EXPERIMENTAL CELL RESEARCH
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2022
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IF 4.145
Runze Zhao,Li Yang,Shuangjian He,Tingting Xia
Intervertebral disc degeneration (IVDD) is a main contributor to induce low back pain, and the pathogenic mechanism of IVDD remains unclear. The nucleus pulposus (NP) is a component of the intervertebral disc (IVD) that provides protection from mechanical stimuli. The matrix stiffness of NP tissue increases during the process of disc degeneration. Although several studies have found that pathological mechanical stimuli induce NP cell senescence, which is relevant for NP degeneration, however, the effect of matrix stiffness on NP cell senescence is not clear. Therefore, in the present study, we used polyvinyl alcohol (PVA) hydrogel with controllable stiffness to mimic the matrix stiffness of normal (4 kPa) and severely degenerated (20 kPa) NP tissue. Rat NP cells were isolated and cultured on substrates with different stiffness, and the cell proliferation , SA-β-gal activity, cell cycle, telomerase activity and the phenotype markers of NP cells were analyzed. Moreover, cytoskeleton staining and NP cellular Young's modulus on different substrates were also measured. To further investigate how substrate stiffness affects NP cell senescence, lysyl oxidase (LOX) was used to restore the extracellular matrix (ECM) synthesis of NP cells. The expression levels of integrin β1 and p38 MAPK were then measured. Our results showed that the 20 kPa substrate significantly induced NP cell senescence compared to the 4 kPa substrate. NP cells cultured on the 20 kPa substrate failed to maintain the expression of their phenotype markers. Furthermore, the 20 kPa substrate induced an increase of Young's modulus of NP cells, which possibly through up regulating the expressions of integrin β1 and p38 MAPK. These results indicated that the integrin β1-p38 MAPK signaling pathway may participated in substrate stiffness induced senescence of NP cells. LOX significantly increased ECM synthesis and inhibited substrate stiffness induced NP cell senescence, which indicated that matrix mechanics may be essential for maintaining the function of NP cell. Our results may provide a new perspective on the mechanism of IVDD by pathological matrix mechanics.
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BIOCHEMICAL PHARMACOLOGY
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2022
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IF 6.1
Yanbei Tu,Lihua Tan,Tao Lu,Kai Wang,Haiyong Wang,Bing Han,Yuxin Zhao,Hanbin Chen,Yanfang Li,Haixia Chen,Meiwan Chen,Chengwei He
The roots of Glycine tabacina are used to treat rheumatoid arthritis (RA) and joint infection in folk medicine. Glytabastan B (GlyB), a newly reported coumestan isolated from this species, was found to significantly attenuate IL-1β-induced inflammation in SW982 human synovial cells at 3 and 6 μM, as evidenced by the decreased levels of pro-inflammatory mediators and matrix metalloproteinases (MMPs). GlyB also suppressed RANKL-induced osteoclastogenesis, decreased the expression of osteoclastogenic markers (NFATc1, CTSK , MMP-9) and osteoclast-mediated bone resorption. Further, GlyB administration (12.5 and 25 mg/kg) significantly inhibited inflammation, osteoclast formation and disease progression in collagen-induced arthritis (CIA) mice. Integration of network pharmacology , quantitative phosphoproteomic and experimental pharmacology results revealed that these beneficial actions were closely associated with the blockade of GlyB on the activation of MAPK , PI3K/AKT and their downstream signals including NF-κB and GSK3β/NFATc1. Drug affinity responsive target stability (DARTS) assay, cellular thermal shift (CETSA) assay and molecular docking analysis confirmed that there were direct interactions between GlyB and its target proteins ERK2 , JNK1 and class Ⅰ PI3K catalytic subunit p110 (α, β, δ and γ), which significantly contributed to the inhibition of activation of MAPK and PI3K/AKT pathways. In conclusion, these results strongly suggest GlyB is a promising multiple-target candidate for the development of agents for the prevention and treatment of RA.
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FISH & SHELLFISH IMMUNOLOGY
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2023
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IF 4.7
Hao Cai,Ke Li,Yilin Yin,Xiaotong Ni,Shiwen Xu
Bis(2-ethylhexyl) phthalate (DEHP) is not only a widely used plasticizer but also a common endocrine disruptor that frequently lingers in water, posing a threat to the health of aquatic organisms . Quercetin (Que) is a common flavonol found in the plant kingdom known for its antioxidant, anti-inflammatory, and immunomodulatory effects. However, it is still unclear whether DEHP can cause pyroptosis and affect the expression of cytokines of grass carp L8824 cells and whether Que has antagonistic effect in this process. In our study, grass carp L8824 cells were treated into four groups after 24 h, namely NC group, DEHP group (1000 μM DEHP), Que group (5 μM Que), and DEHP + Que group (1000 μM DEHP + 5 μM Que). Our results indicate a significant increase in the level of ROS in L8824 cells after exposure to DEHP. DEHP upregulated oxidative stress markers (H 2 O 2 and MDA) and downregulated antioxidant markers (CAT, GSH, SOD , and T-AOC). DEHP also upregulated MAPK and NF-κB signal pathway-related proteins and mRNA expressions (p-p38, p-JNK, p-EPK, and p65). As for cell pyroptosis and its related pathways, DEHP upregulated pyroptosis-related protein and mRNA expressions (GSDMD, IL-1β, NLRP3, Caspase-1, LDH , pro-IL-18, IL-18, and ASC). Finally, DEHP can up-regulated cytokines (IL-6 and TNF-α) expression, down-regulated cytokines (IL-2 and IFN-γ) expression, and antimicrobial peptides (β-defensin, LEAP2, and HEPC). The co-treatment of L8824 cells with DEHP and Que inhibited the activation of the ROS/MAPK/NF-κB axis, alleviated pyroptosis, and restored expression of immune-related indicators. Finally, NAC was applied to reverse intervention of oxidative stress. In summary, Que inhibited DEHP-induced pyroptosis and the influence on cytokine and antimicrobial peptide expression in L8824 cells by regulating the ROS/MAPK/NF-κB pathway. Our results demonstrate the threat to fish health from DEHP exposure and confirmed the harm of DEHP to the aquatic ecological environment and the detoxification effect of Que to DEHP, which provides a theoretical basis for environmental toxicology.
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Food Science and Human Wellness
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2020
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IF 2.455
Ruichang Gao,Wanghui Shu,Yang Shen,Quancai Sun,Wengang Jin,Dajing Li,Ying Li,Li Yuan
Previous studies have suggested that polypeptides extracted from milk, soybean, fish, eggs, and meat possess potential anti-inflammatory effects. To date, few studies have reported the anti-inflammatory function of sturgeon peptides and their underlying mechanisms are unknown. The current study was therefore to determine the anti-inflammatory potential of sturgeon peptides with lipopolysaccharide (LPS)-induced RAW264.7 inflammatory model. Pepsin hydrolysate (PeH) was purified by ultrafiltration and Sephadex G-15 gel filtration chromatography. PeH significantly reduced the inflammatory mediator (NO) and inflammatory cytokines (IL-6、TNF-α and IL-1β) expression in a dose-dependent manner. Moreover, the purified sturgeon peptide (F2) possessed strong antioxidant potential and effectively inhibited DPPH and ABTS free radicals. F2 significantly suppressed the expression of MAPKs, IκBα, and NF-κB p65, indicating that F2 exerted anti-inflammatory influence by the inhibition of MAPK and NF-κB pathways.
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BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
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2013
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IF 3.848
Lin-Hui Zhang,Yong-Liang Jia,Xi-Xi Lin,Hong-Quan Zhang,Xin-Wei Dong,Jun-Ming Zhao,Jian Shen,Hui-Juan Shen,Fen-fen Li,Xiao-Feng Yan,Wei Li,Yu-Qing Zhao,Qiang-Min Xie
Background Ginseng is a traditional Chinese herb that has been used for thousands of years. In the present study, effects and mechanisms of AD-1 were evaluated for its development as a novel anti-lung cancer drug. Methods The cytotoxic activity was evaluated by MTT assay. Flow cytometry was employed to detect cell cycle, apoptosis and ROS. Western blot and immunohistochemistry were used to analyze signaling pathways. Lung cancer xenograft models were established by subcutaneous implantation of A549 or H292 cells into nude mice. Results AD-1 concentration-dependently reduces lung cancer cell viability without affecting normal human lung epithelial cell viability. In A549 and H292 lung cancer cells, AD-1 induces G 0 /G 1 cell cycle arrest, apoptosis and ROS production. The apoptosis can be attenuated by a ROS scavenger — N-acetylcysteine (NAC). In addition, AD-1 up-regulates the expression of p38 and ERK phosphorylation. Addition of a p38 inhibitor SB203580, suppresses the AD-1-induced decrease in cell viability. Furthermore, genetic silencing of p38 attenuates the expression of p38 and decreases the AD-1-induced apoptosis. Treatment with NAC reduces AD-1-induced p38 phosphorylation, which indicates that ROS generation is involved in the AD-1-induced p38 activation. In mice, oral administration of AD-1 (10–40 mg/kg) dose-dependently inhibited the growth of xenograft tumors without affecting body weight and decreases the expression of VEGF, MMP-9 and CD34 in tumor tissue. TUNEL staining confirms that the tumors from AD-1 treated mice exhibit a markedly higher apoptotic index. Conclusions and general significance These data support development of AD-1 as a potential agent for lung cancer therapy.
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BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2025
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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.
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FOOD CHEMISTRY
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2024
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IF 8.5
Yunhao Ma,Xinran Dong,Ying Wang,Zhaoming Wang,Yong Xie,Wendi Zhang,Daodong Pan,Hui Zhou,Baocai Xu
Research conducted previously has demonstrated that apoptosis significantly influences the chicken quality. While ROS are acknowledged as significant activators of apoptosis, the precise mechanism by which they influence muscle cell apoptosis in the post-mortem remains unclear. In this study, chicken samples were treated with rosemarinic acid and H 2 O 2 to induce varying ROS levels, and the ROS-triggered apoptosis mechanism in chicken muscle cells in post-mortem was analyzed. The TUNEL results revealed that elevated ROS levels in chicken were associated with a greater degree of muscle cell apoptosis. Western-blot results suggested that sarcoplasmic ROS could initiate apoptosis through the mitochondrial pathway by activating the MAPK-JNK signaling pathway. Moreover, TEM and shear force results demonstrated that muscle cell apoptosis initiates myofiber fragmentation and structural damage to sarcomeres, ultimately reducing chicken tenderness. This study enhances our understanding of post-mortem muscle cell apoptosis, providing valuable insights for regulating chicken quality.
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PHYTOMEDICINE
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2024
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IF 6.7
Tingwen Zhang,Yue Zhong,Yan Shi,Chengcheng Feng,Lu Xu,Zheng Chen,Xin Sun,Yan Zhao,Xialin Sun
Background The pathogenesis of acute liver injury (ALI) has been a pressing issue in the medical scientific community. We previously found that 5-O-methylvisammioside (MeV) from Saposhnikovia divaricata (Turcz.) Schischk has excellent anti-inflammatory properties. However, the mechanism by which MeV protects against ALI still needs to be deeply investigated. Purpose In the present study, we established an acetaminophen (APAP) -induced ALI mouse model and pre-protected the mice with MeV. Methods & Results Our findings indicate that MeV (5 and 10 mg/kg) lowered the blood levels of alanine aminotransferase and aspartate aminotransferase and reduced the infiltration of inflammatory cells in the liver. MeV initially showed an inhibitory effect on ALI. We then analyzed the molecular mechanisms underlying the effects of MeV by transcriptomic and metabolomic analyzes. Through transcriptomic analysis, we identified 4675 differentially expressed genes between the APAP+MeV group and the APAP-induced ALI group, which were mainly enriched in the MAPK pathway, the TNF pathway, and the NF-κB pathway. Through metabolomic analysis, we found that 249 metabolites in the liver were differentially regulated between the APAP+MeV group and the APAP- induced ALI group, which were mainly enriched in the arachidonic acid pathway. The mRNA expression levels of key genes (encoding TNF-α, p38, AP-1, RelB, IL-1β, and Ptges), as determined by RT-PCR analysis, were consistent with the RNA-seq data. The ELISA results indicate that MeV markedly decreased the serum levels of TNF-α and IL-1β in mice. Finally, the key proteins in the NF-κB and MAPK pathways were examined using immunoblotting. The results showed that MeV decreased IκB-α phosphorylation and inhibited the nuclear translocation of NF-κB. In addition, MeV reduced the hepatic inflammatory burst mainly by inhibiting the phosphorylation of p38 and JNK in the MAPK pathway. Conclusion The present study demonstrated (i) that MeV could ameliorate APAP-induced ALI by inhibiting arachidonic acid metabolism and the TNF, MAPK, and NF-κB pathways, and (ii) that MeV is a promising drug candidate for the prevention of ALI.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Wenyang Zhou,Zhenhao Liu,Xichuan Qiu,Minghao Tian,Baoqiang He,Chao Tang,Qiang Tang,Rupei Ye,Dejun Zhong,Yehui Liao
Following spinal cord injury (SCI), pyroptosis plays a significant role in regulating neuroinflammation during the secondary phase of injury. Although 1,8-cineole possesses anti-inflammatory effects, its role in SCI and underlying molecular mechanisms remains unclear. This study revealed that 1,8-cineole promoted motor function recovery in spinal cord-injured rats, reduced NLRP3 inflammasome-mediated microglial pyroptosis and activation, enhanced neuronal regeneration, and suppressed neuronal apoptosis and glial scar formation. Network pharmacology analysis showed that 1,8-cineole targets the PI3K/AKT and P38 MAPK pathways to inhibit microglial activation and pyroptosis. Finally, using a conditional co-culture system, we demonstrated that 1,8-cineole-treated microglia facilitated neuronal regeneration while inhibiting apoptosis. These findings indicate that 1,8-cineole promotes functional recovery post-SCI by protecting neurons by suppressing microglial pyroptosis and activation through the PI3K/AKT and P38 MAPK axes.
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Frontiers in Pharmacology
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2024
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IF 4.4
Hu Hanqiong,Sun Yifan,Yang Zhen,Che Limuge,Cai Mingyang,Li Xiaoxuan,Huang Xianju,Bagen Hurile,Qiqige Wulan,Guleng Wuyunsiri,Ma Liqun,Tong Haiying
Introduction: Zhachong Shisanwei Pill (ZSP) is a classical Mongolian formula that combines 13 types of Chinese medicinal materials and has been used for treating ischemic stroke (IS) for centuries. However, the underlying molecular mechanisms have yet to be fully elucidated. The aim of this study is to explore potential mechanism of ZSP on nerve cells in cerebral ischemic injury.Methods: To simulate the pathological process of oxidative stress following IS, an injury model using PC12 cells was induced with hydrogen peroxide (H2O2). Afterward, PC12 cells were treated with ZSP medicated serum at low, medium, and high doses. Various assays were conducted to assess cell viability and oxidative stress indicators, including lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), reactive oxygen species (ROS), and mitochondrial membrane potential (MMP). Cell apoptosis was evaluated through morphological assessment and flow cytometry. Additionally, the expression levels of apoptosis-related proteins (Bcl-2, Bax, Caspase-9, Caspase-3, PARP) and signaling pathway proteins (JNK, phosphorylated JNK, ERK, phosphorylated ERK, p38, and phosphorylated p38) were measured using automated Western blotting.Results: Our findings indicate that ZSP medicated serum preconditioning improves the condition of PC12 cells injured by H2O2. Specifically, it increased cell survival rates and reduced LDH release. Additionally, ZSP treatment decreased ROS levels and MDA content, while enhancing the activity of SOD and CAT in the injured PC12 cells. ZSP also reversed the depolarization of mitochondrial membrane potential and protected cells from apoptosis by modulating the expression of apoptosis-related proteins, including Bcl-2, Bax, Caspase-9, Caspase-3, and PARP. Furthermore, the overactivation of the MAPK signaling pathway due to H2O2-induced injury was inhibited, as evidenced by the downregulation of phosphorylated JNK, ERK, and p38 levels.Discussion: Mongolian medicine ZSP demonstrates protective effects against H2O2-induced oxidative stress and apoptosis in PC12 cells. The underlying mechanism may involve the inhibition of the MAPK signaling pathway, enhancement of antioxidant enzyme activity, reduction of intracellular peroxidation levels, and suppression of intrinsic apoptosis pathways.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2025
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IF 6.1
Weimin Zuo,Tingting Lin,Hehuan Zhu,Xiaobi Huang,Yudong Guo,Qihe Long,Yanfeng Liang,Yongyang Chen,Xiaoqing Xu,Yanhong Su,Wenmei Su
As a widely used chemical raw material, the potential exposure threat of bisphenol A is inevitable. At present, there is no effective treatment for the toxicity caused by bisphenol A (BPA). Therefore, it is necessary to find a natural drug to alleviate the toxicity of BPA. In this study, Caenorhabditis elegans was applied to evaluate the protective effect of tremella polysaccharide (TPC) on BPA. The results showed that TPC regained the locomotion and chemotaxis ability induced by BPA. Also TPC protected the dopamine neuron cells against the BPA-induced damage. Moreover, TPC also regulated IIS/PI3K/AKT and MAPK/AMPK pathways to activate daf-16 and skn-1 (homolog to Nrf-2) increase the antioxidant ability in C. elegans . TPC treatment obviously increased the expression of GST-4 as well as the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) to sharply reduced the high reactive oxygen species (ROS) level to help the C. elegans to against the toxicity induced by BPA. Altogether, these results indicated TPC is a promising natural drug to alleviate the toxicity induced by BPA.
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American Journal of Translational Research
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2017
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IF 2.829
Yuanfeng Zhu,Shijun Fan,Ning Wang,Xiaoli Chen,Yongjun Yang,Yongling Lu,Qian Chen,Jiang Zheng,Xin Liu
Activation of NADPH oxidase 2 (NOX2) triggers reactive oxygen species (ROS) generation, both of which are essential for robust microbial clearance by phagocytes. However, it is unknown whether inhibition of NOX2 activation or ROS generation affects cellular phagocytosis. Here, we found that the classic NOX2 inhibitor diphenyleneiodonium (DPI) induced uptake of E. coli by murine peritoneal macrophages through enhancing phagocytosis, and this effect was temperature-sensitive and attenuated by cytochalasin D as well as chemical inhibition of Syk and PLCγ, two downstream kinases involved in actin polymerization during phagocytosis. DPI also decreased the production of TNF-α and IL-6 resulting from E. coli stimulation. The DPI-induced enhancement of phagocytosis was independent of NOX2 inhibition or ROS generation but depended on increased intracellular calcium and activation of the p38 MAPK signaling pathway. Furthermore, DPI enhanced bacterial elimination and ameliorated inflammation in E. coli -infected mice, leading to improved survival. Our results demonstrate that DPI facilitates ROS-independent bacterial phagocytosis by macrophages through activation of calcium and p38 MAPK signaling pathways.
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危险品化学品经营许可证（带存储）