Biomaterials Advances
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2024
·
IF 5.5
Xianzhen Yin,Yihao Wei,Haotian Qin,Jin Zhao,Yixiao Chen,Sen Yao,Nan Li,Ao Xiong,Deli Wang,Peng Zhang,Peng Liu,Hui Zeng,Yingqi Chen
Angiogenesis plays a crucial role in bone regeneration. Hypoxia is a driving force of angiogenesis at the initial stage of tissue repair. The hypoxic microenvironment could activate the hypoxia-inducible factor (HIF)-1α signaling pathway in cells, thereby enhancing the proliferation, migration and pro-angiogenic functions of stem cells. However, long-term chronic hypoxia could inhibit osteogenic differentiation and even lead to apoptosis. Therefore, shutdown of the HIF-1α signaling pathway and providing oxygen at later stage probably facilitate osteogenic differentiation and bone regeneration. Herein, an oxygen tension regulating hydrogel that sequentially activate and deactivate the HIF-1α signaling pathway were prepared in this study. Its effect and mechanism on stem cell differentiation were investigated both in vitro and in vivo . We proposed a gelatin-based hydrogel capable of sequentially delivering a hypoxic inducer (copper ions) and oxygen generator (calcium peroxide). The copper ions released from the hydrogels significantly enhanced cell viability and VEGF secretion of BMSCs via upregulating HIF-1α expression and facilitating its translocation into the nucleus. Additionally, calcium peroxide promoted alkaline phosphatase activity, osteopontin secretion, and calcium deposition through the activation of ERK1/2. Both Cu 2+ and calcium peroxide demonstrated osteogenic promotion individually, while their synergistic effect within the hydrogels led to a superior osteogenic effect by potentially activating the HIF-1α and ERK1/2 signaling pathways.
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BIOMEDICINE & PHARMACOTHERAPY
·
2022
·
IF 7.419
Yuanqiao Ma,Xiaoxiao Xu,Hang Wu,Changbo Li,Peijie Zhong,Zejin Liu,Chuang Ma,Wenhua Liu,Chenyu Wang,Yijie Zhang,Junpeng Wang
Ivermectin has been proposed as a potential anti-inflammatory drug in addition to its antiparasitic activity. Here we investigated the potential role of ivermectin in the pathogenesis of acute lung injury (ALI) using the lipopolysaccharide (LPS)- or bleomycin (BLM)-induced mice models. Male C57BL/6 mice were given ivermectin orally every day for the remainder of the experiment at doses of 1 or 2 mg/kg after 24 h of LPS or BLM treatment. Ivermectin reversed severe lung injury caused by LPS or BLM challenge, including mortality, changes in diffuse ground-glass and consolidation shadows on lung CT imaging, lung histopathological scores, lung wet/dry ratio, and protein content in the bronchoalveolar lavage fluid (BALF). Furthermore, ivermectin also reduced total lung BALF inflammatory cells, infiltrating neutrophils, myeloperoxidase activity, and plasma TNF-α and IL-6 levels in mice treated with LPS or BLM. Finally, the mechanism study showed that LPS or BLM administration increased JNK, Erk1/2, and p38 MAPK phosphorylation while decreasing IκBα expression, an inhibitor of NF-κB. However, ivermectin increased IκBα expression but blocked elevated phosphorylated JNK and p38 MAPK, not Erk1/2, in both ALI mice. These findings suggested that ivermectin may alleviate ALI caused by LPS or BLM in mice, partly via lowering the inflammatory response, which is mediated at least by the inhibition of MAPK and NF-κB signaling. Collectively, ivermectin might be used to treat acute lung injury/acute respiratory distress syndrome.
研究领域:
药理学
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免疫学
·
呼吸病学
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PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2020
·Vol. 24
·期 17
·9667-9681
·
IF 4.486
Li-Juan Wang,Lin He,Lu Hao,Hong-Lei Guo,Xiang-Peng Zeng,Ya-Wei Bi,Guo-Tao Lu,Zhao-Shen Li,Liang-Hao Hu
Chronic pancreatitis (CP) is characterized by persistent inflammation of the pancreas that results in progressive loss of the endocrine and exocrine compartment owing to atrophy and/or replacement with fibrotic tissue. Currently, the clinical therapeutic scheme of CP is mainly symptomatic treatment including pancreatic enzyme replacement, glycaemic control and nutritional support therapy, lacking of specific therapeutic drugs for prevention and suppression of inflammation and fibrosis aggravating in CP. Here, we investigated the effect of isoliquiritigenin (ILG), a chalcone-type dietary compound derived from licorice, on pancreatic fibrosis and inflammation in a model of caerulein-induced murine CP, and the results indicated that ILG notably alleviated pancreatic fibrosis and infiltration of macrophages. Further in vitro studies in human pancreatic stellate cells (hPSCs) showed that ILG exerted significant inhibition on the proliferation and activation of hPSCs, which may be due to negative regulation of the ERK1/2 and JNK1/2 activities. Moreover, ILG significantly restrained the M1 polarization of macrophages (RAW 264.7) via attenuation of the NF-κB signalling pathway, whereas the M2 polarization was hardly affected. These findings indicated that ILG might be a potential anti-inflammatory and anti-fibrotic therapeutic agent for CP.
研究领域:
药理学
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病理学
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免疫学
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Journal of Inflammation Research
·
2021
·
IF 6.922
Yongqing Cai,Bin Li,Dan Peng,Xianfeng Wang,Pan Li,Mingchun Huang,Haiyan Xing,Jianhong Chen
Background Nrf2-Bach1 antioxidant signaling pathway is considered as one of the most important mechanisms of cellular resistance to oxidative injury. The effect of hyperoside (Hyp) on the expression and distribution of Bach1, the relationship of Hyp’s antioxidative effect and the influence of Bach1 remains unclear. Purpose The aim of this study was to investigate the role and mechanisms of Bach1 in the protective effect of Hyp on oxidative liver injury. Methods The protective effect of Hyp on oxidative stress injury was observed in vivo and in vitro. Next, the influence of Hyp on Bach1 expression and distribution, and competitive combination of Nrf2-Bach1 with ARE in H 2 O 2 -induced L02 cell was studied by Western blot, RT-PCR, immunofluorescence and CHIP assay. Finally, the expressions of Crm1, ERK and p38 and their roles on Hyp mediated nuclear export of Bach1 were investigated by Western blot. Results Hyp ameliorated the pathological damage, reduced the liver index, AST, ALT and MDA activities, and increased SOD and GSH levels in the CCl 4 -induced acute liver injury mouse model. Hyp attenuated H 2 O 2 -induced oxidative stress injury in L02 cells. Hyp promoted the early rapid redistribution of Bach1 from nucleus to cytoplasm. CHIP analyses demonstrated that Hyp enhanced the levels of Nrf2-ARE complex, and weakened the levels of Bach1-ARE complex within three hours. In addition, Hyp enhanced transport protein Crm1 expression and ERK1/2 activity. And LMB, a Crm1 inhibitor, attenuated the effect of Hyp on Bach1 nuclear export and anti-oxidation. U0126, an ERK1/2 inhibitor, reduced the effect of Hyp on Crm1 expression and the Bach1 redistribution. Conclusion The hepatoprotective mechanism of Hyp was related to improve Bach1 nuclear export depending on ERK1/2-Crm1 to upregulate the level of Nrf2 binding to ARE.
研究领域:
药理学
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肝病学
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分子生物学
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CURRENT CANCER DRUG TARGETS
·
2023
·Vol. 23
·期 6
·471-481
·
IF 3
Peng Chen,Zhang Chunming,Yu Wenjie,Li Le,Zhang Zhen,Liu Ting,Zhang Yan,Fan Gaiping,Huangfu Hui
Background: Thyroid carcinoma (TC) is a common malignant tumor in human and its incidence has been increasing in recent years. Studies have shown that receptor type protein tyrosine phosphatase epsilon (PTPRE) is a key regulator of tumorigenesis in cancer progression, but its role in
TC has not been revealed. Objective: Here, in this work, we explored the essential role of PTPRE in TC progression. Methods: The expression of PTPRE in TC clinical samples and cell lines was detected by RT-qPCR and Western blot. Cell proliferation was measured by MTT and cell cycle
analysis. Cell migration, invasion and epithelial-mesenchymal transition (EMT) were analyzed by wound healing, transwell, and immunofluorescent staining assays. AKT and ERK1/2 signaling pathway related protein level was analyzed by Western blot. Results: PTPRE was highly expressed in
TC clinical samples and cell lines, especially anaplastic thyroid carcinoma (ATC). High level of PTPRE was associated with tumor size and TNM stage. Upregulated PTPRE promoted cell proliferation, and enhanced the migration, invasion and EMT of TC cells, whereas the knockdown of PTPRE suppressed
these behaviors. Importantly, we confirmed that the AKT and ERK1/2 signaling pathways were activated by PTPRE, reflected by the enhanced protein level of phosphorylated AKT and ERK1/2. Conclusion: Accordingly, we indicated that PTPRE plays an oncogenic role in TC progression via activating
the AKT and ERK1/2 signaling pathway. These findings indicated that modulation of PTPRE expression may as a potential strategy to interfere with the progression of TC.
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Evidence-based Complementary and Alternative Medicine
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2021
·
IF 2.63
Fen Li,Dongsheng Li,Shifan Tang,Jianguang Liu,Jie Yan,Haifeng Chen,Xisheng Yan
Reperfusion of blood flow during ischemic myocardium resuscitation induces ischemia/reperfusion (I/R) injury. Oxidative stress has been identified as a major cause in this process. Quercetin (QCT) is a member of the flavonoid family that exerts antioxidant effects. The aim of this study was to investigate the preventive effects of QCT on I/R injury and its underlying mechanism. To this end, H9c2 cardiomyocytes were treated with different concentrations of QCT (10, 20, and 40 μM) and subsequently subjected to oxygen-glucose deprivation/reperfusion (OGD/R) administration. The results indicated that OGD/R-induced oxidative stress, apoptosis, and mitochondrial dysfunction in H9c2 cardiomyocytes were aggravated following 40 μM QCT treatment and alleviated following the administration of 10 and 20 μM QCT prior to OGD/R treatment. In addition, OGD/R treatment inactivated ERK1/2 signaling activation. The effect was mitigated using 10 and 20 μM QCT prior to OGD/R treatment. In conclusion, these results suggested that low concentrations of QCT might alleviate I/R injury by suppressing oxidative stress and improving mitochondrial function through the regulation of ERK1/2-DRP1 signaling, providing a potential candidate for I/R injury prevention.
研究领域:
心脏病学
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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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高影响因子
Cell Death & Disease
·
2018
·Vol. 9
·期 9
·1-11
·
IF 5.638
Wang Yunchuan,Zheng Jianping,Han Yue,Zhang Yijie,Su Linlin,Hu Dahai,Fu Xiaobing
Junctional adhesion molecule-A (JAM-A) belongs to the immunoglobulin superfamily, it predominantly exists at the tight junctions of epithelial and endothelial cells. JAM-A is known to regulate leukocyte trans-endothelial migration, however, how it affects the proliferation and migration of keratinocytes, the two essential steps during wound healing, has less been explored. In this study, we showed that JAM-A was significantly expressed in normal skin epidermis. RNAi-mediated JAM-A knockdown remarkably promoted the proliferation and migration of keratinocytes. We also found that loss of JAM-A increased the protein levels of p -FAK, p -Erk1/2, and p -JNK; however, FAK inhibitor PF-562271 restrained the expression of p -FAK and p -Erk1/2 elevated by JAM-A RNAi, but not p -JNK, and also slowed down keratinocyte proliferation and migration. Finally, in a rat wound model we showed that absence of JAM-A significantly promoted the wound healing process, while the use of PF-562271 or Erk1/2 inhibitor PD98059 repressed those effects. These data collectively demonstrate that suppressing JAM-A expression could promote the proliferation and migration of keratinocytes and accelerate the healing process of rat skin wounds, potentially via FAK/Erk pathway, indicating that JAM-A might serve as a potential therapeutic target for the treatment of chronic refractory wounds.
研究领域:
分子生物学
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细胞生物学
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伤口愈合研究
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信号通路
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MOLECULAR AND CELLULAR ENDOCRINOLOGY
·
2026
·
IF 3.4
Yanbing Lou,Tingting Yang,Chenglong Xia,Shijun Yang,Huidan Deng,Yanqiu Zhu,Jing Fang,Zhicai Zuo,Hongrui Guo
CCS and ATOX1 is a specific target of copper in hormone secretion of ovarian granulosa cells. • MEK1-ERK1/2 pathway is involved in copper-affected hormone secretion. • Copper affects hormones secretion through CCS and ATOX1 dependent MEK1-ERK1/2 pathway. Steroid hormone synthesis in granulosa cells (GCs) is crucial for normal follicular development and ovulation. Emerging evidence suggests that copper (Cu), a trace element, influences hormone secretion in yak granulosa cells (YGCs); however, the underlying mechanisms remain unclear. In this study, we demonstrated that Cu supplementation upregulates estradiol (E2) and progesterone (P4) secretion in YGCs through the activation of the MEK1-ERK1/2 signaling pathway. Our findings indicate that the Cu chaperones ATOX1 and CCS, but not the Cu-dependent enzyme LOX, are essential for Cu-induced MEK1-ERK1/2 activation and subsequent hormone secretion. Gene silencing of ATOX1 or CCS resulted in reduced MEK1-ERK1/2 phosphorylation and steroidogenesis, highlighting their regulatory roles in this pathway. Although LOX influenced hormone secretion, it did not affect MEK-ERK phosphorylation, suggesting a MEK-independent mechanism. These findings reveal that Cu regulates steroid hormone synthesis in YGCs via a CCS- and ATOX1-dependent MEK1–ERK1/2 pathway, providing new insights into the molecular basis of Cu-associated reproductive disorders in yaks. Download: Download high-res image (289KB) Download: Download full-size image
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NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2026
·
IF 4
Zhang Xiaojuan,Song Yingying,Han Xinyan,Wang Mengxue,Chen Yufeng,Weng Yue,Li Yaxin,Huang Fei,Shi Hailian,Wu Hui,Wu Xiaojun
White peony root ( Paeonia lactiflora Pall.) is the dried root of peony. White peony root has a long history in Traditional Chinese Medicine (TCM) and is primarily used to treat various conditions, including pain, inflammation, and immune system disorders. Paeoniflorin (PF) is one of the main active components of white peony root, and it has multiple functions such as anti-inflammation, immune regulation, and neuroprotection. However, the impact of PF on multiple sclerosis (MS) remains to be fully elucidated. In this study, we observed that PF treatment markedly attenuated neurological symptoms in experimental autoimmune encephalomyelitis (EAE) mice, reduced disease severity, and alleviated spinal cord inflammation and demyelination, indicating a significant neuroprotective effect. PF administration was accompanied by reduced CD4 + T cell infiltration, decreased Th17 cell proportions, and increased Treg cell frequency in vivo. It also balanced Th17/Treg-associated cytokine secretion by suppressing IL-17 and promoting IL-10 expression. In addition, PF modulated the expression of differentiation-related proteins in lymphoid tissues and inhibited inflammatory gene and protein levels. In primary murine CD4 + T cells, PF enhanced Treg differentiation under Treg-polarizing conditions. In Jurkat cells, PF induced phosphorylation of Raf, MEK 1/2 , and ERK 1/2 , together with increased expression of Egr-1 and Foxp3. These findings indicate that PF treatment is associated with modulation of the Treg/Th17 balance in EAE mice and with changes in Raf/MEK 1/2 /ERK 1/2 /Egr-1 signaling in Jurkat cells. In summary, PF treatment ameliorated EAE manifestations, together with restoration of Treg/Th17 homeostasis and activation of the Raf/MEK 1/2 /ERK 1/2 /Egr-1 pathway. However, whether the Raf/MEK 1/2 /ERK 1/2 /Egr-1 signaling axis directly contributes to PF-induced Treg differentiation in primary T cells or to the therapeutic effects of PF in vivo remains to be determined. Graphical abstract PF treatment ameliorated EAE manifestations and was associated with reduced CD4 + T-cell infiltration, restoration of the Th17/Treg balance, and attenuation of CNS inflammation and demyelination in EAE mice. PF also enhanced Treg differentiation in primary murine CD4 + T cells and was associated with the activation of the Raf/MEK 1/2 /ERK 1/2 /Egr-1 signaling axis in Jurkat cells. The causal contribution of this signaling axis to Treg differentiation and the therapeutic effects of PF remains to be determined.
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BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2024
·
IF 4.2
Haocong Zhang,Liangbi Xiang,Hong Yuan,Hailong Yu
Spinal cord injury (SCI) is a severe central nervous system injury and microglia are major participants in neuroinflammation after injury. ADP-ribosylation factor-like GTPase 11 (ARL11) is a GTP-binding protein. Whether ARL11 is involved in the SCI progression is unknown. In the impactor-induced moderate SCI mouse model, ARL11 protein and mRNA expression were significantly increased in the injury site. LPS (100 ng/mL) and IFN-γ (20 ng/mL) were incubated with BV2 cells (immortalized mouse microglial cell line) to drive them into an M1-like phenotype. ARL11 up-regulation was also observed in activated microglia in SCI mice and LPS and IFN-γ treated BV2 cells. Basso Mouse Scale scores and inclined plate test revealed that ARL11 deletion promoted motor function recovery in SCI mice. Pathological examination showed ARL11 knockdown reduced spinal cord tissue damage, increased neuron numbers, and inhibited neuronal apoptosis in SCI mice. ARL11 knockdown notably inhibited IL-1β and IL-6 production in vivo and in vitro. Furthermore, ARL11 deletion significantly inhibited iNOS protein and mRNA expression in vivo and in vitro, and COX-2 expression in vivo . Mechanism studies revealed that ARL11 silencing decreased phosphorylated ERK1/2 protein expression. Additionally, ELF1 knockdown significantly inhibited ARL11 protein and mRNA expression in vitro . ELF1 acted as a transcription activator in regulating ARL11 expression by binding to the promoter. In conclusion, ARL11 knockdown protects neurons by inhibiting M1 microglia-induced neuroinflammation, thereby promoting motor functional recovery in SCI mice. This may occur in part under the regulation of ELF1. Our study provides a new molecular target for SCI treatment.
研究领域:
神经科学
·
炎症
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分子生物学
·
细胞生物学
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高影响因子
BIOLOGY BULLETIN
·
2023
·Vol. 49
·期 2
·S12
·
IF 0.5
Tingting Gan,Liu Xing,Chen Xia,Shi Yichao,Wang Wenbin
Abstract Okadaic acid (OA) is a marine toxin which inhibits protein phosphatases. Its toxicities in several tissues have been well established, but the influence of exposure to low OA concentrations in male reproductive system is poorly understood. Here we aimed to explore the potential reproductive toxicity of OA and the mechanism behind it. The GC-1 cells were exposed to OA, and the changes of proliferation rates were detected. TUNEL assay was also conducted to determine the GC-1 cell apoptosis. Effects of OA on cytoskeleton and cyclin expression were investigated by fluorescein conjugated phalloidin. Potential molecular regulation on proliferation was analyzed based on transcriptomic analysis. OA inhibited the proliferation of GC-1 cells apparently with loss of cell-cell junctions and focal aggregated around the cells. The cyclin D/E mRNA and protein levels significantly decreased and the phosphorylation of ERK1/2 was blocked concordantly in OA treated cells. PPI network analysis pointed out ERK1 as a key node of responsive gene to the injury. In conclusion, OA shows apparent cytotoxicity on spermatogonial cells of male reproductive system and the cytotoxicity present was revealed by affecting the activation of ERK1/2 MAPK pathway which hinders the cyclin expression and actin stress fiber formation further.
研究领域:
毒理学
·
生殖生物学
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细胞生物学
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分子生物学
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高影响因子
Cells
·
2024
·Vol. 13
·期 3
·206
·
IF 5.1
Meng-Yuan Li,Ying Wang,Ying Wu,Xu-Yu Zhao,Zhen-Shan Yang,Bo Li,Si-Ting Chen,Yu-Ying He,Zeng-Ming Yang
(1) Background: Inflammatory responses are implicated in embryo implantation, decidualization, pregnancy maintenance and labor. Both embryo implantation and decidualization are essential to successful pregnancy in rodents and primates. S100A6 is involved in inflammation, tumor development, apoptosis and calcium homeostasis. S100A6 is strongly expressed in mouse decidua, but the underlying mechanisms of how S100A6 regulates implantation and decidualization are poorly defined. (2) Methods: Mouse endometrial stromal and epithelial cells are isolated from day 4 pseudopregnant mouse uteri. Both immunofluorescence and Western blotting are used to analyze the expression and localization of proteins. The molecular mechanism is verified in vitro by Western blotting and the quantitative polymerase chain reaction. (3) Results: From days 4 to 8 of pregnancy, S100A6 is specifically expressed in mouse subluminal stromal cells. Blastocyst-derived lactic acid induces AA secretion by activating the luminal epithelial p-cPLA2. The epithelial AA induces stromal S100A6 expression through the COX2/PGI2/PPAR δ pathway. Progesterone regulates S100A6 expression through the progesterone receptor (PR). S100A6/RAGE signaling can regulate decidualization via EGFR/ERK1/2 in vitro. (4) Conclusions: S100A6, as an inflammatory mediator, is important for mouse implantation and decidualization.Keywords:decidualization;implantation;S100A6;RAGE;inflammation
研究领域:
生殖生物学
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分子生物学
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免疫学
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PubMed
高影响因子
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