ENVIRONMENTAL POLLUTION
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2021
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IF 8.071
Can Wang,Ruina Cui,Congying Niu,Xiali Zhong,Qicheng Zhu,Di Ji,Xianjie Li,Hongxia Zhang,Chunqiao Liu,Lina Zhou,Yanli Li,Guowang Xu,Yanhong Wei
The residue of polychlorinated biphenyls (PCBs) exists throughout the environment and humans are subject to long-term exposure. As such, the potential environmental and health risk caused by low-dose exposure to PCBs has attracted much attention. 3, 3′, 4, 4′, 5-pentachlorobiphenyl (PCB126), the highest toxicity compound among dioxin-like-PCBs, has been widely used and mass-produced. Cardiotoxicity is PCB126's crucial adverse effect. Maintaining proper metabolism underlies heart health, whereas the impact of PCB126 exposure on cardiac metabolic patterns has yet to be elucidated. In this study, we administered 0.5 and 50 μg/kg bw of PCB126 to adult male mice weekly by gavage for eight weeks. Pathological results showed that low-dose PCB126 exposure induced heart injury. Metabolomic analysis of the heart tissue exposed to low-dose PCB126 identified 59 differential metabolites that were involved in lipid metabolism , amino acid metabolism, and the tricarboxylic acid (TCA) cycle. Typical metabolomic characteristic of cardiac hypertrophy was reflected by accumulation of fatty acids (e.g. palmitic, palmitoleic, and linoleic acid), and disturbance of carbohydrates including D-glucose and intermediates in TCA cycle (fumaric, succinic, and citric acid). Low-dose PCB126 exposure increased glycine and threonine, the amino acids necessary for the productions of collagen and elastin . Besides, PCB126-exposed mice exhibited upregulation of collagen synthesis enzymes and extracellular matrix proteins, indicative of cardiac fibrosis. Moreover, the expression of genes related to TGFβ/PPARγ/MMP-2 signaling pathway was perturbed in the PCB126-treated hearts. Together, our results reveal that low-dose PCB126 exposure disrupts cardiac metabolism correlated with hypertrophy and fibrosis. This study sheds light on the underlying mechanism of PCBs' cardiotoxicity and identifies potential sensitive biomarkers for environmental monitoring.
研究领域:
毒理学
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心脏病学
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环境健康
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代谢组学
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DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
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2023
·Vol. 25
·期 5
·1-7
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IF 2.7
Zhiguo Wu,Yuchan Wu,Weicheng Zhong,Qingmei Zhong,Shengfang Rao,Dongshan Yu,Xiaolu Luo,Fang Qiu,Zhiying Song,Di Jin,Maoxing Ai,Yu Lan,Gongchang Zhang,Shufeng Song,Baogang Xie,Shuilin Sun
Aspirin decreases liver fibrosis index and inflammation levels. However, the exact mechanism underlying the effects of aspirin are yet to be elucidated. The aim of the study was to investigate the potential protective effects of aspirin on carbon tetrachloride (CCl4)‑induced hepatic fibrosis in Sprague‑Dawley rats. Rats were divided into four groups, including healthy and CCl4 control and low‑(aspirin 10 mg/kg + CCl4) and high‑dose aspirin group (aspirin 300 mg/kg + CCl4). After 8 weeks treatment, the histopathological examinations of hepatocyte fibrosis in liver and serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), IL‑1β, transforming growth factor‑β1 (TGF‑β1), hyaluronic acid (HA), laminin (LN) and type IV collagen (IV.C) were determined. Histopathological examination suggested that aspirin decreased CCl4‑induced hepatic fibrosis and liver inflammation. The high‑dose aspirin group significantly decreased the serum levels of ALT, AST, HA and LN compared with the CCl4 control group. High‑dose aspirin group significantly decreased the levels of pro‑inflammatory cytokines IL‑1β compared with CCl4 group. The high‑dose aspirin group significantly inhibited the expression of TGFβ‑1 protein compared with CCl4 group. Overall, the present study indicated that aspirin exhibited potent protective effects against CCl4‑induced hepatic fibrosis via inhibition of the TGFβ‑1 pathway and pro‑inflammatory cytokine IL‑1β.
研究领域:
药理学
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肝病学
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炎症
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纤维化
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细胞因子
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DOI
PubMed
高影响因子
Cell Communication and Signaling
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2025
·Vol. 23
·期 1
·1-19
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IF 8.9
Ling Jun,Zhang Jie,Wang Baozhen,FengSong Jing,Li Tao,Chen Jing
Characterized by high malignancy and limited treatment efficacy, triple-negative breast cancer (TNBC) remains a clinically challenging subtype within breast cancer classifications, marked by rapid progression and high mortality. Abnormal activation of the transforming growth factor-β (TGFβ) pathway signaling, a pathway integral to tumor progression, metastasis, angiogenesis and immune evasion, is a common feature in a broad spectrum of malignancies. Owing to the restricted effectiveness of first-line interventions including surgical resection, cytotoxic agents, and radiation therapy for TNBC, novel agents that modulate TGFβ activity represent a compelling therapeutic avenue. Herein, we reported the identification and preclinical evaluation of YH395A, a novel tetrahydro‐β‐carboline derivative derived from the lead compound YR‐290 with virtual screening from pseudo molecular library generated by generative deep learning method. In vitro studies demonstrated that YH395A dose‐dependently inhibited TNBC cell migration and invasion. In vivo, administration of YH395A not only curtailed metastatic dissemination and prevented the extravasation of breast cancer cells into lung parenchyma in mouse models but also significantly reduced tumor growth in a patient‐derived xenograft (PDX) model. Mechanistic analyses indicated that these antitumor effects are mediated via potent inhibition of TGFβ signaling. These cumulative results demonstrate YH395A’s viability as a novel therapeutic agent for TNBC, while emphasizing the necessity for expanded preclinical validation studies.
研究领域:
肿瘤学
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药理学
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计算生物学
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分子生物学
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生物信息学
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药物研发
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2018
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IF 2.559
Zhigang Nie,Sen Chen,Shuang Deng,Linsheng Long,Puji Peng,Mingyong Gao,Shile Cheng,Jiarui Cao,Hao Peng
Objective Glucocorticoids (GCs)-induced osteoblast apoptosis has been identified as an important cause of GCs related osteonecrosis of the femoral head (ONFH). Glycogen synthase kinase 3β (GSK3β) has been proved to mediate dexamethasone (Dex)-induced osteoblast apoptosis. This study aimed to investigate the underlying mechanism of GSK3β in Dex-induced osteoblast apoptosis. Methods Osteoblast cells were transfected with lentivirus expressing GSK3β-shRNA, and a DNA microarray was performed to analyze gene expression after Dex treatment with or without GSK3β-shRNA. Some differentially expressed genes were further validated by quantitative real-time-PCR (qRT-PCR). Results 460 genes were up-regulated (at least 2-fold) with Dex treatment but down-regulated (at least 2-fold) with GSK3β-shRNA treatment. In addition, 315 genes were down-regulated (at least 2-fold) with Dex treatment but up-regulated (at least 2-fold) with GSK3β-shRNA treatment. Among these genes, the apoptosis-related genes Hoxb8 , Kif18a , Dock8, Dlk1, Tnfsf14 , Casq2 , Bcl2l14 and mechanosensation-related gene Piezo2 were selected for further qRT-PCR analysis. 7 of 8 genes (Piezo2, Hoxb8, Kif18a, Dlk1, Tnfsf14, Casq2, Bcl2l14) showed the same tendency between gene chip results and qRT-PCR results. The microarray data also showed that apoptotic pathway, MAPK pathway, TGFβ pathway and Wnt pathway might be related to the mechanism of GSK3β in Dex-induced osteoblast apoptosis. Conclusion Our findings indicate that GSK3β-shRNA treatment can alter various genes expression levels and change diverse signaling pathways involved in Dex-induced osteoblast apoptosis. Furthermore, Piezo2, Hoxb8, Kif18a, Dlk1, Tnfsf14, Casq2 and Bcl2l14 genes may play an important role in the GSK3β-mediated osteoblast apoptosis process.
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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基因组学
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DOI
PubMed
高影响因子
ADVANCED MATERIALS
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2024
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IF 27.4
Chenchen Li,Xiyang Tan,Dashi Deng,Chenfan Kong,Lida Feng,Weijing Wang,Kaida Lin,Yuqing Li,Qifang Lei,Lisha Liu,Tao Tao,Ruile Pan,Guangzhi Li,Song Wu
Thin endometrium (TE) is closely associated with infertility in reproductive medicine. Estrogen therapy gains unsatisfactory outcomes. In this study, an artificial mucus based on dopamine (L-DOPA)-modified hyaluronic acid combining phytoestrogen cajaninstilbene acid and rat urinary exosomes (CUEHD) is constructed for TE treatment using a rat TE model. In the rat TE model, the dominant elastic behavior and adhesive properties of CUEHD guarantee adequate retention, rendering superior synergistic treatment efficacy and favorable biosafety characteristics. CUEHD treatment significantly increases endometrial thickness and promotes receptivity and fertility. Mechanistically, estrogen homeostasis, inflammation inhibition, and endometrial regeneration are achieved through the crosstalk between ER-NLRP3-IL1β and Wnt-β catenin-TGFβ-smad signaling pathways. Moreover, the therapeutic potential of exosomes from human urine and adipose tissue-derived stem cells (ADSCs) and rat ADSCs are also demonstrated, indicating extensive use of the artificial mucus system. Thus, this study illustrates a platform combining phytoestrogen and exosomes with promising implications for TE treatment.
研究领域:
生殖医学
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药理学
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生物医学工程
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分子生物学
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2016
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IF 2.326
Wenjuan Yao,Lei Huang,Qinju Sun,Lifeng Yang,Lian Tang,Guoliang Meng,Xiaole Xu,Wei Zhang
Macrophage foam cell formation triggered by oxLDL is an important event that occurs during the development of atherosclerosis . 2,3,5,4′-Tetrahydroxystilbene-2- O -β- d -glucoside (TSG) exhibits significant anti-atherosclerotic activity. Herein we used U937 cells induced by PMA and oxLDL in vitro to investigate the inhibitory effects of TSG on U937 differentiation and macrophage foam cell formation. TSG pretreatment markedly inhibited cell differentiation induced by PMA, macrophage apoptosis and foam cell formation induced by oxLDL. The inhibition of vimentin expression and cleavage was involved in these inhibitory effects of TSG. The suppression of vimentin by siRNA in U937 significantly inhibited cell differentiation, apoptosis and foam cell formation. Using inhibitors for TGFβR1 and PI3K, we found that vimentin production in U937 cells is regulated by TGFβ/Smad signaling, but not by PI3K-Akt-mTOR signaling. Meanwhile, TSG pretreatment inhibited both the expression of TGFβ1 and the phosphorylation of Smad2 and Smad3, and TSG suppressed the nuclear translocation of Smad4 induced by PMA and oxLDL. Furthermore, TSG attenuated the induced caspase-3 activation and adhesion molecules levels by PMA and oxLDL. PMA and oxLDL increased the co-localization of vimentin with ICAM-1, which was attenuated by pretreatment with TSG. These results suggest that TSG inhibits macrophage foam cell formation through suppressing vimentin expression and cleavage, adhesion molecules expression and vimentin-ICAM-1 co-localization. The interruption of TGFβ/Smad pathway and caspase-3 activation is responsible for the downregulation of TSG on vimentin expression and degradation, respectively.
研究领域:
心血管疾病
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
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