FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Xiazhu Zhou,Hao Yan,Yifan Hong,Yanjun Ding,Jing Chen,Haohui Tang,Yuexin Wei,Chunlan Long,Lianju Shen,Guanghui Wei,Shengde Wu
Polystyrene microplastics (PS-MPs) and di (2-ethylhexyl) phthalate (DEHP), two main composites of plastic products, are always exposed to human at the same time. However, most existing research has focused on single exposure, which is not consistent with the actual exposure circumstance. In this study, single and co-exposure animal model were established. C57/BL6J mice were exposed to corn oil, 20 mg/kg PS-MPs, 200mg/kg DEHP and PS-MPs + DEHP for 28 days. The HE staining showed more serious seminiferous epithelium disorganization in co-exposed mice, indicating that PS-MPs and DEHP co-exposure could aggravate testicular injury. Compared with control group, integrative analysis of transcriptomics and proteomics revealed that PPARγ pathway played a crucial role in PS-MPs and DEHP co-exposure induced testis injury. In vitro, spermatocytes (GC-2) and leydig cells (TM3) were exposed to 50 μM MEHP, 10 mg/L PS-MPs and PS-MPs + MEHP for 48 h. Though PS-MPs and MEHP single exposure also triggered oxidative stress and PPAR pathway, the protein levels showed more remarkable difference in co-exposure group. Furthermore, co-exposure to PS-MPs and MEHP induced lysosomal membrane permeabilization (LMP), which significantly impaired lysosomal-mediated lipid degradation, thereby exacerbating lipid metabolism dysfunction in testicular cells. Treatment with N-Acetylcysteine (NAC) and knockdown of fatty acid-binding protein (FABP4) restored lipophagy flux and reduced lipid droplets deposition. Overall, co-exposure of PS-MPs and DEHP has synergistic toxic effect, inducing oxidative stress, PPARγ activation and lipophagy blockage, finally resulting in unbalanced lipid metabolism and testicular damage.
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PubMed
高影响因子
Food Bioscience
·
2026
·
IF 6.2
Longfei Lv,Sijie Zhang,Bing Huang,Li Ren,Jie Zhang,Zheng Ma
Cigarette consumption remains a preeminent global public health concern, as prolonged exposure to cigarette smoke is fundamentally implicated in the etiology of chronic pulmonary diseases and the manifestation of various malignancies. Apigenin, a bioactive dietary flavonoid widely distributes in botanical sources such as celery, demonstrates significant histoprotective effect. Nevertheless, the underlying mechanism governing apigenin's ability to counteract incipient pulmonary injury induced by cigarette smoke extract (CSE) remains to be delineated. By employing a novel CSE exposure system to establish reproducible in vivo and in vitro injury models, this study demonstrated that apigenin administration dose-dependently attenuates pulmonary apoptosis, as evidenced by the restoration of the Bax/Bcl-2 ratio and the suppression of Caspase-3 activation. Furthermore, apigenin treatment reversed the CSE-induced downregulation of PPARγ and its downstream effector, FATP2. Apigenin also restored intestinal mucosal integrity, promoted the enrichment of the probiotic Clostridia vadinBB60 group, and elevated intestinal difluprednate levels, which strongly correlated with increased glucocorticoid receptor (GR) expression in lung tissue. Mechanistically, apigenin facilitated the recruitment of PGC1α to PPARγ, thereby promoting PPARγ nuclear translocation and subsequent FATP2 activation in CSE-challenged MLE-12 cells. In RAW264.7 macrophages, difluprednate mediated GR nuclear translocation, subsequently suppressing the mRNA expression of the pro-inflammatory cytokines IL-1β and IL-6. Collectively, these findings identify apigenin as a dual-pathway modulator that bridges PPARγ/FATP2-mediated metabolic homeostasis with GR-dependent anti-inflammatory signaling, highlighting its therapeutic potential against smoking-related pulmonary dysfunction and supporting its application as a functional food intervention.
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高影响因子
LIFE SCIENCES
·
2022
·
IF 6.78
Wenjie Zhang,Qin Zhang,Yanrong Zhu,Yajing Zhang,Yufeng Xia,Zhifeng Wei,Yue Dai
Butyrate, given by oral administration or in drinking water, has been shown to improve experimental pulmonary fibrosis (PF) in mice despite of very low bioavailability. The pharmacokinetic-pharmacodynamics disconnection attracts us to explore its anti-PF mechanism in view of the intestinal expression of anti-PF factors. In bleomycin-induced PF in mice, rectal administration of butyrate (500 mg/kg) exhibited a significant anti-PF effect, with a maximum plasma concentration largely lower than the minimum effective concentration (1 mM) at which butyrate inhibited the expression of pro-inflammatory factors by lung epithelial cells and the production of extracellular matrix by lung fibroblasts. The rectal administration of butyrate significantly upregulated the mRNA expression of hepatocyte growth factor (HGF) in the colons of PF mice, but showed no significant effect on the mRNA expression of HGF in the small intestines, lungs and livers. In colon epithelial cells, the monocarboxylate transporter inhibitor α-cyano-4-hydroxycinnamic acid (CHC) abrogated butyrate-induced expression of HGF, indicating that butyrate functions through entering into cells. Butyrate showed no significant effect on the histone acetylation in the promoter region of HGF, suggesting that it promotes HGF expression not by directly affecting the histone deacetylation of HGF but by other pathways. GW9662, the inhibitor of PPARγ, significantly attenuated the effect of butyrate to promote the mRNA expression of HGF. Butyrate was able to enhance the acetylation of PPARγ, and a targeted mutation of lysine at the position 240 (K240) of PPARγ markedly diminished the induction of butyrate on HGF expression, suggesting that butyrate promoted HGF expression in colon epithelial cells by upregulating PPARγ K240 acetylation. In summary, rectal administration of butyrate promotes the expression of HGF in colonic epithelial cells through upregulating PPARγ acetylation via inhibition of HDAC activity. The findings of the present study provide a reasonable explanation for the anti-PF action mode of butyrate based on the ‘lung-gut axis’, and found that intestine-derived butyrate and HGF may be involved in the modulation of the occurrence and progression of PF.
研究领域:
药理学
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肺科学
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胃肠病学
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分子生物学
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DOI
PubMed
高影响因子
iScience
·
2025
·Vol. 28
·期 8
·112744
·
IF 4.1
Ke Li,Xiaoyan Jia,Dawei Guo,Haiming Wang,Haonan Shui,Hongbo Qi,Hua Zhang
Placenta-targeting nano-drugs have emerged as a safe and effective treatment option for preeclampsia (PE). Downregulation of peroxisome proliferator-activated receptor γ (PPARγ) induces dysfunctional placental trophoblasts and facilitates placental reactive oxygen species, which weakens the PGC1α/UCP2 oxidative stress pathway, causing PE symptoms. Herein, rosiglitazone (RGZ), as an effective PPARγ agonist, exhibited great potential in PE treatment. However, low solubility and nonspecific effect limit the clinical application. Therefore, this study presents CGKRK-modified and RGZ-loaded lipid nanoparticles (CRNPs), based on the specific binding of CGKRK to calreticulin highly expressed in human and mouse trophoblasts. CRNP alleviates excessive oxidative stress and improves placental development and fetal growth in L-NAME-induced PE mice. However, it does not cause maternal side effects or fetal malformation in pregnant mice injected with a high dose of CRNP through the tail vein. Consequently, the safe and effective delivery of CRNP optimizes the placental-targeting therapeutic strategy. Natural sciences; Nanoparticles; Biological sciences; Female reproductive endocrinology
研究领域:
纳米医学
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妇产科学
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药理学
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分子生物学
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生殖生物学
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生物科学
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自然科学
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PubMed
高影响因子
CELLULAR SIGNALLING
·
2023
·
IF 4.8
Jinmiao Tian,Lichao Zhang,Xiaoqin La,Xiaxia Fan,Aiping Li,Changxin Wu,Yuxuan An,Shuning Yan,Xiushan Dong,Haitao Wu,Zhuoyu Li
Macrophages in hypoxic regions of advanced colorectal tumors often exhibit M2-type features, but prefer oxygen-consuming lipid catabolism , which is contradictory in oxygen demand and supply. In this study, the results from bioinformatics analysis and intestinal lesions immunohistochemistry of 40 colorectal cancer patients illustrated that glucose-regulatory protein 78 (GRP78) was positively correlated with M2 macrophages. Furthermore, tumor-secreted GRP78 could enter macrophages and polarize them to M2-type. Mechanistically, entered GRP78 located in lipid droplets of macrophages, and elevated protein stabilization of adipose triglyceride lipase ATGL by interacting with it to inhibit its ubiquitination . Increased ATGL promoted the hydrolysis of triglycerides and the production of arachidonic acid (ARA) and docosahexaenoic acid (DHA). Excessive ARA and DHA interacted with PPARγ to encourage its activation, which mediated the M2 polarization of macrophages. In summary, our study showed that secreted GRP78 in the tumor hypoxic microenvironment mediated the domestication of tumor cells to macrophages and maintained tumor immunosuppressive microenvironment by promoting lipolysis, and the lipid catabolism not only provides energy for macrophages but also plays an important role in maintenance of immunosuppressive properties.
研究领域:
肿瘤学
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免疫学
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细胞生物学
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生物化学
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PubMed
高影响因子
Food Science & Nutrition
·
2025
·Vol. 13
·期 11
·e71234
·
IF 3.8
Liang Xue,Chun Cao
Inflammatory bowel disease (IBD) is a complex chronic intestinal inflammatory disease involving immune, genetic and environmental interactions. A disrupted balance in the polarization of intestinal macrophages is a key pathogenic link. This study explored whether octanoic acid (OA)‐rich enteral nutrition (EN) regulated intestinal M1/M2 macrophage polarization via the PPARγ/STAT‐1/STAT‐6 pathway to alleviate IBD. First, to assess the effects of OA‐rich EN on IBD, four groups were established: the sham, IBD, IBD + EN, and IBD + OA‐rich EN. Second, to verify the regulatory role of intestinal M1/M2 macrophage polarization via the PPARγ/STAT‐1/STAT‐6 pathway, six groups were established: the sham, IBD, IBD + OA‐rich EN, IBD + OA‐rich EN with intraperitoneal injections of IFNγ, AS1517499, or SR202. RAW264.7 cells were also used to observe how OA influences LPS/IFNγ‐induced M1 polarization. OA‐rich EN notably alleviated IBD symptoms, activated the PPARγ/STAT‐1/STAT‐6 pathway and remodeled the M1/M2 polarization balance of intestinal macrophages. These effects were greater than those in the IBD + EN group. Blocking the activation of PPARγ, activating STAT‐1 or inhibiting STAT‐6 reversed the protective effect of OA‐rich EN on remodeling the M1/M2 polarization balance of intestinal macrophages and IBD symptoms. In vitro experiments further confirmed that OA regulated macrophage polarization via the PPARγ/STAT‐1/STAT‐6 pathway. This is the first confirmation that OA‐rich EN alleviates IBD by activating PPARγ/STAT‐1/STAT‐6 to regulate macrophage polarization, highlighting its potential as a nutritional therapy for IBD. Octanoic acid‐rich enteral nutrition could regulate the M1/M2 polarization of intestinal macrophages and simultaneously repair the intestinal mucosal barrier by activating the PPARγ/STAT‐1/STAT‐6 pathway, thereby significantly alleviating inflammatory bowel disease‐induced intestinal injury.
研究领域:
免疫学
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胃肠病学
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营养科学
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分子生物学
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PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2025
·
IF 5.5
Chengjun Sun,Qi Zhou,Guanzhi Lai,Shaojun Shi,Ming Han,Wuzheng Xia,Xiangling Wei,Yang Du,Rongji Ye,Shuiguo Tang,Linwei Wu,Shanzhou Huang
Hepatic fibrosis is a progressive liver disease characterized by excessive accumulation of extracellular matrix (ECM) proteins, primarily collagen, in response to chronic liver injury. Despite the availability of treatment options, current therapies face significant challenges, including poor drug targeting and systemic toxicity. In this study, we developed a nanodrug delivery system, Rosiglitazone (RGZ)-loaded perfluoropropane (PFP)-based lipid nanoparticles (LNPs) functionalized with Arg-Gly-Asp (RGD) peptides (RGZ/PFP@LNP-RGD), for ultrasound-assisted targeted therapy of liver fibrosis. RGZ, a selective PPARγ agonist, was encapsulated in LNPs functionalized with RGD peptides, allowing for targeted delivery to activated hepatic stellate cells (aHSCs), the central cells involved in fibrosis progression. PFP, incorporated into the nanoparticle core, serves as an ultrasound-responsive agent, enabling controlled drug release upon ultrasound irradiation. In vitro, RGZ/PFP@LNP-RGD treatment led to a reduction in the expression of key fibrosis markers such as Col Iα1, α-SMA, and TGF-β1 at both the protein and mRNA levels. Ultrasound treatment further enhanced RGZ release from the nanocarriers, improving the inhibition of HSC activation. In vivo, RGZ/PFP@LNP-RGD combined with ultrasound treatment resulted in a marked reduction in liver fibrosis and improved liver function compared to free RGZ treatment. Histological and biochemical assessments confirmed reduced fibrosis marker expression and liver damage. These results suggest that RGZ/PFP@LNP-RGD, especially when combined with ultrasound, offers a promising noninvasive therapeutic strategy for liver fibrosis, with enhanced targeting, controlled drug release, and reduced systemic toxicity.
研究领域:
纳米医学
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药学
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肝病学
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生物医学工程
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分子生物学
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PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2021
·
IF 4.749
Zhenhua Ding,Maohua Chen,Xinyan Tao,Yuan Liu,Jie He,Tao Wang,Xiaohong Li
Obesity is a primary risk factor for type 2 diabetes, cardiovascular diseases, cancer, and other chronic diseases. Current antiobesity medications need frequent administration and show limited efficacy with severe side effects. Herein, browning agent rosiglitazone (Rsg) and antioxidant manganese tetroxide nanoparticles (MnNPs, around 250 nm) are integrated into electrospun short fibers (SF@Rsg-Mn) with a 1.5 μm width and a 20 μm length. Upon injection into inguinal adipose tissues, SF@Rsg-Mn are well retained in the local depots to sustainably release Rsg in 30 days for adipose tissue browning, while MnNPs on the fiber surface continuously scavenge adipose reactive oxygen species (ROS) for an extended period of time. Synergistic inhibition of fat accumulation through ROS scavenging and white adipocyte browning has been demonstrated for the first time, and the optimal synergistic ratio of Rsg and MnNPs is determined to be 1/14 via combination index examination. SF@Rsg-Mn inhibit lipid accumulation through downregulation of adipogenic gene PPARγ while promoting energy expenditure through upregulation of brown-specific gene UCP1 and mitochondrial function gene COX7A1. In a diet-induced obesity mouse model, a single injection of SF@Rsg-Mn into inguinal adipose tissues has accomplished a synergistic effect on body weight loss, fat reduction, glucose, and lipid metabolic improvement while minimizing adverse effects on other tissues, thereby paving the way to efficacious, safe, and practical treatment of obesity.
研究领域:
药理学
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代谢研究
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纳米医学
·
肥胖研究
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PubMed
高影响因子
Environmental Chemistry and Ecotoxicology
·
2025
·
IF 8.2
Jinzhi Ren,Ying Peng,Chenyang Sun,Yining Zhang,Jianjun Li,Simin Xia,Caixia Gao,Yimeng Wang,Xiangping Nie
There is an urgent need for a more efficient and ethical approach to chemical toxicity assessment. The emergence of New Approach Methodologies (NAMs) based on fish embryos transcriptomics provides a promising alternative. Triphenyl phosphate (TPP) — a pervasive contaminant in estuaries — disrupts lipid homeostasis in mammals via PPARγ activation, yet its ecotoxicological impacts on estuarine fish remain unknown. Leveraging NAMs, this study integrates concentration-dependent transcriptomics (CDT), molecular docking, and phenotypic toxicity assays to unravel effects of TPP on embryonic development and lipid metabolism in the benthic fish Mugilogobius chulae . We found that TPP induced significant lethality (LC₅₀ = 1.86 × 10 6 ng/L) and teratogenicity (EC₅₀ = 5.27 × 10 5 ng/L), suppressing spontaneous movement, heart rate, and hatching. At concentrations of 5270 ng/L and 52,700 ng/L, TPP elevated triglycerides, total cholesterol, and hepatotoxicity markers (alanine aminotransferase / aspartate aminotransferase). CDT analysis identified fatty acid metabolism pathways as the most sensitive targets, with TPP upregulating PPARγ while downregulating CD36 and ACSL5 — indicating blocked fatty acid oxidation and explaining lipid accumulation. Crucially, co-exposure with PPARγ antagonist GW9662 reversed metabolic disorders, validating the mechanistic role of PPARγ. Furthermore, molecular docking confirmed that TPP binds PPARγ with agonist-like affinity. This work establishes a NAM-based framework for deciphering the toxicity of contaminants of emerging concern in estuarine ecosystems, offering novel tools for ecological risk assessment.
研究领域:
生态毒理学
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环境科学
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毒理基因组学
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分子生物学
·
水生毒理学
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高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6
Li-Yuan Wei,Yu-Wei Lin,Jia-Chun Luo,Yi-Xian Li,Yu-Tao Hu,Shi-Yao Guo,Zhi Jiang,Dan-Dan Zhao,Shuo-Bin Chen,Zhi-Shu Huang
ABSTRACT Due to the emerging global epidemic of obesity, developing safe and effective agents for anti-obesity is urgently needed. Our previous study found that 2-pyrimidinylindole derivative Wd3d exhibited potential anti-obesity activity. Herein, to further optimize the potential moiety, structural modifications were proceeded for two rounds in this study. Firstly, we designed, synthesized, and evaluated 36 new derivatives of 2-pyrimidinylindole scaffold with different substituents on the indole ring and pyrimidine ring to investigate their structure-activity relationship (SAR). Then, analogs with potent activity had the aldehyde group replaced with the acylhydrazone group to reduce cytotoxicity and improve metabolic stability. Detailed SAR studies and animal evaluation experiments led to the discovery of the compound 9ga , which significantly reduced TG accumulation with an EC 50 value of 0.07 μM and showed relatively low cytotoxicity with an IC 50 value of around 24 μM. Oral administration of 9ga effectively prevented the excessive growth of body weight and lessened fat mass as well as liver mass, decreased lipid accumulation in the liver and blood, and improved the heart injury parameter in the diet-induced obesity mouse model significantly better than Wd3d . A mechanism study showed that 9ga regulated the lipid metabolism during early adipogenesis by inhibiting PPARγ pathway. In conclusion, our study further highlights the anti-obesity potential of 2-pyrimidinylindole derivatives in diet-induced obesity.
研究领域:
药理学
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药物化学
·
肥胖研究
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
·
IF 4.2
Yi Chu,Sisi Gui,Yazhen Zheng,Jingwu Zhao,Yaxiang Zhao,Yingying Li,Xiaodong Chen
Non-alcoholic fatty liver disease (NAFLD) is closely associated with the body's energy metabolism. A potential strategy to regulate energy metabolism, combat obesity, and reduce NAFLD is by enhancing adipocyte thermogenesis and increasing energy expenditure. In this study, our objective was to examine the effects of phenolic extracts derived from Magnolia officinalis on the regulation of NAFLD. Specifically, we investigated the impact of Magnolol or Honokiol treatment on high-fat diet (HFD)-induced obese C57BL6/J male mice. Firstly, we monitored energy metabolism, dissected tissues, and analyzed tissue sections. Additionally, we conducted experiments on HepG2 and primary adipocytes to gain insights into the roles of Magnolol or Honokiol. To further understand the effects of these compounds on related signaling pathways and marker genes, we performed molecular docking, dual-luciferase assays, and interfered with target genes. Our findings revealed that Magnolol or Honokiol activate the peroxisome proliferator activated receptor alpha (PPARα) signaling pathway, leading to the alleviation of NAFLD. This activation promotes fatty acid oxidation, reduces lipogenesis, and enhances the expression and secretion of FGF21. Notably, Fibroblast growth factor 21 (FGF21), secreted by the liver, plays a crucial role in improving communication between the liver and adipocytes while also promoting the browning of adipose tissue. Additionally, Magnolol or Honokiol activate the peroxisome proliferator activated receptor gamma (PPARγ) signaling pathway, resulting in increased uncoupling protein 1 (UCP1) expression, heightened heat production in adipose tissue, and anti-obesity. Therefore, Magnolol or Honokiol alleviate NAFLD, promote adipose tissue browning and resist obesity through dual activation of PPARα/γ.
研究领域:
药理学
·
代谢
·
分子生物学
·
营养学
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2020
·Vol. 42
·期 3
·470-481
·
IF 5.064
Xie Qiu-shi,Zhang Jia-xin,Liu Ming,Liu Pei-hua,Wang Zhong-jian,Zhu Liang,Jiang Ling,Jin Meng-meng,Liu Xiao-nan,Liu Li,Liu Xiao-dong
P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are involved in intestinal barrier. Short-chain fatty acids (SCFAs) play important roles in maintaining intestinal barrier. In this study we explored how SCFAs affected the expression and function of intestinal P-gp and BCRP in rats. Rats received 150 mM acetate, propionate or butyrate in drinking water for 4 weeks. In SCFA-treated rats, the expression and function of intestinal P-gp were decreased, but those of intestinal BCRP were increased; intestinal p-p65 was also decreased, which was positively related to P-gp protein expression. Among the three SCFAs tested, butyrate exhibited the strongest induction or inhibitory effect, followed by propionate and acetate. Similar results were observed in mouse primary enterocytes and Caco-2 cells treated with acetate (5 mM), propionate (2 mM), or butyrate (1 mM). In Caco-2 cells, addition of butyrate, vorinostat, and valproate (two classic HDAC inhibitors), Bay117082 (selective inhibitor of NF-κB activation) or NF-κB p65 silencing significantly decreased the expression of P-gp and the level of phosphorylated p65 (p-p65). Furthermore, butyrate attenuated the expression of P-gp and p-p65 induced by TNF-α (NF-κB activator) and theophylline (HDAC activator). However, vorinostat, valproate, Bay117082, TNF-α or p65 silencing hardly affected BCRP protein expression. But GW9662 (selective PPARγ antagonist) or PPARγ silencing abolished BCRP induction by butyrate and troglitazone (PPARγ agonist). SCFAs-treated rats showed higher intestinal protein expression of PPARγ, which was positively related to BCRP protein expression. Butyrate increased plasma exposure of fexofenadine but decreased that of rosuvastatin following oral dose to rats. In conclusion, SCFAs exert opposite effects on the expression and function of intestinal P-gp and BCRP; butyrate downregulated P-gp expression and function possibly via inhibiting HDAC/NF-κB pathways; butyrate induced BCRP expression and function partly via PPARγ activation.
研究领域:
药理学
·
胃肠病学
·
分子生物学
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PubMed
高影响因子
危险品化学品经营许可证（带存储）