Journal of Advanced Research
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2021
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IF 10.479
Zhenxing Liang,Ying Chen,Zheng Wang,Xue Wu,Chao Deng,Changyu Wang,Wenwen Yang,Ye Tian,Shaofei Zhang,Chenxi Lu,Yang Yang
Introduction Adriamycin (ADR) is an efficient and common broad-spectrum anticancer drug. However, the cumulative and dose-dependent toxicity induced by ADR severely limits its application in the clinic. Previous studies found that psoralidin (PSO) exhibits remarkable therapeutic effects against multiple cancers. Objectives The aim of this study was to determine if PSO has beneficial effects on ADR-induced cardiotoxicity and to investigate the underlying mechanisms. Methods ADR-induced cardiotoxicity models were established in BALB/c mice and HL-1 cardiomyocytes. A series of experimental methods were used to evaluate the effects of PSO on cardiac function indicators, blood biochemical parameters, histopathology, oxidative stress, apoptosis, mitochondrial function, fibrosis, and SIRT1/PPARγ signaling. Results PSO significantly improved cardiac function indicators, blood biochemical parameters, and mitochondrial function and reduced the degree of myocardial fibrosis, oxidative stress, and apoptosis in ADR-injured mice. PSO significantly increased cell viability, inhibited the release of LDH, reduced oxidative stress and apoptosis, and improved mitochondrial function in ADR-injured HL-1 cells. Moreover, we also demonstrated there was cross-talk between SIRT1 and PPARγ, as shown by SIRT1 siRNA significantly decreasing the expression of PPARγ and GW9662 (a PPARγ antagonist), which remarkably reduced the expression of SIRT1. Conclusion In summary, this study proved for the first time the beneficial effect of PSO on ADR-induced cardiotoxicity through activation of the SIRT1/PPARγ signaling pathway. Therefore, these findings may favor PSO as a potential cardioprotective drug candidate to alleviate ADR-induced cardiotoxicity in the clinic and improve the application of ADR in oncotherapy.
研究领域:
药理学
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心脏病学
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肿瘤学
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细胞生物学
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分子生物学
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FASEB JOURNAL
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2020
·Vol. 34
·期 4
·4904-4917
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IF 4.966
Xianglu Ji,Tianjing Liu,Shuyi Zhao,Jianjun Li,Lianyong Li,Enbo Wang
Chondrocyte apoptosis plays an important role in the developmental dysplasia of the hip (DDH) development. It has been found that WNT1 inducible signaling pathway protein 2 (WISP-2) and peroxisome proliferator-activated receptor γ (PPARγ) are involved in cell apoptosis. In this study, we performed the straight-leg swaddling DDH rat model and we found that cartilage degradation and chondrocyte apoptosis were remarkably increased in DDH rats in vivo . Moreover, we found that WISP-2 was upregulated in hip acetabular cartilage of DDH rats compared to control rats. Next, the effects of WISP-2 on chondrocyte apoptosis and its possible underlying mechanism were examined in vitro. The lentivirus-mediated gain- and loss-of-function experiments of WISP-2 and peroxisome proliferator-activated receptor γ (PPARγ) for cell viability and apoptosis were performed in primary rat chondrocytes. The results showed that the overexpression of WISP-2 induced chondrocyte apoptosis, and knockdown of WISP-2 could suppress the chondrocyte apoptosis induced by advanced glycation end products (AGE). Additionally, WISP-2 could negatively regulate the expression of PPARγ in chondrocytes. Moreover, the knockdown of PPARγ promoted chondrocyte apoptosis and overexpression of PPARγ abated the increased apoptosis and decreased cell viability of chondrocytes induced by WISP-2. This study demonstrated that WISP-2 might contribute to chondrocyte apoptosis of hip acetabular cartilage through regulating PPARγ expression and activation, which may play an important role in the development of DDH.
研究领域:
骨科
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分子生物学
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细胞生物学
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Drug Design Development and Therapy
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2025
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IF 5.1
Guojiang Tian,Fan Dong,Ai Fu,Shanglei Lai,Jundi Yu,Jingjing Ni,Qinchao Ding,Yueping Jin
Purpose Oleanolic acid (OA), a naturally occurring pentacyclic triterpenoid, has been reported to possess anti-inflammatory and barrier-protective properties. However, its molecular mechanism in the context of ulcerative colitis (UC) remains unclear.Methods In this study, we evaluated the therapeutic potential of OA (25 and 50 mg/kg/day) in a dextran sulfate sodium (DSS)-induced acute colitis model in C57BL/6 mice.Results Oral administration of OA significantly alleviated clinical symptoms of colitis, including weight loss, colon shortening, increased disease activity index (DAI), and histopathological injury. Additionally, OA demonstrated potent anti-inflammatory effects by suppressing the production of pro-inflammatory cytokines and promoting anti-inflammatory cytokines. It also restored redox homeostasis by enhancing antioxidant defenses and reducing lipid peroxidation. OA also restored intestinal barrier integrity, as evidenced by increased tight junction protein expression and decreased intestinal permeability. Mechanistically, OA was found to inhibit the activation of the NF-κB signaling pathway, as evidenced by reduced phosphorylation of IKKα/β and p65, and decreased degradation of IκBα. A key finding was that OA restored the expression of PPARγ, a known negative regulator of NF-κB. OA promoted the accumulation of peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor essential for maintaining intestinal epithelial homeostasis and anti-inflammatory signaling. OA inhibited the ubiquitin-mediated proteasomal degradation of PPARγ, thereby stabilizing its protein levels in colonic tissue. Pharmacological inhibition of PPARγ with GW9662 abolished the protective effects of OA on intestinal inflammation and epithelial barrier function, confirming that PPARγ activation is required for OA-mediated protection.Conclusion These findings identify a previously unrecognized mechanism whereby OA protects against colitis through post-translational stabilization of PPARγ. Our study not only highlights the therapeutic value of OA as a potential intervention for UC but also provides mechanistic insight into the regulation of nuclear receptor homeostasis during intestinal inflammation.
研究领域:
药理学
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免疫学
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胃肠病学
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分子生物学
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天然产物研究
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Algal Research-Biomass Biofuels and Bioproducts
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2026
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IF 5
Yunmei Yin,Pei Wang,Zhen Zhang,Hongxiang Zhao,Meicong Xiao,Ran Chen,Kun Li,Shiqi Zhou,Rongqing Zhang
Astaxanthin's anti-atherosclerotic targets/pathways identified via network pharmacology and cellular assays. • Astaxanthin alleviates endothelial injury via dual anti-inflammatory and antioxidant effects. • Astaxanthin acts through PPARγ/NF-κB axis, with GW9662 reversing its regulatory effect. Astaxanthin, a lipophilic carotenoid predominantly derived from microalgae such as Haematococcus pluvialis , exhibits potent anti-inflammatory and antioxidant properties. Despite previous reports of its anti-atherosclerotic effects, the underlying molecular mechanisms of astaxanthin remain unclear. This study aimed to elucidate the pharmacological mechanisms of astaxanthin in alleviating atherosclerosis progression via an integrated approach of network pharmacology, molecular docking, and in vitro experimental validation. Molecular docking revealed strong binding affinities between astaxanthin and core targets including TNF, IL-6, and PPARγ. In vitro experiments demonstrated that astaxanthin attenuated oxidative stress and suppressed the secretion of pro-inflammatory cytokines in oxidized low-density lipoprotein (ox-LDL)-induced human umbilical vein endothelial cells (HUVECs). Mechanistically, astaxanthin upregulated PPARγ expression and reduced the phosphorylation of p65 and IκBα, two key components of the NF-κB pathway. Co-treatment with the specific PPARγ antagonist GW9662 abrogated these protective effects, confirming a PPARγ-dependent regulatory mechanism. These findings indicate that astaxanthin exerts anti-atherosclerotic effects by modulating the PPARγ/NF-κB signaling axis, highlighting its potential as a functional food ingredient for cardiovascular protection.
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FREE RADICAL BIOLOGY AND MEDICINE
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2026
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IF 8
Zhe Li,Bingbing Liu,Lianghong Zhou,Na Chen,Yi Wang,Su Yang,Xinyi Fan,Yuan Wang,Xiaodong Chen
Sarcopenic obesity (SO), characterized by concurrent muscle loss and excessive adiposity, lacks effective interventions. This study investigated the enhanced effects of the selenomethionine (Se-Met) and magnolol (Mag) combination against SO using an integrated computational-experimental approach. Network pharmacology and molecular docking predicted peroxisome proliferator-activated receptor γ (PPARγ) and the nuclear factor erythroid 2-related factor 2 - glutathione peroxidase 4 (Nrf2 - GPX4) axis as core targets, which was corroborated by single-cell transcriptomic data analysis showing their co-expression in muscle progenitor cells. In high-fat diet (HFD)-fed mice, the combined Se-Met and Mag treatment ameliorated metabolic dysregulation, reduced intramuscular lipid deposition, and improved muscle function more effectively than monotherapies. In C2C12 myotubes, the combination co-activated PPARγ to enhance lipid clearance and potentiated the Nrf2-GPX4 antioxidant axis. Notably, it modulated ferroptosis-related signaling by downregulating acyl-CoA synthetase long-chain family member 4 (ACSL4) and upregulating ferritin heavy chain 1 (FTH1) and heme oxygenase-1 (HO-1), an effect abolished by Nrf2 inhibition. Pharmacological inhibition of either PPARγ or Nrf2 reversed the protective benefits. Our findings reveal that Se-Met and Mag in combination target PPARγ and Nrf2-GPX4 pathways while regulating ferroptosis-related signaling to alleviate ferroptosis-associated markers, with phenotypic characteristics consistent with ferroptosis inhibition, thereby offering a novel nutraceutical strategy for SO.
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2026
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IF 2.5
Weiwei Yang,Shulan Pang,Yi Li,Jiahong Chen,Qiuhong Jiao,Ailin Liu,Tiansen Liu,Tao Huang,Hongjie Wang,Xiufeng Xu,Yuqing Zhang,Peikang Dong,Tao Wang
Integrative computational analyses identify PPARG as a key target of polydatin in aortic dissection. • Docking and MD support stable binding of polydatin to PPARγ and Keap1. • Transcriptomic and WGCNA analyses link polydatin to oxidative-stress regulation. • Polydatin attenuates BAPN-induced aortic dissection in mice. • Polydatin may protect the aortic wall via the PPARγ/Nrf2 antioxidant axis. Aortic dissection (AD) is a life-threatening vascular disease characterized by medial degeneration, extracellular matrix (ECM) destruction, inflammation, and oxidative stress. Polydatin (PD), a natural stilbene glucoside, has cardiovascular protective potential, but its mechanism against AD remains unclear. This study investigated the therapeutic mechanism of PD in AD by integrating network pharmacology, transcriptomic analysis, weighted gene co-expression network analysis (WGCNA), molecular modeling, and in vivo validation. IGF1, PPARG, and KDR were identified as core targets in the PD–AD network, with PPARG prioritized for its association with vascular redox homeostasis, inflammation, and antioxidant defense. Molecular docking and molecular dynamics simulations indicated stable interactions between PD and PPARγ and Keap1, a key regulator of Nrf2 stability. In a β-aminopropionitrile (BAPN)-induced AD mouse model, PD significantly reduced aortic dilation and medial injury, preserved elastic fiber architecture, and attenuated ECM degradation. PD also decreased ROS and MDA levels, restored SOD, GSH-Px, and CAT activities, and upregulated PPARγ, Nrf2, HO-1, and NQO1 expression. These findings suggest that PD alleviates AD by restoring vascular redox homeostasis, potentially involving PPARγ-associated signaling and Nrf2-related antioxidant responses, supporting PD as a potential therapeutic candidate for AD-related vascular degeneration. Download: Download high-res image (327KB) Download: Download full-size image
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Theranostics
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2018
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IF 8.537
Feng Zhang,Shuai Lu,Jianlin He,Huanhuan Jin,Feixia Wang,Li Wu,Jiangjuan Shao,Anping Chen,Shizhong Zheng
Rationale: Hepatic stellate cells (HSCs) are liver-specific pericytes regulating vascular remodeling during hepatic fibrosis. Here, we investigated how ligustrazine affects HSC pericyte functions. Methods: Rat HSC-T6 and human HSC-LX2 cells were cultured, and multiple molecular experiments including real-time PCR, Western blot, flow cytometry, immunofluorescence, electrophoretic mobility shift assay and co-immunoprecipitation were used to elucidate the underlying mechanisms. Molecular simulation and site-directed mutagenesis were performed to uncover the target molecule of ligustrazine. Rats were intoxicated with CCl 4 for evaluating ligustrazine's effects in vivo . Results: Ligustrazine inhibited angiogenic cytokine production, migration, adhesion and contraction in HSCs, and activated PPARγ. Selective PPARγ inhibitor GW9662 potently abrogated ligustrazine suppression of HSC pericyte functions. Additionally, HIF-1α inhibitor PX-478 repressed HSC pericyte functions, and ligustrazine inhibited the transcription of HIF-1α, which was diminished by GW9662. Moreover, ligustrazine downregulation of HIF-1α was rescued by knockdown of SMRT, and ligustrazine increased PPARγ physical interaction with SMRT, which was abolished by GW9662. These findings collectively indicated that activation of PPARγ by ligustrazine led to transrepression of HIF-1α via a SMRT-dependent mechanism. Furthermore, molecular docking evidence revealed that ligustrazine bound to PPARγ in a unique double-molecule manner via hydrogen bonding with the residues Ser289 and Ser342. Site-directed mutation of Ser289 and/or Ser342 resulted in the loss of ligustrazine transrepression of HIF-1α in HSCs, indicating that interactions with both the residues were indispensable for ligustrazine effects. Finally, ligustrazine improved hepatic injury, angiogenesis and vascular remodeling in CCl 4 -induced liver fibrosis in rats. Conclusions: We discovered a novel ligand activation pattern for PPARγ transrepression of the target gene with therapeutic implications in HSC pericyte biology and liver fibrosis.
研究领域:
药理学
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细胞生物学
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分子生物学
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肝病学
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American Journal of Translational Research
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2020
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IF 3.375
Runzi Gao,Wenhui Ji,Tianwei Xia,Yanxing Fan,Wei Wei,Le Shi,Jinzhu Liu,Chao Zhang,Lezhen Xue,Jirong Shen
Osteonecrosis of the femoral head (ONFH) is a common disorder that may be idiopathic, caused by trauma, or associated with alcohol or glucocorticoid use. The goals of early treatment include delaying or avoiding hip replacement, but there are no effective treatments for early-stage disease. The aim of the present study was to evaluate the effects of treatment with 3D-printed porous titanium alloy scaffold combined with daily intraperitoneal trans-cinnamaldehyde (TCA) in a dog model of ONFH. Four weeks after creation of the ONFH model, MRI examination of the femoral head showed the characteristic “double line sign” of ONFH, verifying the validity of our model. After another 12 weeks, femoral head specimens were harvested and examined by gross inspection; micro-computed tomography; histologic staining (hematoxylin and eosin; Masson); immunohistochemical analysis and quantitative real-time polymerase chain reaction analysis. Gross inspection of the femoral head in untreated ONFH animals at 16 weeks after model creation showed pale, exfoliating articular cartilage and disordered trabecular bone. Treatment with 3D-printed titanium alloy porous scaffold combined with TCA ameliorated the pathologic ONFH changes and significantly reduced inmature bone tissue as well as imature collagen in the femoral head, as shown by Masson staining. This treatment also increased VEGF, BMP2, β-catenin, b-FGF, and RUNX2 expression and decreased PPARγ expression, compared with untreated ONFH. In conclusion, 3D-printed titanium alloy porous scaffold combined with TCA can effectively improve ONFH, which may be related to local repair. This provides the theoretical basis for a new treatment strategy for ONFH.
研究领域:
骨科
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再生医学
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药理学
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生物医学工程
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CELLULAR & MOLECULAR BIOLOGY LETTERS
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2022
·Vol. 27
·期 1
·1-13
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IF 8.702
Zhu Shenglong,Wang Wei,Zhang Jingwei,Ji Siyu,Jing Zhe,Chen Yong Q.
Background A comprehensive understanding of the molecular mechanisms of adipogenesis is a critically important strategy for identifying new targets for obesity intervention. Methods Transcriptomic and lipidomic approaches were used to explore the functional genes regulating adipogenic differentiation and their potential mechanism of action in OP9 cells and adipose-derived stem cells. Oil Red O staining was used to detect oil droplets in adipocytes. Results RNA sequencing (RNA-seq) showed that Slc25a5 expression was significantly upregulated in adipogenic differentiation. Depletion of Slc25a5 led to the suppressed expression of adipogenesis-related genes, reduced the accumulation of triglycerides, and inhibited PPARγ protein expression. Moreover, the knockdown of Slc25a5 resulted in significant reduction of oxidative phosphorylation (OXPHOS) protein expression (ATP5A1, CQCRC2, and MTCO1) and ATP production. The RNA-seq and real-time quantitative polymerase chain reaction (RT–qPCR) results suggested that adipogenic differentiation is possibly mediated by ERK1/2 phosphorylation, and this hypothesis was confirmed by intervention with PD98059 (an ERK 1/2 inhibitor). Conclusions This study indicates that Slc25a5 inhibits adipogenesis and might be a new therapeutic target for the treatment of obesity.
研究领域:
分子生物学
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细胞生物学
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肥胖研究
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Frontiers in Pharmacology
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2022
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IF 5.988
Yuhang Ge,Fei Zhen,Ziqi Liu,Zhaowei Feng,Gui Wang,Chu Zhang,Xingqi Wang,Ying Sun,Xiaohui Zheng,Yajun Bai,Ruiqin Yao
Preterm white matter injury (PWMI) is the most common form of brain damage in premature infants caused by hypoxia-ischemia (HI), inflammation, or excitotoxicity. It is characterized by oligodendrocyte precursor cell (OPC) differentiation disorder and dysmyelination. Our previous study confirmed that alpha-asarone (α-asaronol), a major compound isolated from the Chinese medicinal herb Acorus gramineus by our lab, could alleviate neuronal overexcitation and improve the cognitive function of aged rats. In the present study, we investigated the effect and mechanism of α-asaronol on myelination in a rat model of PWMI induced by HI. Notably, α-asaronol promoted OPC differentiation and myelination in the corpus callosum of PWMI rats. Meanwhile, the concentration of glutamate was significantly decreased, and the levels of PPARγ and glutamate transporter 1 (GLT-1) were increased by α-asaronol treatment. In vitro, it was also confirmed that α-asaronol increased GLT-1 expression and recruitment of the PPARγ coactivator PCG-1a in astrocytes under oxygen and glucose deprivation (OGD) conditions. The PPARγ inhibitor GW9662 significantly reversed the effect of α-asaronol on GLT-1 expression and PCG-1a recruitment. Interestingly, the conditioned medium from α-asaronol-treated astrocytes decreased the number of OPCs and increased the number of mature oligodendrocytes. These results suggest that α-asaronol can promote OPC differentiation and relieve dysmyelination by regulating glutamate levels via astrocyte PPARγ-GLT-1 signaling. Although whether α -asaronol binds to PPARγ directly or indirectly is not investigated here, this study still indicates that α -asaronol may be a promising small molecular drug for the treatment of myelin-related diseases.
研究领域:
神经科学
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药理学
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儿科
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分子生物学
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高影响因子
MOLECULAR NEUROBIOLOGY
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2026
·Vol. 63
·期 1
·374
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IF 4.3
Zhao Chen-di,Liu Nan-feng,Samad Abdus,Tian Zhen,Xu Hong-mei,Tian Jiao
Depression is a widespread neuropsychiatric disorder with the current therapeutic approaches achieving only suboptimal efficacy. Neferine is the main bioactive component of Nelumbinis plumula with multiple pharmacological functions. This study sought to investigate the antidepressant activity of neferine and elucidate its underlying mechanisms. Network pharmacology analysis was performed to uncover the molecular targets and pathways involved in neferine’s antidepressant effects. The interaction of neferine with the core target was demonstrated by molecular docking and molecular dynamics simulation. The mouse model of depression triggered by chronic corticosterone (CORT) administration was utilized to validate the impact of neferine on core targets and pathways. We found that neferine remarkably attenuated CORT-induced depressive-like behaviors in mice. A total of 178 overlapping targets were acquired through the intersection of neferine and depression-related genes. The protein–protein interaction (PPI) network analysis revealed nine pivotal hub genes, namely AKT1, TNF, ESR1, PPARG, JUN, HIF1A, CASP3, NFKB1, and MMP9. Functional enrichment analysis indicated that these targets predominantly mapped to the TNF signaling pathway in depression. Molecular docking and molecular dynamics simulation showed that neferine has strong binding stability with PPARγ, a key molecule involved in regulating the TNF pathway. The results of animal experiments found that a PPARγ antagonist abolished neferine-induced alleviation of depressive-like behaviors. Moreover, neferine suppressed TNF/NF-κB pathway activation and attenuated neuronal loss in the hippocampus, potentially through activating PPARγ. Collectively, our study suggested that neferine produced antidepressant effects by suppressing hippocampal inflammation and neuronal loss through inhibiting the TNF/NF-κB signaling pathway. These preclinical evidence laid a foundation for further exploring the role of neferine in treating depression. Graphical
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Frontiers in Pharmacology
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2026
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IF 5.4
Fang Wang,Yan Qing Liu,Jun Nan Wei,Xiao Fen Wang,Feng Qin Li,Xiu Jia Tian,Dan Li,Yu Xuan Gao,Xin Zhi Guo,Xue Yan Li,Ping Luo
Introduction Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent chronic liver disorder characterized by intrahepatic lipid accumulation, oxidative stress, and inflammatory responses, underscoring the urgent need for effective therapeutic strategies. D-limonene, a cyclic monoterpenoid primarily derived from citrus fruits, possesses well-documented antioxidant, anti-fibrotic, and wound-healing properties. However, its therapeutic potential in MASLD remains largely unexplored. Methods To evaluate the therapeutic efficacy of D-limonene, a rat model of MASLD was established using a high-fat diet (HFD). An integrated approach combining metabolomics, transcriptomics, and network analysis was employed to identify key signaling pathways and molecular targets. The expression levels of candidate targets were validated by RT-qPCR and Western blotting. Molecular docking simulations were performed to predict the binding affinity between D-limonene and the target proteins. Furthermore, a cellular thermal shift assay (CETSA) was conducted to confirm direct binding and protein stabilization. In parallel, cellular experiments using BRL-3A and HepG2 cells were carried out to assess the effect of D-limonene on lipid accumulation. Results D-limonene treatment significantly ameliorated liver injury, reduced excessive lipid deposition, attenuated inflammation, and suppressed oxidative stress in HFD-induced rats. Integrated multi-omics and network analyses identified the PPAR signaling pathway as the core pathway mediating the regulatory effects of D-limonene on lipid metabolism, with PPARγ and SCD-1 pinpointed as key downstream targets. RT-qPCR and Western blot analyses confirmed that D-limonene significantly downregulated the expression of both PPARγ and SCD-1. Molecular docking simulations revealed stable binding of D-limonene to PPARγ and SCD-1. Importantly, CETSA further demonstrated that D-limonene directly binds to and stabilizes these two proteins. Consistently, cellular assays showed that D-limonene significantly reduced lipid accumulation in BRL-3A and HepG2 cells by inhibiting the PPARγ/SCD-1 axis. Conclusion Collectively, these findings suggest that D-limonene alleviates HFD-induced MASLD, and its protective effects may be mediated, at least in part, through inhibition of the PPARγ/SCD-1 axis. This study provides preliminary evidence supporting the potential development of D-limonene as a targeted therapeutic agent for MASLD. Further studies are warranted to validate these findings and elucidate additional underlying mechanisms.
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