BIOORGANIC CHEMISTRY
·
2021
·
IF 5.275
Juan Sun,Han-Yu Liu,Yi-Heng Zhang,Ze-Yu Fang,Peng-Cheng Lv
Thiazolidinedione (TZD) is a novel peroxides proliferator activated receptor γ (PPAR γ ) agonist with many side effects. Herein, we developed a series of novel TZD analogues as partial agonists targeting PPAR γ . The study of anti-hyperglycemic activity and anti-inflammatory activity enabled us to identify a novel compound, 4 g , which quickly recover the blood glucose of mice at the concentration of 100 mg/kg, and show similar anti-inflammatory activity to ibuprofen at the concentration of 20 mg/kg. The competitive binding assay confirmed direct binding of 4 g to the LBD of PPAR γ with IC 50 being 1790 nM, and dose-dependently increased the transcriptional activity of PPAR γ . Besides, through computer-aided drug design software simulation docking, it was found that compound 4 g showed the best binding ability to target protein PPAR γ . Furthermore, because of the introduction of benzene containing group at N3 position, the stability of H12 in the active pocket is reduced and the stability of H3 and β -fold is increased, showing the characteristics of some PPAR γ agonists, based on the docking model analysis. Together, these results suggest that 4 g is a promising PPAR γ agonist that deserves further investigation.
研究领域:
药理学
·
药物化学
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DOI
PubMed
高影响因子
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
·
2022
·Vol. 63
·期 3
·29-29
·
IF 4.925
Peng Zhang,Lei Tian,Jiayu Bao,Shang Li,Ao Li,Ya Wen,Jingyi Wang,Ying Jie
Purpose:To investigate the effects of isotretinoin on the ocular surface and to explore the possible mechanisms.Methods:Rats were treated with isotretinoin 20 mg/kg/d for five months and tested monthly for tear secretion, fluorescein staining, and infrared photography. After five months of treatment, tissues were harvested for routine staining to evaluate the morphological changes; and real-time polymerase chain reaction, Western blot, and immunohistochemistry to study the expression of associated genes and their products such as forkhead box protein O1 (FoxO1), forkhead box protein O3, peroxisome proliferator–activated receptor γ (PPARγ), adipose differentiation–related protein, elongation of very long chain fatty acids protein 4, fatty acid binding protein 4, matrix metalloproteinase-9, and interleukin-6.Results:Systemically, isotretinoin-treated rats have a significantly lower body weight that controls and apparent skin damage. Locally, although there was no alteration in tear secretion, a significant corneal involvement indicated by increased fluorescein staining scores, and also the contrast of meibomian gland was significantly reduced but no significant atrophy of the acinus was found. In addition, isotretinoin causes a decrease in conjunctival goblet cells. Furthermore, isotretinoin treatment did not cause the upregulation ofFoxO1and inflammation related genes but significantly suppressed the expression ofPPARγpathway.Conclusions:Isotretinoin does not cause a significant atrophy of the acinus and a significant change ofFoxO1expression in the meibomian gland. Isotretinoin causes meibomian gland dysfunction, affecting meibocyte differentiation and qualitative and quantitative changes in the meibum, throughPPARγpathway.
研究领域:
眼科
·
药理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2025
·
IF 4.7
Hongyan Lin,Shuaijun Cui,Xinye Xu,Qingqing Chen,Jiazi Ge,Dongxuan Ai,Jie Zhu,Yuheng Tao,Liqun Wang,Lingyu Ruan,Wenhao Ge
18β-Glycyrrhetinic acid (18β-GA) is the main active component of licorice and one of the most promising lead compounds in traditional Chinese herbal medicine. Previous studies have shown that 18β-GA can act as a PPARγ agonist to exert antitumor activity. However, the number of reported 18β-GA derivatives as PPARγ agonists is limited and they have significant toxic side effects, which greatly restricts their application and development. To obtain highly effective and low-toxic PPARγ agonists, through structure-activity relationship (SAR) analysis, we constructed a molecular library of 18β-GA derivatives containing 13,440 compounds and screened out 14 novel 18β-GA ester derivatives. The selected compounds were evaluated for their antitumor activity in vitro. The results showed that most of the compounds exhibited strong anti-proliferative activity against five human cancer cell lines, especially the human colon cancer cell line HT-29, without significant toxicity to normal cell lines. Among them, C1 had the strongest anti-proliferative activity against HT-29, with an IC 50 value of 12.25 μM, which was 12 times higher than that of its parent nucleus 18β-GA. C1 can block the cell cycle of HT-29 cells in G2/M phase, significantly inhibit their migration and induce their apoptosis. Molecular docking and dynamics simulation results suggested that C1 could stably bind to the active pocket of PPARγ. Further PPARγ activity analysis and drug-likeness prediction results indicated that C1 could act as a PPARγ agonist to exert antitumor effects and had certain drug-likeness, which is worthy of further study.
研究领域:
药理学
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药物化学
·
肿瘤学
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DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR LIFE SCIENCES
·
2022
·Vol. 79
·期 7
·1-22
·
IF 9.207
Song Chang-Chun,Pantopoulos Kostas,Chen Guang-Hui,Zhong Chong-Chao,Zhao Tao,Zhang Dian-Guang,Luo Zhi
Iron is an essential micro-element, involved in multiple biological activities in vertebrates. Excess iron accumulation has been identified as an important mediator of lipid deposition. However, the underlying mechanisms remain unknown. In the present study, we found that a high-iron diet significantly increased intestinal iron content and upregulated the mRNA expression of two iron transporters ( zip14 and fpn 1). Intestinal iron overload increased lipogenesis, reduced lipolysis and promoted oxidative stress and mitochondrial dysfunction. Iron-induced lipid accumulation was mediated by hypoxia-inducible factor-1 α (HIF1α), which was induced in response to mitochondrial oxidative stress following inhibition of prolyl hydroxylase 2 (PHD2). Mechanistically, iron promoted lipid deposition by enhancing the DNA binding capacity of HIF1α to the pparγ and fas promoters. Our results provide experimental evidence that oxidative stress, mitochondrial dysfunction and the HIF1α-PPARγ pathway are critical mediators of iron-induced lipid deposition.
研究领域:
营养学
·
生物化学
·
分子生物学
·
细胞生理学
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产品关联
DOI
PubMed
高影响因子
ACTA BIOCHIMICA ET BIOPHYSICA SINICA
·
2024
·
IF 3.3
Yanyan Heng,Wei Wei,Linzhong Cheng,Feifei Wu,Haoyu Dong,Jingxia Li,Jianing Fu,Bingjie Yang,Xinyue Liang,Chunyan Liu,Haiju Li,Haihua Liu,Pengfei Zhang
Diabetes accelerates vascular senescence, which is the basis for atherosclerosis and stiffness. The activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and oxidative stress are closely associated with progressive senescence in vascular smooth muscle cells (VSMCs). The vascular protective effect of FGF21 has gradually gained increasing attention, but its role in diabetes-induced vascular senescence needs further investigation. In this study, diabetic mice and primary VSMCs are transfected with an FGF21 activation plasmid and treated with a peroxisome proliferator-activated receptor γ (PPARγ) agonist (rosiglitazone), an NLRP3 inhibitor (MCC950), and a spleen tyrosine kinase (SYK)-specific inhibitor, R406, to detect senescence-associated markers. We find that FGF21 overexpression significantly restores the level of catalase (CAT), vascular relaxation, inhibits the intensity of ROSgreen fluorescence and p21 immunofluorescence, and reduces the area of SA-β-gal staining and collagen deposition in the aortas of diabetic mice. FGF21 overexpression restores CAT, inhibits the expression of p21, and limits the area of SA-β-gal staining in VSMCs under high glucose conditions. Mechanistically, FGF21 inhibits SYK phosphorylation, the production of the NLRP3 dimer, the expression of NLRP3, and the colocalization of NLRP3 with PYCARD (ASC), as well as NLRP3 with caspase-1, to reverse the cleavage of PPARγ, preserve CAT levels, suppress ROSgreen density, and reduce the expression of p21 in VSMCs under high glucose conditions. Our results suggest that FGF21 alleviates vascular senescence by regulating the SYK-NLRP3 inflammasome-PPARγ-catalase pathway in diabetic mice.
研究领域:
内分泌学
·
心血管生物学
·
分子生物学
·
药理学
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产品关联
DOI
PubMed
高影响因子
Theranostics
·
2021
·
IF 11.556
Yumeng Miao,Yun Zheng,Yanzhi Geng,Ling Yang,Na Cao,Yue Dai,Zhifeng Wei
Background: Peroxisome proliferator-activated receptor gamma (PPARγ) has the ability to counter Th17 responses, but the full mechanisms remain elusive. Herein, we aimed to elucidate this process in view of cellular metabolism, especially glutaminolysis. Methods: MTT, CCK-8, Annexin V-FITC/PI staining or trypan blue exclusion assays were used to analyze cytotoxicity. Flow cytometry and Q-PCR assays were applied to determine Th17 responses. The detection of metabolite levels using commercial kits and rate-limiting enzyme expression using western blotting assays was performed to illustrate the metabolic activity. ChIP assays were used to examine H3K4me3 modifications. Mouse models of dextran sulfate sodium (DSS)-induced colitis and house dust mite (HDM)/lipopolysaccharide (LPS)-induced asthma were established to confirm the mechanisms studied in vitro . Results: The PPARγ agonists rosiglitazone and pioglitazone blocked glutaminolysis but not glycolysis under Th17-skewing conditions, as indicated by the detection of intracellular lactate and α-KG and the fluorescence ratios of BCECF-AM. The PPARγ agonists prevented the utilization of glutamine and thus directly limited Th17 responses even when Foxp3 was deficient. The mechanisms were ascribed to restricted conversion of glutamine to glutamate by reducing the expression of the rate-limiting enzyme GLS1, which was confirmed by GLS1 overexpression. Replenishment of α-KG and 2-HG but not succinate weakened the effects of PPARγ agonists, and α-KG-promoted Th17 responses were dampened by siIDH1/2. Inhibition of KDM5 but not KDM4/6 restrained the inhibitory effect of PPARγ agonists on IL-17A expression, and the H3K4me3 level in the promoter and CNS2 region of the il-17 gene locus down-regulated by PPARγ agonists was rescued by 2-HG and GLS1 overexpression. However, the limitation of PPARγ agonists on the mRNA expression of RORγt was unable to be stopped by 2-HG but was attributed to GSH/ROS signals subsequent to GLS1. The exact role of PPARγ was proved by GW9662 or PPARγ knockout, and the mechanisms for PPARγ-inhibited Th17 responses were further confirmed by GLS1 overexpression in vivo . Conclusion: PPARγ agonists repressed Th17 responses by counteracting GLS1-mediated glutaminolysis/2-HG/H3K4me3 and GSH/ROS signals, which is beneficial for Th17 cell-related immune dysregulation.
研究领域:
免疫学
·
细胞代谢
·
药理学
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产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2022
·
IF 5.223
Suwen Liu,Zhang Lu,Chang Liu,Xuedong Chang,Buhailiqiemu Apudureheman,Shiguo Chen,Xingqian Ye
Castanea mollissima shells are a by-product of Chinese chestnut processing and contain many polyphenols. Macrophage polarization plays an important role in the progression of atherosclerosis (AS). We investigated the action of Castanea mollissima shell polyphenols (CSPs), with proanthocyanidin C1 and proanthocyanidin B1 as the main phenolic components, on macrophages. CSPs (40 μg/mL) significantly decreased inflammatory cytokines secretion in M1-type macrophages (p < 0.01). The addition of AG490, a JAK2 inhibitor, enhanced the regulatory effect of CSPs. CSPs also significantly upregulated the protein expressions of PPARγ, LXRα, and ABCA1/G1 (p < 0.01); however, this effect was inhibited by adding the PPARγ blocker GW9662. Therefore, CSPs possibly inhibit M1 type macrophage polarization to reduce inflammation by inhibiting the JAK2/STAT3 signaling pathway; however, it is not dependent on this. Furthermore, the activation of the PPARγ-LXRα-ABCA1/G1 pathway increases cholesterol efflux. Our study suggests that CSPs may act as functional food agents in the prevention of and adjuvant therapy for atherosclerosis.
研究领域:
药理学
·
免疫学
·
分子生物学
·
心血管疾病
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产品关联
DOI
高影响因子
JOURNAL OF FOOD BIOCHEMISTRY
·
2021
·Vol. 45
·期 4
·e13668
·
IF 2.72
Jing-Yu Duan,Yong-Jian Wang,Wei Chen,Yang-Qi Zhao,Zhong-Hui Bai,Liang-Liang He,Chun-Ping Zhang
The fruits of Swietenia macrophylla King have been processed commercially to a variety of health foods and healthcare products and exhibited antidiabetic, anti-inflammatory, antimutagenicity, antitumor activity, and so on. This study was aimed to examine the glucose consumption in human hepatoma HepG2 cells and the expression of PPARγ of limonoids isolated from the fruits of S . macrophylla . The phytochemical investigation of the fruits led to the isolation of ten limonoids which structures were elucidated by spectroscopic analysis as swietenine ( 1 ), khayasin T ( 2 ), 6-deoxyswietenine ( 3 ), 3- O -tigloylswietenolide ( 4 ), swietenolide ( 5 ), 3,6- O,O -diacetylswietenolide ( 6 ), 7-deacetoxy-7-oxogedunin ( 7 ), fissinolide ( 8 ), proceranolide ( 9 ), 7-deacetoxy-7α-hydroxygedunin ( 10 ), and compound 10 was isolated from this plant for the first time. The glucose consumption assay revealed that compounds 1 , 2 , 3 , 5, and 9 could promote glucose consumption significantly in normal hyperglycemia-induced HepG2 cells, furthermore, compounds 1 , 5, and 9 had a better effect on promoting glucose consumption in insulin-resistant HepG2 cells. In addition, compounds 1 and 5 could dramatically enhance the expression of PPARγ protein in insulin-resistant HepG2 cells according to the western blotting analysis result. Practical applications Swietenia macrophylla King belongs to the family Meliaceae and the fruits have been exhibited a wide range of biological activities, such as antidiabetic, anti-inflammatory, antimutagenicity, antitumor activity, and so on. Phytochemical investigations of S . macrophylla have revealed that limonoids and triterpenoids were effective antidiabetic agents. However, the mechanism of these limonoids to antidiabetic activity is unclear. In this study, limonoids were isolated from the fruit of S . macrophylla and their effects on the glucose consumption of insulin-resistant HepG2 cells were studied. The results showed that compounds 1 and 5 could dramatically enhance the expression of PPARγ protein in insulin-resistant HepG2 cells, which will give aid to explore the mechanism of these limonoids in the treatment of type 2 diabetes. Therefore, this research might facilitate further research and development of S . macrophylla .
研究领域:
药理学
·
生物化学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY
·
2020
·Vol. 85
·期 4
·786-797
·
IF 1.516
Wang Yuanyuan,Guo Shanqi,Jia Yingjie,Yu Xiaoyu,Mou Ruiyu,Li Xiaojiang
Prostate cancer (PCa) is one of the important factors of cancer deaths especially in the western countries. Hispidulin (4′,5,7-trihydroxy-6-methoxyflavone) is a phenolic flavonoid compound proved to possess anticancer properties, but its effects on PCa are left to be released. The aims of this study were to investigate the effects and the relative mechanisms of Hispidulin on PCa development. Hispidulin administration inhibited proliferation, invasion, and migration, while accelerated apoptosis in Du145 and VCaP cells, which was accompanied by PPARγ activation and autophagy enhancement. The beneficial effects of Hispidulin could be diminished by PPARγ inhibition. Besides, Hispidulin administration suppressed PCa tumorigenicity in Xenograft models, indicating the anticancer properties in vivo. Therefore, our work revealed that the anticancer properties of Hispidulin might be conferred by its activation on PPARγ and autophagy.
研究领域:
肿瘤学
·
药理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NEUROSCIENCE RESEARCH
·
2025
·Vol. 103
·期 7
·e70064
·
IF 3.4
Sun Hong,Liu GuoYan,Wu JiaWen,Yu Xin,Zhan ShuQin,Reng HongWei,Chen MengYing,Cheng YuXuan
Chronic epilepsy is mainly characterized by spontaneous recurrent seizures (SRS). The peroxisome proliferator activated receptor gamma/phosphatase and tensin homolog/protein kinase B (PPARγ/PTEN/Akt) pathway is involved in the pathogenesis of SRS and neuronal loss. Curcumin is a natural compound, and previous studies have shown it provides neuroprotection via anti-inflammation and anti-oxidant effects in many central nervous system (CNS) diseases. In the present study, we show that curcumin regulates the abnormal expression of PTEN and Akt in the SRS phase, improves the neuronal loss in the hippocampus, and suppresses SRS development and seizure spike activity in epileptic rats. More importantly, these effects are reversed by the PPARγ antagonist, T0070907, suggesting that curcumin exerts neuroprotective and anti-epileptic effects through the PPARγ/PTEN/Akt signaling pathway. Other studies have shown that curcumin can cross the BBB and has a safety profiles and pleiotropic pharmacological effects. Thus, our data support the proposition that curcumin might be a potential neuroprotective and anti-epileptic agent for chronic epilepsy.
研究领域:
神经病学
·
分子生物学
·
药理学
·
转化医学
·
中枢神经系统疾病
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2022
·
IF 9.988
Jiabin Hong,Mengzhu Jiang,Lihao Guo,Juntong Lin,Yao Wang,Huanwen Tang,Xiaoshan Liu
The health risks of triphenyl phosphate (TPhP) have increased since its widespread application. Using placental trophoblast cell line JEG-3, we demonstrated that TPhP could induce endoplasmic reticulum stress (ERS) and cell apoptosis through PPARγ-mediated lipid metabolism . However, the developmental toxicity of TPhP through the placenta is not known. In this study, prenatal TPhP exposure to mice was investigated. Pregnant mice were orally exposed to TPhP (1 and 5 mg/kg) from embryonic day 0 (E0) until delivery. The results showed that TPhP could accumulate in placenta and impair pregnancy outcomes. After exposure, at E18, placental hormone chorionic gonadotrophin and testosterone levels were significantly decreased, but progesterone and estradiol levels were significantly increased, and placental angiogenesis was activated in the low-dose exposure group. While, in the high-dose exposure group, only estradiol levels were significantly increased. Different with the effect on hormone level or angiogenesis, TPhP significantly increased PPARγ and its regulated lipid transport proteins FABP, FATP, and CD36, and induced lipid accumulation in placental trophoblasts of both low- and high-exposure group. RNA-seq analysis of the placenta identified differentially expressed genes that were mainly involved in the ERS and MAPK signaling pathways. Western blot analysis verified that the protein levels related to ERS stress and apoptosis were significantly increased. To further confirm the role of PPARγ in TPhP mediated placental toxicity, pregnant mice were orally exposed to TPhP (1 mg/kg) or TPhP (1 mg/kg) + GW9662 (PPARγ inhibitor, 2 mg/kg) from E0 until delivery. The results showed that GW9662 could ameliorate the effect of TPhP on placental lipid accumulation, ERS and cell apoptosis, suggesting that PPARγ mediated the placental toxicity of TPhP. Overall, our results indicated that prenatal TPhP exposure impaired pregnancy outcomes, at least partly through PPARγ regulated function of trophoblast.
研究领域:
毒理学
·
生殖生物学
·
分子生物学
·
内分泌学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2024
·
IF 10.8
Qian Liu,Xiaoxun Lu,Ganzhong Liao,Fuhui Yan,Miaoliang Wu,Zhi Bai,Huanwen Tang,Xiaoshan Liu
Triphenyl phosphate (TPhP) is a widely used organophosphate flame retardant, the health risks of TPhP are a global concern. In this study, we found that prenatal TPhP exposure at human relevant concentration induced hyperlipidemia in male offspring, it increased serum levels of triglyceride, total cholesterol, and low-density lipoprotein cholesterol. Placental trophoblast-derived extracellular vesicles (T-EVs) could transport to the fetus through maternal-fetal circulation. TPhP significantly upregulated the protein level of peroxisome proliferator activated receptor γ (PPARγ) in T-EVs. Similar to TPhP, gestational exposure to T-EVs isolated from TPhP exposed mice placentae induced the same effects. While, gestational intervention with GW9662 (PPARγ inhibitor) or GW4869 (EVs secretion inhibitor) would alleviate the disturbed lipid metabolism induced by TPhP. Meanwhile, in vitro experiments verified that TPhP upregulated PPARγ in HTR8/SVneo cells derived EVs, and these EVs promoted adipogenesis in preadipocyte 3T3-L1 cells. Knock down of PPARγ in HTR8/SVneo could alleviate the adipogenensis effects of EVs derived from TPhP exposed HTR8/SVneo cells. These results demonstrate that TPhP exposure induces hyperlipidemia in male offspring by upregulating PPARγ in T-EVs. Our study provides new insights into the metabolic disruptive effects of TPhP, and emphasizes the mediating effects of placental T-EVs on gestational environmental stress in fetal development.
研究领域:
环境健康
·
发育生物学
·
代谢
·
毒理学
✓ 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）