disease plaguing the elderly. Recently, chondrocyte ferroptosis has been demonstrated to promote the progression of OA. Peroxisome proliferator-activated receptor-γ (PPARγ) is an important factor in maintaining cartilage health. However, the relationship between PPARγ and chondrocyte ferroptosis in OA and its mechanism is completely unclear.Methods We established a surgically induced knee OA rat model to investigate PPARγ and chondrocyte ferroptosis in OA. Rat knee specimens were collected for Safranin O/Fast Green staining and immunohistochemical staining after administered orally placebo or pioglitazone (PPARγ agonist) for 4 weeks. We used RSL3 to establish a chondrocyte ferroptosis model cultured in vitro to study the role of PPARγ activation toward ferroptosis, mitochondrial function, and PTEN-induced putative kinase 1 (Pink1)/Parkin-dependent mitophagy. GW9662 (PPARγ antagonist), Mdivi-1 (mitophagy inhibitor), and chloroquine (mitophagy inhibitor) were employed to investigate the mechanism of PPARγ-Pink1/Parkin-dependent mitophagy in the inhibition of ferroptosis.Results We found that PPARγ activation by pioglitazone attenuated not only OA but also inhibited the expression of the ferroptosis marker acyl-CoA synthetase long-chain family member 4 (ACSL4) at the same time in rats. Furthermore, in vivo and in vitro data indicated that PPARγ activation restored Pink1/Parkin-dependent mitophagy, improved mitochondrial function, inhibited chondrocyte ferroptosis, and delayed the progression of OA.Conclusion sThe present study demonstrated that PPARγ activation attenuates OA by inhibiting chondrocyte ferroptosis, and this chondroprotective effect was achieved by promoting the Pink1/Parkin-dependent mitophagy pathway.
研究领域:
骨科
·
细胞生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Biology
·
2025
·
IF 2.6
Shuai Wang,Ting He,Tong Fu,Yu Zhu,Yixin Wei,Wenlong Xie,Huanming Shen,Ya Luo,Boan Li,Huiling Guo,Weihua Li
Brown adipose tissue (BAT) is crucial for maintaining whole-body metabolic homeostasis and combating obesity and metabolic disorders. SOX4 collaborates with EBF2 to promote the expression of thermogenic genes in BAT, but it is unclear whether there are mechanisms independent of this regulation. However, it is found that SOX4 can directly interact with the promoter regions of thermogenic genes, thereby activating their expression. Simultaneously, early B cell factor 2 (EBF2) and peroxisome proliferator-activated receptor-γ (PPARγ) can independently interact with SOX4, forming two distinct complexes that promote the expression of thermogenic genes. Phenotypically, the deletion of SOX4 in BAT of mice ( Ucp1 Cre+ -Sox4 f/f ( Sox4-BKO )) leads to the downregulation of thermogenic and oxidative phosphorylation genes, as well as a reduction in mitochondrial numbers. Furthermore, Sox4-BKO mice are more susceptible to obesity, glucose intolerance, and insulin resistance when subjected to a high-fat diet (HFD). Consistently, the loss of SOX4 results in increased cellular triglyceride content and reduced expression levels of thermogenic genes in vitro. Together, a novel mechanism by which SOX4 regulates thermogenesis in BAT is elucidated, offering a promising strategy to address obesity and metabolic disorders.
研究领域:
分子生物学
·
内分泌学
·
代谢学
·
脂肪生物学
·
转录调控
·
系统生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SHOCK
·
2023
·
IF 3.1
Zhang Dewen,He Jian,Ding Xian,Wang Rui,Chen Wei
Background We explored the efficacy and main biological mechanism of geniposide intervention in sepsis. Methods A sepsis model was established in male BALB/c mice through cecal ligation and puncture (CLP). Different doses of geniposide (20 or 40 mg/kg) were administered intravenously at 0 and/or 24 h after CLP surgery. The survival rate of different groups was observed. Additionally, the expression levels of CD16 and MHC-II in monocytes were assessed using flow cytometry. The concentration of TNF-α, IL-1β, IL-6, and IL-10 in the serum were measured by ELISA. We also observed the biological effects of geniposide on CD16 and MHC-II expression levels in RAW264.7 cells, as well as the secretion of TNF-α, IL-1β, IL-6, and IL-10, in the LPS-induced RAW264.7 cell model. The PPARγ levels were determined using western blot analysis. Results Intravenous administration of 40 mg/kg of geniposide at 0 h after CLP significantly improved the survival outcomes in the septic mouse model, with no significant benefits from low dosing (20 mg/kg) or delayed administration (24 h). The effective dose of geniposide significantly decreased the serum cytokine TNF-α, IL-1β, IL-6, and IL-10 concentrations in septic mice ( P < 0.05). Notably, in vitro assays showed that geniposide specifically increased the IL-10 level. Geniposide significantly reduced the CD16 expression ( P < 0.05) and increased MHC-II expression in monocytes ( P < 0.05). Additionally, geniposide elevated the PPARγ level in monocytes ( P < 0.05). Conclusions High-dose early-stage geniposide administration significantly improved the survival rate in a CLP mouse sepsis model by modulating the monocyte phenotype and regulating the cytokine network (IL-6/IL-10 levels). The pharmacological mechanism of geniposide action might be exerted primarily through PPARγ upregulation.
研究领域:
免疫学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Fangyuan Chen,Qingmei Liu,Lei Ma,Cuishi Yan,Haiman Zhang,Zhi Zhou,Wei Yi
Recent studies have identified selective peroxisome proliferator-activated receptor γ (PPARγ) modulators, which synergistically engage in the inhibition mechanism of PPARγ-Ser273 phosphorylation, as a promising approach for developing safer and more effective antidiabetic drugs. Herein, we present the design, synthesis, and evaluation of a new class of organo-Se compounds, namely, benzothiaselenazole-1-oxides (BTSAs), acting as potent, reversible, and selective PPARγ covalent modulators. Notably, 2n, especially (R)-2n, displayed a high binding affinity and superior antidiabetic effects with diminished side effects. This is mainly because it can reversibly form a unique covalent bond with the Cys285 residue in PPARγ-LBD. Further mechanistic investigations revealed that it manifested such desired pharmacological profiles primarily by effectively suppressing PPARγ-Ser273 phosphorylation, enhancing glucose metabolism, and selectively upregulating the expression of insulin-sensitive genes. Collectively, our results suggest that (R)-2n holds promise as a lead compound for treating T2DM and also provides an innovative reversible covalent warhead reference for future covalent drug design.
研究领域:
药理学
·
药物化学
·
糖尿病研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Inflammation Research
·
2025
·
IF 4.1
Meng-Ke Song,Meng-Qi Wang,Yu-Qing Ruan,Can Cui,Wen-Gang Chen,Opeyemi Joshua Olatunji,Yan Li,Jian Zuo
Introduction: Qing-Luo-Yin (QLY) is an anti-rheumatic herbal formula potentially activating PPARγ. The study investigated if and how this property contributes to its anti-angiogenesis effects.Methods: Adjuvant-induced arthritis (AIA) rats were orally treated by QLY or rosiglitazone (a PPARγ agonist), and their monocytes and lymphocytes were co-cultured reciprocally in vitro with different sera. Healthy littermates received blood transfusion from QLY-treated or AIA model rats. Two days ahead of sacrifice, a matrigel plug was implanted in the recipients. AIA serum-incubated THP-1 monocytes and Jurkat T cells were treated by a mixture comprised sinomenine, berberine and palmatine. Jurkat T cells-related media and T0070907 were used to stimulate human umbilical vein endothelial cells (HUVECs).Results: QLY and rosiglitazone similarly alleviated joint injuries, synovial angiogenesis and metabolic disorders in AIA rats. Although QLY impaired inflammatory phenotype of AIA rat monocytes in vivo, it cannot be achieved or sustained in vitro. Lymphocytes of QLY-treated AIA rats had a weak inflammatory phenotype and failed to induce inflammatory polarization of monocytes. AIA blood-induced angiogenesis in the matrigel plug, a phenomenon invisible in QLY group. QLY therapy inhibited pathogenic functions of AIA rats’ lymphocytes, shown by changes of cytokines network in the recipients’ joints, where these cells accumulated. The related compounds affected secretion of Jurkat T cells cultured in AIA serum, which lost the potential in activating HUVECs. This effect disappeared in presence of T0070907, a PPARγ inhibitor.Conclusion: Angiogenesis amelioration during QLY therapy is an indirect result from PPARγ activation-caused functional changes of T cells.
研究领域:
药理学
·
免疫学
·
风湿病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CHROMATOGRAPHY A
·
2024
·
IF 3.8
Zilong Zhang,Jiahuan Chen,Lixiang Chen,Kaihua Long,Lejing Qu,Silin Huang,Xinyi Yuan,Xu Ji,Qian Li,Xinfeng Zhao
Functional protein immobilization forms the basis for bio-detections. A series of one-point, site-specific immobilization methods have been developed, however, it still remains as a challenge how to avoid the proteins to move in all directions as well as conveniently regenerate the bio-devices. Herein, we have developed a bivalent affinity binding-inspired method for PPARγ immobilization using DNA aptamer and nickel-nitrilotriacetic acid (Ni 2+ -NTA) chelation. The specific DNA aptamer ( Apt 2 ) was selected by an on-column systematic evolution of ligands by exponential enrichment (SELEX) method with affinity of (1.57 ± 0.15) × 10 5 M −1 , determined by isothermal titration calorimetry (ITC). Apt 2 and nickel-nitrilotriacetic acid (Ni 2+ -NTA) were modified on macroporous silica gels via L-α-allylglycine as a linker. They respectively interacted with PPARγ and 6×His tag via bivalent affinity binding for the receptor immobilization. After comprehensive surface characterization, PPARγ was proved to be successful immobilized. Chromatographic studies revealed that the immobilized PPARγ has conformation selectivity, which discriminated agonist and antagonist of the receptor. Ligand-binding parameters (affinity and rate constant) of four agonists (rosiglitazone, pioglitazone, troglitazone, and magnolol) with PPARγ were determined. Troglitazone showed the lowest dissociation rate constant. The binding affinities (3.28 × 10 7 , 1.91 × 10 6 , 2.25 × 10 7 , and 2.43 × 10 7 M −1 ) were highly consistent with the data obtained using purified receptor in solution (2.16 × 10 7 , 4.52 × 10 6 , 1.20 × 10 7 , and 1.56 × 10 7 M −1 ), offering reliable bio-detection method for PPARγ and its ligands. Due to the biocompatibility of nuclear receptor with DNA, it is conceivable that the bivalent affinity-based method will be a general method for the immobilization of other nuclear receptors, which may provide selective conformation and improved ligand-binding activity for the receptors.
研究领域:
生物化学
·
分子生物学
·
生物技术
·
分析化学
✓ 已验证
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2025
·
IF 7.3
Qiuhui Qian,Ji Wu,Cuizhen Wang,Zheng Yang,Ying Cheng,Yuansi Zheng,Xuedong Wang,Huili Wang
As a synthetic rubber antioxidant, the environmental monitoring concentrations of N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine (6-PPD) have exceeded the risk threshold, attracting widespread attention. Although investigations into the harmful effects on zebrafish have commenced, a comprehensive exploration of its toxicological impacts and underlying molecular mechanisms remains to be conducted. By using zebrafish as a model, this study systematically evaluated 6-PPD-induced lipid metabolism disorders and inflammation response following environmental exposure. Bioinformatics analysis revealed that 6-PPD target genes enriched in the hepatitis B pathway, indicating potential hepatic toxicity via inflammatory pathways. Therefore, we hypothesize that 6-PPD could trigger hepatotoxicity through the crosstalk between lipid metabolism and inflammation. Further experiments substantiated this hypothesis by showing lipid accumulation in the liver following 6-PPD exposure, along with elevated triglyceride (TG) and total cholesterol (TC) levels, and imbalanced expression of lipid metabolism-related marker genes. Additionally, 6-PPD exposure induced the accumulation of reactive oxygen species (ROS) and inhibited the differentiation and maturation of immune cells, resulting in immune evasion. Most of these abnormalities were exacerbated in a dose-dependent manner with increasing concentrations of 6-PPD. The addition of the PPARγ pathway agonist puerarin (PUE) or NF-κB pathway inhibitor quinazoline (QNZ) to 6-PPD exposure group mitigated these toxic effects, validating our conjecture that lipid metabolism disorder and inflammatory responses may result from the regulation of the PPARγ/NF-κB pathway.
研究领域:
环境毒理学
·
分子生物学
·
发育生物学
·
免疫学
✓ 已验证
DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2024
·
IF 3.8
Peiyu Xue,Xinyong You,Li Ren,Weiming Yue,Zheng Ma
Kaempferol can exert biological functions by regulating various signaling pathways. This study evaluated the ameliorative effect of kaempferol on lipid accumulation using oleic acid and palmitic acid-treated HepG2 cells and high-fat diet mice. In vitro oil red O staining showed that kaempferol treatment improved lipid accumulation ( p < 0.001 for TG content and p < 0.05 for TC content). Immunofluorescence, Western blot analysis and RT-qPCR showed that kaempferol could promote nuclear translocation of PPARγ and reduce the expression of PPARγ, C/EBPβ, and SREBP-1c. Dietary intervention with kaempferol could reduce the lipid accumulation in hepatocytes and inflammatory cell infiltration, as well as attenuated serum levels of IL-6 and TNF-α in HFD-fed mice ( p < 0.001 for IL-6 and p < 0.01 for TNF-α at kaempferol 60 mg/kg/d). Meanwhile, histopathological examination revealed that there was no substantial damage or distinct inflammation lesions in organs at the experimental dose, including the heart, lung, kidney, and spleen. The aforementioned research findings can serve as references for further preclinical investigations on the potential of kaempferol to mitigate lipid accumulation.
研究领域:
药理学
·
分子生物学
·
营养学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）