RSC Medicinal Chemistry
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2026
·
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
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2026
·
IF 6.6
Fuhui Yan,Liwen Peng,Xiao Han,Xingxing Han,Miaoliang Wu,Zhi Bai,Xiaoshan Liu
Triphenyl phosphate (TPhP) is a commonly used organophosphorus flame retardant, and its potential health risks to mothers and infants are considerable. Our previous research revealed that gestational TPhP exposure significantly reduces the depth of placental implantation and impairs uterine spiral arteries remodelling, leading to preeclampsia (PE)-like symptoms, but the underlying mechanism remains unclear. In this study, we further demonstrate that TPhP activated the transcription of Phosphatase and tensin homolog (PTEN) by activating peroxisome proliferator activated receptor gamma (PPARγ). This activation subsequently inhibits the PI3K-AKT-mTOR signaling pathway, modulates autophagy homeostasis, and inhibits the migration and invasion of extravillous trophoblast (EVT) cells. Notably, knockdown of PTEN or PPARγ with shRNA, or inhibition of autophagy with chloroquine (CQ) alleviates the TPhP-induced inhibition of EVT cells migration or invasion. Furthermore, using an established murine intrauterine exposure model, we confirmed that TPhP activates PPARγ, increases PTEN expression in placental trophoblast, inhibits the PI3K-AKT-mTOR signaling pathway and disturbs autophagy homeostasis. Collectively, these findings elucidate that TPhP inhibits EVT cells migration and invasion via the PPARγ-PTEN-PI3K-AKT-mTOR mediated autophagy pathway, providing a new toxicity pathway in placental toxicology. Additionally, this study provides new insights into the etiological research of PE.
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ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2025
·
IF 11.3
Pu Chen,Ziyuan Li,Gan Miao,Xiaopeng Tang,Chengying Zhou,Li Zhao,Xiaoting Jin,Guangbo Qu,Yuxin Zheng,Guibin Jiang
Organophosphate esters (OPEs) have emerged as a significant environmental concern due to their widespread occurrence and potential human health risks. The presence of OPEs in human blood suggests direct interactions with hematological components, which may compromise hemostatic balance and lead to adverse health outcomes. Despite the critical role of hemostatic balance in maintaining blood stability, the effects of OPEs on this system remain poorly understood. This investigation was undertaken to delineate the effects and potential mechanisms of OPEs that modulate hemostasis, utilizing in silico approach and high-throughput in vitro investigation. We analyzed 85 environmentally prevalent OPEs for their structural descriptors and affinity for proteins essential to hemostatic function. The multiple linear regression implicated aryl-OPEs, distinguished by their benzene ring scaffold, as potent disruptors of hemostatic balance. This analysis result was rigorously validated through the in vitro hemostatic balance assays. Further investigation through network toxicology, artificial intelligence (α-Fold) algorithms, and an agonist cotreatment assay revealed proliferator-activated receptor γ (PPARγ) as a key mediator of aryl-OPEs induced hemostatic disruption. By integrating in vitro experimental insights with in vivo exposure data, we concluded that specific aryl-OPEs, such as bisphenol a bis (diphenyl phosphate) (BDP) and cresyl diphenyl phosphate (CDP), pose a moderate risk to the hemostatic balance of the general population. Our findings not only contribute to the prioritization of OPEs risk management but also establish a methodology for assessing the hematological toxicity of emerging pollutants.
研究领域:
环境科学
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毒理学
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生物信息学
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
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IF 6.1
Xuan Liu,Xijuan Ren,Zhonghua Fan,Penghui Mao,Mingqing Qian,Tingting Qian,Ying Yang,Hui Liu,Li Wang
Triphenyltin (TPT), a widely utilized organotin compound, serves marine, agricultural, and industrial applications. TPT is commonly found in estuaries and coastal regions. However, recent studies on environmental pollution have identified TPT as a pollutant due to its pronounced pollutant characteristics and potential implications for human health. Research from the past has demonstrated that TPT can cause issues with lipid metabolism. However, the specific metabolites affected and the involvement of the PPAR pathway remain unknown. Herein, male Sprague-Dawley (SD) rats received oral administration of TPT at daily doses of 0.5, 1, and 2 mg/kg for a period of 28 days. To investigate the abnormal metabolism in TPT-exposed rats, liver samples were analyzed using LC-MS/MS non-targeted metabolomics. Validated in vitro experiments were also performed using BRL-3A cells. This study suggests that exposure to TPT causes liver injury, increases lipid accumulation, and alters PPARγ expression levels. The findings highlight the need for restrictions on its use and further investigation of its toxic effects on other organs and systems to better assess its potential impact on human health.
研究领域:
毒理学
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环境科学
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代谢组学
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分子生物学
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内分泌学
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MOLECULAR GENETICS AND GENOMICS
·
2025
·Vol. 300
·期 1
·1-16
·
IF 2.1
Tian Xinyuan,Bai Xiaoping,Han Yunqi,Ye Yu,Peng Meiling,Cui Hongwei,Li Kai
PPAR γ, as a widely present receptor in tissues, plays a key role in lipid metabolism, energy balance, inflammatory response, and cell differentiation. It plays an important role in the occurrence and development of various tumors, including prostate cancer, gastric cancer, lung cancer, etc., by regulating lipid metabolism. However, the specific mechanism by which it affects lung cancer growth is not yet clear. To investigate how PPAR γ affects lung cancer cell growth by altering ALDH1A3 levels through its impact on lipid metabolism. Bioinformatics analysis was used to predict the correlation between PPAR γ, ALDH1A3 and lung cancer. Based on the results of bioinformatics analysis, PPAR γ activator (Pioglitazone, Pio) and ALDH1A3 inhibitor (diethylaminobenzaldehyde, DEAB) were used to act on lung cancer cells and observe their growth. After measuring the IC50 value of the drug in vitro experiments, lipid metabolomics analysis was conducted to identify the significant changes in differential metabolites and metabolic pathways under the combined influence of Pio and DEAB. Through bioinformatics analysis, it was found that there were significant differences in the levels of PPAR γ and ALDH1A3 between lung cancer and normal lung tissues, and ALDH1A3 was positively correlated with PPAR γ. AUC analysis found that PPAR γ and ALDH1A3 have good predictive value in the diagnosis and prognosis of lung cancer. GSEA enrichment analysis showed that PPAR γ and ALDH1A3 were significantly correlated with lipid oxidation. Combining relevant literature to demonstrate the inhibitory effect of PPAR γ receptors on lung cancer cells and the ability of PPAR γ activation to inhibit ALDH1A3 levels. Further in vitro CCK-8 and IC50 measurements of lung cancer cells A549 and H1299 were conducted, followed by non targeted lipidomics analysis. It was found that the metabolic pathways upregulated by activation of PPAR γ and inhibition of ALDH1A3 included glycerophospholipid metabolism, cholesterol metabolism, arachidonic acid metabolism, and fat digestion and absorption, with glycerophospholipid metabolism pathway accounting for the highest percentage. Conclusion: PPAR γ activation can inhibit the production of ALDH1A3, alter the glycerophospholipid metabolism pathway, and thus inhibit the proliferation of lung cancer cells. This study confirms that PPAR γ affects lung cancer proliferation by influencing the glycerophospholipid metabolism pathway.
研究领域:
肿瘤学
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分子生物学
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代谢学
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药理学
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BIOCHEMICAL PHARMACOLOGY
·
2026
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IF 6.5
Cheng Fu,Tianyi Hu,Xiangli Zhao,Yahui Huang,Jiang zhang,Lan Zhu,Jun Yang,Gang Chen
Rhein, an anthraquinone-derivative monomer isolated from the rhubarb plant, is the active ingredient of the drug Diacerein® (generic name: diacetylrhein), which possesses anti-inflammatory and antioxidant properties. It has been reported that rhein is effective in protecting against cerebral and retinal ischemia–reperfusion injury (IRI), but whether it can protect against renal IRI remains unknown. Here, a lethal renal IRI model was established with a 100 % mortality rate in untreated mice. Treatment with 100 mg/kg of rhein for 5 consecutive days before ischemia resulted in 100 % survival, maximal preservation of renal function, and a significant reduction in pathological damage, apoptosis and inflammation. In addition, rhein pretreatment significantly inhibited the upregulation of NLRP3, caspase-1, IL-1β and NGAL seen in the IRI control group. Through a series of experiments (including Co-Immunoprecipitation (Co-IP), pull-down, molecular dynamics simulation and surface plasmon resonance (SPR)), we confirmed that rhein has a strong binding affinity with PPARγ. By using the specific inhibitor T0070907 to block PPARγ, the protective effect of rhein on renal IRI in vivo and the protective effect on cell damage in the NLRP3 inflammasome activation model induced by (LPS + Nig) in vitro can be largely eliminated. We demonstrate here that rhein can potently protect against lethal renal IRI in mice. This protection is mainly achieved by targeting and enhancing the expression of PPARγ, thereby inhibiting the activation of the NLRP3 inflammasome. Thus, rhein may be therapeutically useful for the clinical prevention and treatment of renal IRI.
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BRITISH JOURNAL OF PHARMACOLOGY
·
2026
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IF 7.5
Chang Liu,Zhuoqun Wang,Linxin Zhang,Di Yang,Zhihong Zhang,Xiaoli Cui,Ali H. Eid,Mengyang Wang
Background and Purpose Fangchinoline (FAN), a bioactive bisbenzylisoquinoline alkaloid from Stephania tetrandra , shows protective potential against angiotensin II (Ang II)-induced hypertensive heart failure (HF), particularly involving mitophagy and ferroptosis, remain unclear. We investigated the effects of FAN on Ang II-induced cardiac remodelling and HF. Experimental Approach A hypertensive heart failure model was established in C57BL/6 mice via 4-week Ang II infusion. FAN was administered during the final 2 weeks. Cardiac function was assessed by echocardiography and pathological remodelling was evaluated by histological staining. RNA sequencing of cardiac tissue was performed to investigate the mechanism of anti-heart failure action of FAN. The potential binding proteins of FAN were verified by molecular docking, drug affinity response target stability (DARTS), cellular thermal shift assay (CETSA) and surface plasmon resonance assay (SPR). In vitro , neonatal rat ventricular myocytes (NRVMs) were used to investigate the effects of FAN on cellular hypertrophy, mitophagy and ferroptosis. Key Results In vivo , FAN treatment significantly ameliorated cardiac hypertrophy, dysfunction and fibrosis. These protective effects were independent of blood pressure-lowering actions. Mechanistically, FAN activates PGC-1α to enhance mitophagy and suppress STAT6-PPARγ signalling, thereby inhibiting ferroptosis and restoring redox homeostasis. In vitro , FAN reduced Ang II-induced NRVM hypertrophy, ROS production and mitochondrial membrane potential depolarisation, and confirmed the modulation of mitophagy and ferroptosis markers. Conclusions and Implications We demonstrate that FAN alleviates Ang II-induced HF through a mechanism involving the activation of PGC-1α-mediated mitophagy and regulation of the STAT6-PPARγ pathway, ultimately suppressing cardiomyocyte ferroptosis. These results offer new perspectives for HF treatment. Graphical FAN mitigates HF by engaging PGC-1α-mediated mitophagy and STAT6-PPARγ to counteract ferroptosis.
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ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2026
·
IF 12.2
Zhendong Yang,Tingyu Li,Wenyuan Su,Wangjing Zhai,Zhengzhe Wan,Yong Liang,Ting Ruan,Guibin Jiang
The activation of peroxisome proliferator-activated receptor γ (PPARγ) represents a primary biological mechanism underlying the adverse effects of environmental adipogens. However, a holistic understanding of the composition profiles of PPARγ agonists in complex environmental matrices remains elusive. In this study, an integrated workflow of knowledge-based suspect screening combined with in vitro bioassays enabled the comprehensive identification and prioritization of the main contributing components in indoor dust from Chinese residential areas. All mixed dust extracts activated PPARγ within the exposure concentration range (7.8 × 10–2–10 mg dust/mL assay medium). A total of 123 putative agonists covering 35 structural categories were found, among which 30 chemicals were verified as specific PPARγ agonists through reference standards and in vitro assays. These agonists could explain up to 84% of the effect in the mixed dust extracts, with phthalates (31% ± 19%), fatty acids (12% ± 9%), quaternary ammonium compounds (2% ± 1%), and hydrocarbon surfactants (2% ± 1%) being the major contributors. The concentration addition model was validated to effectively characterize the combined effects of these PPARγ agonists via the artificial mixture experiments. These results suggest that the workflow holds promise for the overall perception of bioactive components related to toxicological end points in environmental samples.
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MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2018
·Vol. 447
·期 1
·137-149
·
IF 2.561
Wu Weiche,Wang Sisi,Xu Ziye,Wang Xinxia,Feng Jie,Shan Tizhong,Wang Yizhen
Betaine, a neutral zwitterionic compound, could regulate intramuscular fat (IMF) deposition and meat quality. However, the efficacy is controversial. Moreover, the regulatory mechanism of betaine on lipid metabolism in skeletal muscle cells remains unclear. Therefore, in this study, we examined the effects and regulatory mechanism of betaine on lipid accumulation in adipogenic-differentiated C2C12 cells. We found that adipogenic-induced C2C12 cells treated with 10 mM betaine for 24 and 48 h had more lipid accumulation than the control group. Real-time PCR and Western blot results revealed that betaine treatment did not alter the expression of lipolysis and lipid oxidation-related genes, but dramatically increased the expression of peroxisome proliferator-activated receptor γ (PPARγ) and its target genes such as fatty acid binding protein 4 (aP2), fatty acid synthase (FAS) and lipoprteinlipase (LPL). Furthermore, betaine combined with PPARγ inhibitor GW9662 treatment showed that betaine elevated C2C12 lipid accumulation through upregulation of PPARγ. Mechanistically, we found that betaine promoted PPARγ expression and lipid accumulation through inhibition of extracellular regulated protein kinases1/2 (ERK1/2) signalling pathway. These results demonstrate that betaine acts through ERK1/2-PPARγ signalling pathway to regulate lipid metabolism in adipogenic-differentiated skeletal muscle cells, which could provide some useful information for controlling muscle lipid accumulation by manipulating ERK1/2 and PPARγ signalling pathway.
研究领域:
生物化学
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细胞生物学
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分子生物学
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营养学
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CELL BIOLOGY AND TOXICOLOGY
·
2026
·
IF 5.7
Zhao Bingbing,Zhang Zhengwei,Li Xiaoxue,Dong Shiyun,Zhong Xin,Li Zhitao,Jin Ye,Bai Yun,Wei Can
Liver fibrosis represents a major unmet clinical challenge, and induction of hepatic stellate cell (HSCs) senescence has emerged as a promising therapeutic strategy to halt or reverse fibrotic progression. PPARγ is a key regulator of HSCs quiescence; however, the downstream molecular mechanisms mediating its pro-senescence effects remain poorly defined. Here, we demonstrate that PPARγ expression is markedly reduced in a CCl₄-induced mouse liver fibrosis model and that its restoration drives HSC inactivation and senescence. Through integrated bioinformatics analysis and functional validation in PPARγ-overexpressing HSC-T6 cells, we identified leukemia inhibitory factor receptor (LIFR) as a direct transcriptional target of PPARγ. Mechanistically, PPARγ upregulates LIFR to suppress STAT3 phosphorylation, thereby downregulating fibrosis markers CO Ⅰ and α-SMA, elevating P21 and γ-H2A.X, and reducing CCND1. Crucially, LIFR knockdown abolished all PPARγ-mediated effects, confirming its indispensable role in this axis. Furthermore, combined treatment with the STAT3 inhibitor WP1066 synergistically enhanced PPARγ-driven HSC senescence in a LIFR-dependent manner. These findings establish a PPARγ-LIFR-STAT3 signaling cascade as a critical regulator of HSCs fate, and suggest that pharmacological activation of this axis represents a tractable approach for fibrosis resolution.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Xi Zeng,Liefeng Zhang,Jiye He,Yurui Zhang,Hong Lu,Zhuohui Liu,Zhiwei Wang,Zhifeng Wei
Ecliptae Herba is a well-known traditional Chinese medicine, and used for the bleeding and immunity-related diseases in China. This study was aimed to explore the alleviation and mechanisms of eclipta total saponins (ETS) on radiation enteritis (RE). ETS were extracted using the percolation method, and the main active components, Ecl1 and Ecl2, were quantified with HPLC analysis to be 20.39 % and 50.42 %, respectively. Subsequently, a mouse model of RE was established to evaluate the therapeutic effect of ETS and reveal the main active components. The results demonstrated that ETS and Ecl2, but not Ecl1, significantly ameliorated RE in mice, as evidenced by reduced disease activity index scores, shortened colon length, and the down-regulated MPO activity and histopathological injury in colons. Furthermore, ETS and Ecl2 also reversed the increased intestinal permeability and crypt damage. In vitro, Ecl2 obviously inhibited ionizing radiation (IR)-induced apoptosis in HUVECs. This effect was associated with a down-regulated Bax/Bcl2 ratio, release of Cyt-C, and subsequent inhibition of the Caspase-3/PARP cascade. Molecular docking results revealed that Ecl2 potentially binds to the anti-apoptotic proteins PPARγ, but not Bcl2. Additionally, Ecl2 was found to increase the nuclear translocation of PPARγ and the transcription of its downstream target genes CAV1 , aP2 , and CD36. GW9662 abolished Ecl2-mediated anti-apoptosis effects in HUVECs. Collectively, ETS possesses the ability to ameliorate RE, and Ecl2 may act as the main effector component. Ecl2 regulates the Bax/Bcl2-Caspase-3/PARP cascade to inhibit IR-induced apoptosis of endothelial cells by activating PPARγ.
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Cell Communication and Signaling
·
2025
·Vol. 23
·期 1
·1-18
·
IF 8.9
Zhang Jiaqi,Li Jinjin,Cheng Mengting,Zhou Haiyang,Zhang Xiaochen,Yan Hao,Xu Zhifei,Yang Bo,He Qiaojun,Gao Zizheng,Chen Xueqin,Luo Peihua
Sotorasib, the first FDA-approved KRAS G12C inhibitor, has demonstrated remarkable clinical efficacy in non-small cell lung cancer (NSCLC). However, its clinical utility is hampered by life-threatening interstitial lung disease (ILD), whose molecular basis remains unknown. Through the integration of transcriptomic and metabolomic analyses, we revealed that sotorasib activates PPAR-γ signaling, upregulating fatty acid oxidation (FAO) via its downstream effector CPT1B. This metabolic shift triggered mitochondrial ROS overproduction, which drives alveolar epithelial apoptosis and fibrosis in vivo and in vitro . Mechanistically, sotorasib directly binds to PPAR-γ via Thr325, facilitated by FABP4-mediated nuclear translocation, amplifying its transcriptional activity via a feedforward loop. Pharmacological inhibition of FABP4 attenuated PPAR-γ activation, mitigated ROS-driven apoptosis, and rescued pulmonary fibrosis in mice. Taken together, these findings identify the FABP4-PPARγ-CPT1b axis as a novel off-target mechanism of sotorasib-induced lung toxicity and propose FABP4 inhibition as a promising therapeutic target to enhance its clinical safety.
Section
Graphical
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