ENVIRONMENT INTERNATIONAL
·
2024
·
IF 10.3
Bilin Zhao,Shuang Zheng,Gaoxiang Yang,Zhijun He,Jiewei Deng,Lijuan Luo,Xinyan Li,Tiangang Luan
Aryl organophosphorus flame retardants (aryl-OPFRs), commonly used product additives with close ties to daily life, have been regrettably characterized by multiple well-defined toxicity risks. Triphenyl phosphate (TPHP) and tri-o-cresyl phosphate (TOCP), two structurally similar aryl-OPFRs, were observed in our previous study to exhibit contrasting immunotoxic effects on THP-1 macrophages, yet the underlying mechanisms remain unclear. This study sought to address the knowledge gap by integrating transcriptomic and metabolomic analyses to elucidate the intricate mechanisms. During individual omics analyses, we unfortunately only obtained highly similar results for both TPHP and TOCP, failing to identify the key reasons for their differences. These results revealed comparable disturbances induced by both compounds, including disruptions in nucleic acid synthesis and energy metabolism, blocking ADP to ATP conversion by reducing TCA cycle intermediates, consequently leading to ATP depletion. However, through integrative analysis, specific pathways affected by each compound were successfully identified, shedding light on their unique effects. TPHP reduced GTP levels necessary for Rap1 activation, thereby inhibiting phagocytosis and adhesion of THP-1 macrophages. Conversely, TOCP stimulated the mTOR signaling pathway, enhancing phosphorylation of downstream proteins S6K, RHOA, and PKC, consequently promoting immune responses. This study not only clarified the distinct immunotoxic mechanisms of TPHP and TOCP but also provided critical insights into how structural variations in aryl-OPFRs can lead to markedly different immune responses, thereby informing future risk assessments and regulatory strategies for these compounds.
研究领域:
毒理学
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2022
·
IF 5.195
Jinfeng Shang,Qiannan Li,Tingyue Jiang,Lei Bi,Yinghui Lu,Jiakang Jiao,Qi Song,Mingxue Yan,Lizha Shabuerjiang,Jingyi Wang,Xin Liu
Ethnopharmacological relevance Huanglian Jiedu Decoction (HLJDD) has the effect of clearing heat and detoxifying, and has been considered as an effective prescription for cerebral ischemia (CI) for thousands of years in traditional Chinese medicine (TCM). It can improve the quality of life of patients with ischemic stroke, but its pharmacological mechanism remains unclear. Aim of the study The study aimed to explore the pharmacological action and potential mechanism of HLJDD against CI by systems pharmacology, proteomics and in vivo experiments. Materials and methods In this study, databases such as TCMIP V2.0 and Genecards were used to predict compounds, targets and CI related targets, and network topology criteria of protein-protein interaction (PPI) network was used to screen core targets. The Database for Annotation, Visualization and Integrated Discovery database (DAVID) was used to discover biological processes and pathways. In addition, molecular docking was performed between the screened core biological active compounds and targets to verify the binding activity. Finally, proteomics and Western blot were performed on cerebral cortex tissues of middle cerebral artery occlusion (MCAO) model rats with HLJDD intervention to further verify the predicted results. Results 77 compounds and 308 targets of HLJDD were identified, 54 of which were predicted to be associated with cerebral ischemia. PPI network and enrichment results showed that 8 targets, including AKT1, PTGS2 and TLR4 , were core targets of HLJDD in CI. And 19 signaling pathways, including Rap1 signaling pathway, cAMP signaling pathway and arachidonic acid metabolism, were identified as key pathways to the therapeutic activity of HLJDD in CI. Combined with proteomics studies, we identified that Rap1 signaling pathway and upstream and downstream targets were the key mechanisms. Molecular biology experiments showed that RAP1A and AKT expression levels were significantly up-regulated in middle cerebral artery occlusion (MCAO) rats treated with HLJDD ( P < 0.0001), GRIN1 expression level was significantly down-regulated ( P < 0.0001). However, ACTB expression level was slightly down-regulated ( P > 0.05), which may be related to the biological function. Conclusion This study confirms the pharmacological effect of HLJDD on cerebral ischemia. These results indicate that HLJDD mediates various pathways such as inhibition of apoptosis , regulation of oxygen balance, inhibition of excitatory toxicity and maintenance of basic cell functions to improve CI by regulating Rap1 signaling pathway.
研究领域:
药理学
·
神经科学
·
中医
·
分子生物学
·
生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Chinese Medicine
·
2024
·Vol. 19
·期 1
·1-17
·
IF 5.3
Gao Jiaming,Guo Hao,Li Junmei,Zhan Min,You Yue,Xin Gaojie,Liu Zixin,Fan Xiaodi,Gao Qinghe,Liu Jianxun,Zhang Yehao,Fu Jianhua
Background Buyang Huanwu Decoction (BYHWD) is a traditional Chinese medicine to treat the syndrome of qi deficiency and blood stasis. Platelets play an important role in regulating thrombus and inflammation after ischemic injury, studies have shown that BYHWD regulate myocardial fibrosis and exert anti-inflammatory effects through IL-17 and TLR4 pathways, but the mechanism of platelet activation by BYHWD in stable coronary heart disease is still unknown. In the present study, model of left anterior descending coronary artery ligation was applied to investigate the mechanisms of BYHWD on modulating platelets hyperreactivity and heart function after fibrosis of ischemic myocardial infarction (MI). Methods Myocardial infarction model was constructed by ligation of the left anterior descending coronary artery. The rats were randomly divided into five groups: sham, model, MI with aspirin (positive), MI with a low dosage of BYHWD (BYHWD-ld) and MI with a high dosage of BYHWD (BYHWD-hd) for 28 days. Results Coronary artery ligation prominently induced left ventricle dysfunction, increased cardiomyocyte fibrosis, which was accompanied by platelets with hyperreactivity, and high levels of inflammatory factors. BYHWD obviously reversed cardiac dysfunction and fibrosis, increased the thickness of the left ventricular wall, and inhibited aggregation ratio and CD62p expression. BYHWD restored the mitochondrial respiration of platelets after MI, concomitant with an increased telomere expression and decreased inflammation. According to the result of transcriptome sequencing, we found that 106 differentially expressed genes compared model with BYHWD treatment. Enrichment analysis screened out the Ras-related protein Rap-1 (Rap1) signaling pathway and platelet activation biological function. Quantitative real-time PCR and Western blotting were applied to found that BYHWD reduced the expression of Rap1/PI3K-Akt/Src-CDC42 genes and attenuated the overactivity of PI3 kinase/Rap1/integrin α(IIb)β(3) pathway. Conclusion BYHWD reduced inflammation and platelet activation via the PI3 kinase/Rap1/integrin α(IIb)β(3) pathway and improved heart function after MI. Graphical Abstract
研究领域:
中医
·
心脏病学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Ye Liu,Sicheng Li,Jinjian Huang,Xuanheng Li,Ze Li,Canwen Chen,Guiwen Qu,Kang Chen,Yitian Teng,Rui Ma,Xiuwen Wu,Jianan Ren
Open abdomen (OA), a major advance in modern trauma surgery, enables the treatment of severe abdominal trauma, infections, and hypertension by temporarily closing the abdominal cavity without suturing. Although OA can reduce mortality rates, it also presents challenges such as disruption of the abdominal environment, intestinal exposure, and impaired wound healing. Current temporary abdominal closure (TAC) techniques using polypropylene (PP) mesh are susceptible to abrasion and rupture of the intestine, leading to adhesions and serious complications such as intestinal fistulas and chronic wounds. These complications seriously impact outcomes due to mesh rigidity and its incompatibility with surrounding tissues. In this study, we designed a multifunctional hydrogel composed of GelMA (Gelatin Methacryloyl) and SilMA (Silk Fibroin Methacryloyl) as a promising solution for open abdominal wound repair. In vitro experiments confirmed the biocompatibility, self-healing properties, pro-angiogenic effects, and promotion of macrophage polarization. In vivo studies revealed that the GelMA-SilMA hydrogel could enhance abdominal wall tissue thickness and integrity via isolating the peritoneal cavity, protecting the intestinal tract, polarizing macrophages, promoting collagen formation, inducing neovascularization, inhibiting oxidative stress, and suppressing inflammation. Furthermore, immunofluorescence, immunohistochemistry, and RNA sequencing were employed to evaluate the wound healing mechanisms of GelMA-SilMA hydrogels. The results demonstrated that the hydrogels can promote angiogenesis, inhibit inflammation and immune responses, and enhance wound healing by activating the HIF-a-VEGF signaling pathway, RAP1 signaling pathway, and PI3K-AKT signaling pathway. Hence, the multifunctional GelMA-SilMA hydrogel has tremendous potential for clinical use in open abdominal wound repair.
研究领域:
生物医学工程
·
组织工程
·
伤口愈合
·
材料科学
·
外科技术
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）