TOXICOLOGY
·
2021
·
IF 4.221
Zhen-Dong Zhang,Ya-Jun Yang,Xi-Wang Liu,Zhe Qin,Shi-Hong Li,Jian-Yong Li
Paraquat (PQ) is an effective and commercially important herbicide that is widely used worldwide. However, PQ is highly toxic and can cause various complications and acute organ damage. Aspirin eugenol ester (AEE) is a potential new compound with anti-inflammatory and antioxidant stress pharmacological activity. The present study was to reveal the therapeutic effects and the protective effect of AEE against PQ-induced acute lung injury (ALI) with the help of PQ-induced oxidative damage in A549 cells and PQ-induced lung injury in rats. AEE might have no significant therapeutic effect on PQ-induced lung injury in rats. However, AEE had a significant protective effect on PQ-induced lung injury in rats. AEE pretreatment significantly reduced the stimulatory effect of PQ on malondialdehyde (MDA), the inhibitory effect of PQ on catalase (CAT) activity, superoxide dismutase (SOD) activity, glutathione peroxidase (GPx) activity, the ratio of GSH/GSSH, the activity of caspase-3 and the overexpression of p38 mitogen-activated protein kinase (MAPK) phosphorylation in vivo . In vitro , A549 cells were treated with 250 μM PQ for 24 h. Incubation of A549 cells with PQ led to apoptosis, and increased the level of superoxide anions, reactive oxygen species (ROS), malondialdehyde and the activity of caspase-3 and up-regulation of phosphorylated p38-MAPK, reduced mitochondrial membrane potential (ΔΨm) and the activity of SOD. However, after 24 h on AEE pretreatment of A549 cells, the above-mentioned adverse reactions caused by PQ were significantly alleviated. In addition, AEE pretreatment reduced p38-MAPK phosphorylation in PQ-treated A549 cells. SB203580, the specific p38-MAPK inhibitor, and p38-MAPK shRNA attenuated the activation of the p38-MAPK signaling pathway. N-acetylcysteine (NAC) reduced the level of phosphorylated p38-MAPK and the production of intracellular ROS and inhibited apoptosis. The results showed that AEE may inhibit PQ-induced cell damage through ROS/p38-MAPK-mediated mitochondrial apoptosis pathway.
研究领域:
药理学
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毒理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2023
·
IF 8.9
Mengxing Cui,Qianmei He,Ziwei Wang,Yongjiang Yu,Huan Gao,Ziqi Liu,Honghao Peng,Han Wang,Xue Zhang,Daochuan Li,Liping Chen,Xiumei Xing,Yongmei Xiao,Wen Chen,Qing Wang
Micro/nano-plastics (MPs/NPs) are a newly discovered environmental pollutant that can be ingested by humans through food and drinking water. In this study we evaluated the impact of MPs/NPs on the intestinal barrier and its mechanism. Doses of MPs/NPs were used to treat Caco-2/HT29-MTX in-vitro model and in-vivo model. In in-vitro model, 20 nm polystyrene nanoplastics (PS-NPs) had higher cytotoxicity than larger particles (200 nm and 2000 nm), and led to the increase of the permeability along with the decreased expression of tight junction proteins. Intriguingly, 20 nm PS-NPs elevated the expression of MUC2 simultaneously. Further studies revealed that PS-NPs increased the expression of HO1 through ROS generation, and then activated p38 to elevate IL-10 secretion in Caco-2 cell. The IL-10 secreted by Caco-2 cell promoted the expression of MUC2 in HT29-MTX cell through STAT1/3. Elevated MUC2 expression alleviates the cytotoxicity of PS-NPs. Besides, increased intestinal permeability and up-regulation of MUC2 through Ho1/p38/IL-10 pathway was also observed in 20 nm PS-NPs treated mouse model. In conclusion, PS-NPs can induce the intestinal toxicity and result in the increased adaptive expression of MUC2 to resist this adverse effect. People with inadequate mucin expression need to pay more attention to the toxicity of PS-NPs. This study provided a valuable insight for clarifying the mechanism and potential risk of intestinal toxicity induced by nanoplastics.
研究领域:
环境科学
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毒理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Xiaoyu Zhang,Peiwen Li,Jin Zhou,Ziliang Zhang,Huan Wu,Xinyu Shu,Wang Li,Yi Wu,Yu Du,Dongyuan Lü,Shouqin Lü,Ning Li,Mian Long
Liver sinusoidal endothelial cells (LSECs) are highly specific endothelial cells which play an essential role in the maintenance of liver homeostasis . During the progression of liver fibrosis, matrix stiffening promotes LSEC defenestration, however, the underlying mechanotransduction mechanism remains poorly understood. Here, we applied stiffness-tunable hydrogels to assess the matrix stiffening-induced phenotypic changes in primary mouse LSECs. Results indicated that increased stiffness promoted LSEC defenestration through cytoskeletal reorganization. LSECs sensed the increased matrix stiffness via focal adhesion kinase (FAK), leading to the activation of p38-mitogen activated protein kinase activated protein kinase 2 (MK2) pathway, thereby inducing actin remodeling via LIM Kinase 1 (LIMK1) and Cofilin . Interestingly, inhibition of FAK or p38-MK2 pathway was able to effectively restore the fenestrae to a certain degree in LSECs isolated from early to late stages of liver fibrosis mice. Thus, this study highlights the impact of mechanotransduction in LSEC defenestration, and provides novel insights for potential therapeutic interventions for liver fibrosis.
研究领域:
细胞生物学
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肝病学
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力学生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
·
2025
·
IF 4.2
Yongpeng Fang,Xudong Niu,Weifang Zhao,Huali Zhang
Myocardial ischemia/reperfusion (I/R) injury is a major cause of various adverse cardiovascular outcomes associated with excessive mitophagy and cardiomyocyte ferroptosis. Paired-related homeobox 1 (PRRX1) is a transcriptional factor involved in cardiovascular injury. However, whether and how PRRX1 regulates excessive mitophagy and cardiomyocyte ferroptosis during myocardial I/R injury remains unclear. Oxygen-glucose deprivation and reperfusion (OGD/R)-treated AC16 cardiomyocytes and myocardial I/R-induced rats were used as in vitro and in vivo models. Our results showed that PRRX1 expression was upregulated in AC16 cells after OGD/R treatment. PRRX1 silencing mitigated OGD/R-induced excessive mitophagy by increasing the mitochondrial membrane potential, adenosine triphosphate and p62 levels, and reducing LC3 II/I level in AC16 cells. In addition, PRRX1 knockdown attenuated OGD/R-induced lactate dehydrogenase (LDH) release and cardiomyocyte ferroptosis by decreasing reactive oxygen species, Fe 2+ and acyl-CoA synthetase long-chain family member 4 (ACSL4) levels, and increasing glutathione (GSH) and glutathione peroxidase 4 (GPX4) levels. Furthermore, PRRX1 transcriptionally promoted FK506 binding protein 5 (FKBP5), and increased p38 MAPK activation in AC16 cells. FKBP5 overexpression reversed the effects of PRRX1 silencing on excessive mitophagy and cardiomyocyte ferroptosis in OGD/R-treated AC16 cells. These effects were mitigated by a p38 MAPK inhibitor. Finally, PRRX1 downregulation mitigated myocardial I/R injury by reducing heart infarction and creatine kinase-myocardial band (CK-MB) levels in rat models. These findings demonstrate that PRRX1 silencing attenuates OGD/R-induced excessive mitophagy and cardiomyocyte ferroptosis by decreasing FKBP5 expression and inactivating p38 MAPK signaling, indicating the cardioprotective potential of PRRX1 silencing in myocardial I/R injury.
研究领域:
心血管生物学
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分子医学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Antioxidants
·
2022
·Vol. 11
·期 8
·1498
·
IF 7.675
Chongshan Dai,Qinzhi Zhang,Linjie Shen,Gaurav Sharma,Haiyang Jiang,Zhanhui Wang,Jianzhong Shen
Quinocetone (QCT), a member of the quinoxaline 1,4-di-N-oxides (QdNOs) family, can cause genotoxicity and hepatotoxicity, however, the precise molecular mechanisms of QCT are unclear. This present study investigated the protective effect of quercetin on QCT-induced cytotoxicity and the underlying molecular mechanisms in human L02 and HepG2 cells. The results showed that quercetin treatment (at 7.5–30 μM) significantly improved QCT-induced cytotoxicity and oxidative damage in human L02 and HepG2 cells. Meanwhile, quercetin treatment at 30 μM significantly inhibited QCT-induced loss of mitochondrial membrane potential, an increase in the expression of the CytC protein and the Bax/Bcl-2 ratio, and an increase in caspases-9 and -3 activity, and finally improved cell apoptosis. Quercetin pretreatment promoted the expression of the phosphorylation of p38, Nrf2, and HO-1 proteins. Pharmacological inhibition of p38 significantly inhibited quercetin-mediated activation of the Nrf2/HO-1 pathway. Consistently, pharmacological inhibitions of the Nrf2 or p38 pathways both promoted QCT-induced cytotoxicity and partly abolished the protective effects of quercetin. In conclusion, for the first time, our results reveal that quercetin could improve QCT-induced cytotoxicity and apoptosis by activating the p38/Nrf2/HO-1 pathway and inhibiting the ROS/mitochondrial apoptotic pathway. Our study highlights that quercetin may be a promising candidate for preventing QdNOs-induced cytotoxicity in humans or animals.Keywords:quercetin;quinocetone;oxidative stress;apoptosis;p38/Nrf2/HO-1 pathway;NF-κB pathway
研究领域:
毒理学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2020
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IF 4.152
Lei Liu,Yali Miao,Xuetao Shi,Huichang Gao,Yingjun Wang
Phosphorous-containing biopolymers have been applied to expedite the regeneration of damaged bone tissue by stimulating the function of phosphorous groups in natural bones. However, the underlying mechanism of phosphorous-containing biopolymers in promoting osteogenic differentiation is unclarified. Herein, we synthesized phosphorylated chitosan hydrogels by incorporating phosphocreatine into chitosan molecular chains under mild conditions. The introduction of phosphate groups improved properties of protein adsorption and calcium deposition without affecting the morphology of hydrogels. Our results showed that phosphorylated chitosan hydrogels could not only promote alkaline phosphatase activity and mineralization but also upregulate the expression of osteogenic-related genes and proteins. Meanwhile, application of c-Jun N-terminal kinase inhibitor SP600125 and p38 mitogen-activated protein kinase inhibitor SB203580 repressed the expression of osteogenic-related markers in gene and protein levels. To the best of our knowledge, it is reported for the first time that phosphorous-containing biopolymers promote osteogenic differentiation of osteoblasts via JNK and p38 signaling pathways.
研究领域:
生物材料
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组织工程
·
骨再生
·
细胞信号
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 14
·7666
·
IF 6.208
Ping Li,Yiting Yang,Zijin Lin,Shijin Hong,Ling Jiang,Han Zhou,Lu Yang,Liang Zhu,Xiaodong Liu,Li Liu
Liver injury is often associated with hepatic retinopathy, resulting from accumulation of retinal toxins due to blood–retinal barrier (BRB) dysfunction. Retinal pigment epithelium highly expresses MRP1/Mrp1. We aimed to investigate whether liver injury affects the function and expression of retinal Mrp1 using bile duct ligation (BDL) rats. Retinal distributions of fluorescein and 2,4-dinitrophenyl-S-glutathione were used for assessing Mrp1 function. BDL significantly increased distributions of the two substrates and bilirubin, downregulated Mrp1 protein, and upregulated phosphorylation of p38 and MK2 in the retina. BDL neither affected the retinal distribution of FITC-dextran nor expressions of ZO-1 and claudin-5, demonstrating intact BRB integrity. In ARPE-19 cells, BDL rat serum or bilirubin decreased MRP1 expression and enhanced p38 and MK2 phosphorylation. Both inhibiting and silencing p38 significantly reversed the bilirubin- and anisomycin-induced decreases in MRP1 protein. Apparent permeability coefficients of fluorescein in the A-to-B direction (Papp, A-to-B) across the ARPE-19 monolayer were greater than Papp, B-to-A. MK571 or bilirubin significantly decreased Papp, A-to-Bof fluorescein. Bilirubin treatment significantly downregulated Mrp1 function and expression without affecting integrity of BRB and increased bilirubin levels and phosphorylation of p38 and MK2 in rat retina. In conclusion, BDL downregulates the expression and function of retina Mrp1 by activating the p38 MAPK pathway due to increased bilirubin levels.Keywords:bile duct ligation;blood–retinal barrier;multidrug resistance-associated protein 1;liver injury;p38 MAPK;bilirubin
研究领域:
药理学
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神经科学
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病理学
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产品关联
DOI
PubMed
高影响因子
LIFE SCIENCES
·
2023
·
IF 6.1
Haijie Wu,Xiaohu Shi,Yingda Zang,Xiaodi Zhao,Xikun Liu,Weida Wang,Wenying Shi,Clarence T.T. Wong,Li Sheng,Xiaoguang Chen,Sen Zhang
Aims Cisplatin is a widely-used drug in the clinical treatment of tumors, but kidney nephrotoxicity is one of the reasons that limits its widespread use. We previously found that 7-hydroxycoumarin-β-D-glucuronide (7-HCG) was one of metabolites of skimmin and highly enriched in the kidneys and maintained a high blood concentration in skimmin-treated rats. Therefore, we investigated whether 7-HCG has a protective effect on cisplatin-induced acute kidney injury. Materials and methods Male C57BL/6 mice were continuously administered 7-HCG for five days, and on the third day, an intraperitoneal injection of cisplatin was given to induce acute kidney injury. After 72 h, the mice were sacrificed for analysis. Serum and renal tissue were collected for renal function evaluation. RNA sequencing was used to explore mechanism, and further validated by western blot and immunohistochemistry. In addition, pharmacokinetic study of oral 7-HCG administration was performed to examine how much 7-hydroxycoumarin (7-HC) was metabolized and 7-HC possible effect on renal protection. Key findings 7-HCG significantly reduced serum BUN and SCR levels, and alleviated pathological damage in renal tissue, and reduced the renal index. RNA sequencing revealed that 7-HCG could reverse p38 MAPK regulation and apoptosis. By western blotting, it was found that 7-HCG could reduce renal injury by reducing p-p38, p-ERK, p-JNK, cleaved-caspase3 and Bax. The immunohistochemical results of cleaved-caspase3 were consistent with western blotting. 7-HCG also significantly reduced the production of ROS in kidney tissue. Pharmacokinetic experiments have shown that 7-HCG in the blood increased rapidly and was eliminated slowly, with an average t 1/2β of 18.3 h. And the concentration of 7-HCG in the target organ kidney was about 4 times higher than that in blood. Significance Our findings indicate that 7-HCG could exert its protective effect against cisplatin-induced acute kidney injury by inhibiting apoptosis via p38 MAPK regulation and elucidates its pharmacokinetics.
研究领域:
药理学
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肾病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2022
·Vol. 37
·期 7
·1551-1562
·
IF 4.109
Dan Song,Yuan Liu,Yaxin Yao,Feng Liu,Wenjing Tao,Xiaolong Zhou,Runsheng Li,Xiaowei Zhang,Xiangchen Li
The aim of this study was to assess the protective effect and potential mechanism of melatonin against bisphenol A (BPA)-induced apoptosis and oxidative damage in FLK-BLV cells. The results showed that BPA reduced cell viability in a dose- and time-dependent manner, caused cell shrinkage and induced oxidative stress and apoptosis in FLK-BLV cells, which were effectively reversed by melatonin. In addition, BPA caused autophagy flux impairment, which was confirmed by the increased of LC3-II and p62 levels, whereas melatonin treatment effectively reduced p62 levels under BPA treatment, and reversed apoptosis-related protein expression patterns caused by BPA. However, inhibition of autophagy by CQ partially abolished the protective effect of melatonin on apoptosis, suggesting that melatonin against BPA-induced oxidative injury and apoptosis by activating autophagy pathway. Moreover, we found that melatonin inhibited BPA-induced the activation of p38 MAPK, which was comparable to SB203580 pretreatment, and companied by the activation of autophagy and decreases of apoptosis when compared to BPA alone, indicating that melatonin protected against BPA-induced apoptosis partially through the p38 MAPK-autophagy pathway. In conclusion, these results suggest that melatonin may prevent BPA-induced FLK-BLV cell damage by inhibiting p38/MAPK signaling pathway and activating autophagy, and it could be a potential therapeutic compound in preventing BPA-induced cell damage.
研究领域:
细胞生物学
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毒理学
·
药理学
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2016
·
IF 4.32
Xinxin Yan,Wen Yang,Zengwu Shao,Shuhua Yang,Xianzhe Liu
Carbon nanomaterials are becoming increasingly significant in biomedical fields since they exhibit exceptional physicochemical and biocompatible properties. Today, the stem cells offer potentially new therapeutic approaches in tissue engineering and regenerative medicine. However, the induction of differentiation into specific lineages remains challenging, which provoked us to explore the biomedical applications of carbon nanomaterials in stem cells. In this study, we investigated the interactions between graphene/single-walled carbon nanotube (G/SWCNT) hybrids and rat mesenchymal stem cells (rMSCs) and focused on the proliferation and differentiation of rMSCs treated with G/SWCNT hybrids. Cell viability and morphology were evaluated using cell counting kit-8 assay and immunofluorescence staining, respectively. Osteogenic differentiation evaluated by alkaline phosphatase activity of MSCs proved to be higher after treatment with G/SWCNT hybrids, and the mineralized matrix nodule formation was also enhanced. In addition, the expression levels of osteogenic-associated genes were upregulated, while the adipocyte-specific markers were downregulated. Consistent with these results, we illustrated that the effect of G/SWCNT hybrids on the process of osteogenic differentiation of rMSCs can be modulated by activating the p38 signaling pathway and inhibiting the extracellular signal-regulated kinase 1/2 pathway. Nevertheless, our study suggests that carbon nanomaterials offer a promising platform for regenerative medicine in the near future.
研究领域:
生物医学工程
·
纳米技术
·
干细胞研究
·
再生医学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2025
·
IF 4.3
Wan Yu-hui,Cheng Zeng-jing,Fan Ling-xiang,Yang De-hong,Chen Bing-lin,Chen Xiang-xin,Zhu Qing
Subarachnoid hemorrhage (SAH) is associated with high mortality and morbidity rates. In its early stages, a substantial influx of blood into the subarachnoid space triggers excessive activation of microglia, which markedly contributes to early brain injury (EBI), a pivotal determinant of poor prognosis. Tremella fuciformis polysaccharides (TFPSs), as acidic heteropolysaccharides from the fruiting bodies of Tremella, exhibit robust anti-inflammatory characteristics and many biological properties. Nonetheless, the impact of TFPSs on EBI after SAH has yet to be reported, and the molecular mechanisms underlying these effects remain elusive. We used in vivo and in vitro models to study the effects of TFPSs on microglia post-SAH. Network pharmacology analysis was used to predict the targets of TFPSs and the pathways through which it exerts its therapeutic effects. These predictions were subsequently corroborated through flow cytometry, Western blotting, immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA), and quantitative real‑time polymerase chain reaction, both in vivo and in vitro. After 24 h post-SAH, TFPS-treated mice presented improved neurological function and reduced cerebral edema. TFPSs reversed microglial activation, enhanced phagocytic ability, and reduced neuronal apoptosis. Network pharmacology identified KDR as a potential target of TFPSs, with the P38 MAPK pathway as the downstream pathway. TFPSs attenuated KDR expression, inhibited the P38 MAPK/NF-κB pathway, reduced inflammatory cytokine expression, and increased microglial phagocytic capacity post-SAH. This investigation revealed that TFPSs may ameliorate EBI after SAH, potentially via the regulation of the KDR-mediated P38 MAPK/NF-κB pathway and phagocytic function.
研究领域:
神经科学
·
药理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2023
·
IF 5.1
Asmaa S.A. Hammad,Mohamed M. Sayed-Ahmed,Sara Mohamed Naguib Abdel Hafez,Ahmed R.N. Ibrahim,Mohamed M.A. Khalifa,Mahmoud El-Daly
Chemotherapy-induced peripheral neuropathy is a common adverse effect associated with a number of chemotherapeutic agents including paclitaxel (PTX) which is used in a wide range of solid tumors . Development of PTX-induced peripheral neuropathy (PIPN) during cancer treatment requires dose reduction which limits its clinical benefits. This study is conducted to investigate the role of toll like receptor-4 (TLR4) /p38 signaling and Klotho protein expression in PIPN and the role of trimetazidine (TMZ) in this pathway. Sixty-four male Swiss albino mice were divided into 4 groups (n = 16); Group (1) injected intraperitoneally (IP) with ethanol/tween 80/saline for 8 successive days. Group (2) received TMZ (5 mg/kg, IP, day) for 8 successive days. Group (3) treated with 4 doses of PTX (4.5 mg/kg, IP) every other day over a period of 7 days. Group (4) received a combination of TMZ as group 2 and PTX as group 3. The Effect of TMZ on the antitumor activity of PTX was studied in another set of solid Ehrlich carcinoma (SEC)-bearing mice that was similarly divided as the above-mentioned set. TMZ mitigated tactile allodynia , thermal hypoalgesia , numbness and fine motor discoordination associated with PTX in Swiss mice. The results of the current study show that the neuroprotective effect of TMZ can be attributed to inhibition of TLR4/p38 signaling which also includes a reduction in matrix metalloproteinase-9 (MMP9) protein levels as well as the proinflammatory interleukin-1β (IL-1β) and preserving the levels of the anti-inflammatory IL-10. Moreover, the current study is the first to demonstrate that PTX reduces the neuronal levels of klotho protein and showed its modulation via cotreatment with TMZ. In addition, this study showed that TMZ neither alter the growth of SEC nor the antitumor activity of PTX. In conclusion, we suggest that (1) Inhibition of Klotho protein and upregulation of TLR4/p38 signals in nerve tissues may contribute to PIPN. (2) TMZ attenuates PIPN by modulating TLR4/p38 and Klotho protein expression without interfering with its antitumor activity.
研究领域:
肿瘤学
·
药理学
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神经科学
·
免疫学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）