Cell Communication and Signaling
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2025
·Vol. 23
·期 1
·1-18
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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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INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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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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JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Su Li,Caolin Zhong,Wei Jiang,Baojun Zheng,Ruoxin Xiang,Beixuan Yang,Chaozhan Lin,Chenchen Zhu,Meiqi Wang
Ethnopharmacological relevance Huzhang Erjin Decoction (HED) is a Traditional Chinese Medicine (TCM) Formula that possesses the efficiency of clearing heat, eliminating dampness, purging the liver and gallbladder. It has been clinically used in the treatment of inflammation related to hepatobiliary disease, including cholestasis, cholecystitis and jaundice. However, the mechanism of HED for its therapeutic effects has not been explored. Aim of the study This study aimed to investigate the potential mechanism of HED in ameliorating cholestatic hepatitis based on an integrative approach with metabolomics and network pharmacology. Materials and methods In this study, the pharmacodynamic effect of HED was evaluated based on alpha-naphthylisothiocyanate (ANIT)-induced cholestatic hepatitis mice. Furthermore, network pharmacology analysis was conducted to explore the potential mechanism of HED. Meanwhile, serum metabolomics analysis was performed to investigate the key metabolic pathways and biological processes regulated by HED. Furthermore, related targets and pathways were focused, according to a comprehensive analysis combined with metabolomics and network pharmacology. Molecular docking simulations were performed to evaluate the interactions between components of HED and the targets against cholestatic hepatitis. Finally, the regulatory effects of HED on the expression levels of key proteins in the peroxisome proliferator-activated receptor gamma (PPARγ) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) pathways were investigated both in vitro and in vivo . Results Our research findings demonstrate that HED significantly enhances liver function and alleviates liver injury in cholestatic hepatitis mice, including bile acid accumulation, hepatic necrosis and inflammatory infiltration. Furthermore, according to the combined enrichment of network pharmacology analysis and metabolomics study, HED primarily modulates cholestatic hepatitis via the regulation of lipid metabolism and bile acid metabolism to intervene in cholestatic hepatitis. Additionally, molecular docking studies revealed a high affinity and activity between the hub gene PPARG (PPARγ) and emodin in HED. Furthermore, the in vivo and in vitro results demonstrated that HED significantly promoted the expression of PPARγ and decreased the expression levels of NLRP3 and its associated proteins. In vitro , suppression of PPARγ attenuated the efficacy of HED. These findings suggested that HED modulated the PPARγ/NLRP3 signaling pathway, thereby improving cholestatic hepatitis and alleviating liver injury. Conclusion This study systematically assessed the efficacy of HED in the intervention of cholestatic hepatitis and explored the targets by integrating metabolomics and network pharmacology approaches, then elucidated its mechanism based on experiments both in vitro and in vivo . It was demonstrated that HED ameliorated cholestatic hepatitis in mice by regulating the PPARγ/NLRP3 pathway.
研究领域:
中药学
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药理学
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代谢组学
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生物信息学
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Research
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2025
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IF 10.7
Ningning He,Mengjie Mu,Xiaofang Li,Qingyuan Hao,Kaiwei Chen,Xinnan Zhao,Yang Sun,Haoyu Wang,Zhinan Wu,Hewei Liang,Mengmeng Wang,Liang Xiao,Tao Yu,Zhi-Peng Wang,Jixing Peng,Yuanqiang Zou,Shangyong Li
Antibiotic cocktails (ABX) serve as potent therapeutic interventions for refractory ulcerative colitis (UC), yet invariably induce gut dysbiosis. This study demonstrates that pectin oligosaccharides synergistically enhance ABX efficacy by restoring gut microbiota balance and selectively enriched antibiotic-resistant Parabacteroides goldsteinii in a colitis mouse model. Our results further indicate that the gavage administration of P. goldsteinii AM58-2XD markedly alleviated colitis via enhancing the branched-chain amino acid metabolic pathway, particularly by facilitating valine metabolism. Notably, these anticolitis effects were partially attenuated in P. goldsteinii ΔilvE mutants, which are defective in valine-derived isobutyrate (IBN) biosynthesis. We further demonstrated that exogenous IBN supplementation effectively alleviated colitis symptoms in mice and enhanced gut barrier function via activation of the peroxisome proliferator-activated receptor γ (PPARγ) pathway. Conditional knockout of PPARγ in Caco-2 intestinal epithelial cells markedly abrogated the IBN-induced enhancement of tight junctions, thereby substantiating the critical role of the IBN-PPARγ pathway in metabolite-mediated mucosal repair. Collectively, we delineate a prebiotic/probiotic–metabolite axis wherein P. goldsteinii facilitates mucosal repair via IBN/PPARγ-dependent epithelial metabolic reprogramming. This insight redefines antibiotic-resistant commensals as precise biotherapeutics for microbiota restoration in refractory UC management.
研究领域:
微生物组学
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炎症性肠病
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代谢生物学
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黏膜免疫
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转化医学
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肠道微生态
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Reproductive Biology and Endocrinology
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2018
·Vol. 16
·期 1
·1-11
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IF 2.852
Ge Xie,Pan Peng,Jing Jun,Hu Xuechun,Chen Li,Qiu Xuhua,Ma Rujun,Jueraitetibaike Kadiliya,Huang Xuan,Yao Bing
The Sertoli cell is the only somatic cell within the seminiferous tubules, and is vital for testis development and spermatogenesis. Rosiglitazone (RSG) is a member of the thiazolidinedione family and is a peroxisome proliferator-activated receptor-γ (PPARγ) agonist. It has been reported that RSG protects various types of cells from fatty acid-induced damage. However, whether RSG serves a protective role in Sertoli cells against palmitic acid (PA)-induced toxicity remains to be elucidated. Therefore, the aim of the present study was to investigate the effect of RSG on PA-induced cytotoxicity in Sertoli cells. MTT assay and Oil Red O staining revealed that RSG ameliorated the PA-induced decrease in TM4 cell viability, which was accompanied by an alleviation of PA-induced lipid accumulation in cells. In primary mouse Sertoli cells, RSG also showed similar protective effects against PA-induced lipotoxicity. Knockdown of PPARγ verified that RSG exerted its protective role in TM4 cells through a PPARγ-dependent pathway. To evaluate the mechanism underlying the protective role of RSG on PA-induced lipotoxicity, the present study analyzed the effects of RSG on PA uptake, and the expression of genes associated with both fatty acid oxidation and triglyceride synthesis. The results demonstrated that although RSG did not affect the endocytosis of PA, it significantly elevated the expression of carnitine palmitoyltransferase (CPT)-1A, a key enzyme involved in fatty acid oxidation, which indicated that the protective effect of RSG may have an important role in fatty acid oxidation. On the other hand, the expression of CPT1B was not affected by RSG. Moreover, the expression levels of diacylglycerol O-acyltransferase (DGAT)-1 and DGAT2, both of which encode enzymes catalyzing the synthesis of triglycerides, were not suppressed by RSG. The results indicated that RSG reduced PA-induced lipid accumulation by promoting fatty acid oxidation mediated by CPT1A. The effect of RSG in protecting cells from lipotoxicity was also found to be specific to Sertoli cells and hepatocytes, and not to other cell types that do not store excess lipid in large quantities, such as human umbilical vein endothelial cells. These findings provide insights into the cytoprotective effects of RSG on Sertoli cells and suggest that PPARγ activation may be a useful therapeutic method for the treatment of Sertoli cell dysfunction caused by dyslipidemia.
研究领域:
药理学
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细胞生物学
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内分泌学
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2023
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IF 6.1
Shuhua Shan,Jiaqi Zhou,Ruopeng Yin,Lizhen Zhang,Jiangying Shi,Qinqin Qiao,Zhuoyu Li
Non-alcoholic fatty liver disease (NAFLD) is a serious health problem worldwide. Impeding fatty acid uptake may be an attractive therapeutic strategy for NAFLD. In the current study, we found that millet bran protein hydrolysate (MBPH) prepared by in vitro gastrointestinal bionic digestion exhibits the potential of anti-NAFLD in vitro and in vivo, characterized by the alleviation of hepatic steatosis and the reduction of lipid accumulation. Further, MBPH significantly decreased the expression levels of fatty acid uptake related genes (FABP1, FABP2, FABP4, CD36, and CPT-1α) of liver tissue in a NAFLD mice model through activating peroxisome proliferator-activated receptor γ (PPARγ) and efficiently restrained the fatty acid uptake of liver tissue, thus exerting anti-NAFLD activity. As expected, the anti-NAFLD effect induced by MBPH, characterized by the alleviation of hepatic vacuolar degeneration, hepatic steatosis, and fibrosis, was effectively abrogated with PPARγ inhibitor (GW9662) treatment. These results indicate that the retardant of fatty acid uptake induced by PPARγ activation may be the critical factor for the anti-NAFLD effect of MBPH. Collectively, MBPH has the potential as a next-generation dietary supplementation for the prevention and treatment of NAFLD.
研究领域:
营养学
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药理学
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肝病学
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分子生物学
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胃肠病学
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Frontiers in Pharmacology
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2025
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IF 4.8
Bin Chen,Guanghui Wang,Jianbo Zhou,Lina Han,Li Li,Chengbin Sun
Introduction: Hypertensive nephropathy (HN) is a common complication of hypertension. Clinically, there is an urgent need for new HN treatment strategies. Sijunzitang (SJZT) is widely used in clinical practice, but its therapeutic effects and pharmacological mechanisms in the treatment of HN remain unclear.Methods: The active components, key targets, and potential pharmacological mechanisms of SJZT in treating HN were investigated through mass spectrometry, network pharmacology, and molecular docking. Subsequently, we validated the therapeutic effects of SJZT and the potential mechanisms using an Angiotensin II (Ang II)-induced HN mouse model and primary renal fibroblasts in vitro.Results: Network pharmacology identified 87 active components and 26 potential therapeutic targets of SJZT in treating HN, among which PPARγ, TNF, CRP, ACE, and HIF-1α were identified as key targets. Molecular docking demonstrated strong binding affinity between the core active components (Licoisoflavone B, Glabrone, and Frutinone A) and PPARγ. Animal experiments revealed that SJZT attenuated renal damage and extracellular matrix deposition in HN model mice. In vitro experiments revealed that SJZT suppressed Ang II-induced renal fibroblasts activation, as evidenced by reduced cell viability, α-SMA, and Collagen I expression. Mechanistically, SJZT alleviated hypertensive renal fibrosis through PPARγ upregulation in renal fibroblasts, subsequently inducing autophagy activation.Conclusion: This preclinical study establishes that SJZT ameliorates HN through a multi-component, multi-target, and multi-pathway mechanism. Key findings confirm that SJZT activates autophagy via PPARγ upregulation, which subsequently inhibits renal fibroblast activation and attenuates HN progression. These results provide a pharmacological foundation for the translational application of SJZT in HN treatment.
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JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A
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2019
·Vol. 107
·期 11
·2414-2424
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IF 3.221
Xiaopei Wu,Honglian Dai,Chao Xu,Langlang Liu,Shipu Li
Biomaterials can be used as carriers of antioxidant or drug to the oxidative injury site of tissue and decrease intracellular oxidative stress levels, however, low dosage delivery or unstable molecular structure of antioxidant or drug limited the long-term sustained release. A chemically stable antioxidant molecule is essential to serve as antioxidant structure components of biomaterials that may provide the relatively high antioxidant content and persisting local antioxidant release with the degradation of materials. In this study, we used citric acid modified polyvinyl alcohol (PVA-C) as a model biomaterial to investigate the role of citric acid on the material stimulated antioxidant and anti-inflammatory effects. In cellular-based assays, PVA-C extracts showed a protective effects on bone marrow mesenchymal stem cells (BMSCs) under oxidative stress. It could enhance the antiapoptotic ability of stem cells by inhibiting reactive oxygen species. Further studies revealed that PVA-C extracts upregulated the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) and superoxide dismutase [Mn] (SOD2). in vivo animal assays, PVA-C extracts showed significant inhibitory effects on the oxidative stress and inflammatory reaction which were induced by lipopolysaccharide (LPS). These findings suggest that the citric acid modified polymer can regulate the redox signaling of stem cells and tissues by the release of citric acid from materials, leading to enhanced oxidative stress-induced degenerative diseases and inflammatory diseases therapy.
研究领域:
材料科学
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生物材料
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细胞生物学
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药学
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JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Hongxuan Yang,Yun Liang,Yue’e Chen,Lin Liu,Yingfang Wang,Qiting Dou,Jinmei Gong,Zijing Liao,Junqiu Dong,Xuguang Hu
Ethnopharmacological relevance Lonicera japonica Thunb (honeysuckle), a traditional Chinese medicine, has been historically used to clear heat, detoxify, and dispel wind-heat. Modern research has identified various bioactive constituents from honeysuckle, supporting its potential in managing inflammatory and metabolic disorders. However, the anti-hyperuricemic activity and mechanism of its peptide components remain unexplored. Aim of the study: This study aimed to investigate the anti-hyperuricemic effect of honeysuckle-derived peptides and the underlying mechanisms, with a focus on uric acid production, excretion, and gut microbiota modulation. Materials and methods Nine novel peptides were identified from honeysuckle by HPLC-MS/MS and screened through molecular docking against xanthine oxidase (XOD). In vitro XOD inhibition and antioxidant assays were performed. A hyperuricemic mouse model was induced by potassium oxonate and hypoxanthine. Mice were treated with honeysuckle peptides at low, medium, and high doses. Serum biomarkers, renal and ileal histopathology, protein and mRNA expression of PGC-1α/PPARγ/ABCG2 pathway components, and gut microbiota composition (16S rRNA sequencing) were analyzed. Results Molecular docking confirmed strong binding between the peptides and XOD. In vitro , honeysuckle peptides significantly inhibited XOD activity and exhibited potent antioxidant capacity. In vivo , peptide treatment effectively reduced serum uric acid, XOD, creatinine, and blood urea nitrogen levels, alleviated renal and intestinal tissue damage, and suppressed inflammatory cytokines. The treatment also significantly upregulated the renal PGC-1α/PPARγ/ABCG2 pathway at both protein and mRNA levels. Furthermore, the peptides restored gut microbial diversity and corrected the Firmicutes/Bacteroidota ratio. Conclusion Honeysuckle peptides ameliorate hyperuricemia through a dual mechanism: inhibiting uric acid production by suppressing XOD activity and promoting its renal excretion by activating the PGC-1α/PPARγ/ABCG2 pathway, coupled with restoring gut microbiota homeostasis. This study provides a pharmacological basis for the traditional use of honeysuckle and highlights its peptides as promising candidates for managing hyperuricemia.
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EXPERIMENTAL NEUROLOGY
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2026
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IF 4.8
Zhenyu Wu,Xufang Huo,Yubing Huang,Taowu Gong,Pengcheng Zhao,Yuhang Zhu,Qingfan Zeng
Although hypertension (HYP) consistently predicts cognitive decline, the precise pathogenic cascade within the brain remains elusive. Here we interrogated whether the PPARγ/ACSL3 axis governs HYP-elicited hippocampal ferroptosis and consequent cognitive dysfunction. This study aimed to explore the role of the PPARγ/ACSL3 axis in HYP-induced neuronal ferroptosis and cognitive impairment. In the HYP rat model, behavioral tests (Morris water maze and Y-maze tests) demonstrated that rats in the hypertensive group had a significant decline in learning and memory. Mechanistically, the AngII-AT1R axis was found to be activated in the hippocampus, accompanied by typical ultrastructural features of ferroptosis, increased iron accumulation, elevated oxidative stress, and downregulation of PPARγ, ACSL3, and key ferroptosis defense proteins (GPX4, XCT, and FPN1). In vitro, ACSL3 overexpression alleviated AngII-induced neuronal ferroptosis. Furthermore, the PPARγ agonist rosiglitazone attenuated lipid peroxidation and iron overload by transcriptionally upregulating ACSL3, a direct regulatory relationship confirmed by dual-luciferase reporter assay. In conclusion, under hypertensive conditions, BRAS activation inhibits the PPARγ/ACSL3 axis via the AngII-AT1R pathway, aggravates lipid peroxidation and ferroptosis in hippocampal neurons, and ultimately contributes to cognitive decline. This study provides new experimental evidence for the mechanism research and therapeutic target exploration of HYP-related cognitive impairment.
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PHYTOMEDICINE
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2026
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IF 11.3
Ying Hua,Zhenyu Wu,Ying Li,Yulei Pan,Xingpan Xin,Shihui Zhou,Shihan Zhao,Yongsheng Fan,Chengping Wen,Jinjun Ji,Li Xu
Background Cutaneous involvement is a common manifestation of systemic lupus erythematosus (SLE), and dyslipidemia has emerged as a metabolic factor that aggravates lupus-associated skin injury. Purpose This study investigated the effects of Xijiao Dihuang Decoction derived formula (XJDHD) on dyslipidemia-aggravated lupus skin injury and its underlying immunometabolic mechanisms. Methods A high-fat diet (HFD)-exacerbated lupus-like skin injury model was established in lupus-prone mice. Histopathological, lipid metabolic, inflammatory, and oxidative stress analyses were conducted. Mechanistic exploration integrated molecular docking, network pharmacology, RNA sequencing, and macrophage-based assays. Results XJDHD markedly alleviated HFD-aggravated lupus-like skin lesions, reduced lipid accumulation, and suppressed cutaneous inflammation. Integrated analyses identified PPARγ-associated fatty acid oxidation and mitochondrial regulation as central pathways. XJDHD enhanced fatty acid oxidation, restored mitochondrial homeostasis, reduced oxidative stress, and inhibited pro-inflammatory macrophage polarization. PPARγ, ACADM, and NDUFAB1 were identified as key targets. Conclusion XJDHD attenuates dyslipidemia-associated lupus skin injury by restoring immunometabolic balance through regulation of fatty acid oxidation and mitochondrial homeostasis via the PPARγ-ACADM-NDUFAB1 axis, supporting metabolic-targeted herbal therapy for cutaneous manifestations in SLE.
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ACTA DIABETOLOGICA
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2024
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IF 3.1
Zhang Ling,Zhao Jing,Peng Zhou,Zhang Zhongxiao,Huang Shan,Dong Xiaohua,Gao Jianfang,Guo Xirong
Background Obesity, defined as excessive or abnormal body fat accumulation, which could significantly increase the risk of cardiovascular disease, type 2 diabetes mellitus (T2DM) diseases and seriously affect people’s quality of life. More than 2 billion people are overweight, and the incidence of obesity is increasing rapidly worldwide, it has become a widely concerned public health issue in the world. Diverse evidence show that active metabolites are involved in the pathophysiological processes of obesity. Aims However, whether the downstream catabolite of tryptophan, 3-indole acrylic acid (IA), is involved in obesity remains unclear. Methods We collected the samples of serum from peripheral blood of obesity and health controls, and liquid chromatography–mass spectrometry (LC-MS) was performed to identify the plasma levels of IA. Additionally, we verified the potential benefits of IA on human preadipocytes and HFD- induced zebrafish by cell viability assay, flow cytometry assay, Oil red O staining, total cholesterol (T-CHO), triglyceride (TG) and nonesterified free fatty acids (NEFA) measurements and Nile Red staining. RNA-Seq, functional analysis and western blot revealed the mechanisms underlying the function of IA. Results We found that the content of IA in peripheral blood serum of overweight people was significantly lower than that of normal people. In addition, supplementation with IA in zebrafish larvae induced by a high fat diet (HFD) dramatically reduced HFD induced lipid accumulation. IA had no effect on proliferation and apoptosis of preadipocytes, but significantly inhibited adipogenesis of preadipocytes by down-regulate CEBPα and PPARγ. RNA-Seq and functional analysis revealed that IA regulated the adipogenesis of preadipocytes through stimulate the phosphorylation of STAT1. Conclusions Taken together, IA has been identified as a potent metabolite for the prevention or treatment of obesity. Graphic Abstract
研究领域:
代谢
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分子生物学
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营养学
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药理学
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