BEHAVIOURAL BRAIN RESEARCH
·
2023
·
IF 2.7
Ni-Na Song,Ying Zhao,Chuang Sun,Jun Zhang,Guang-Jun Lin,Xiao-Wei Yin,Chun-Ye Ma
Neuronal apoptosis is considered one of the hallmarks of ischemic stroke . Dual specificity phosphatase 10 (DUSP10), a member of the dual-specificity phosphatase family, which is involved in the regulation of apoptosis process. This study aimed to investigate the effect of on apoptosis in primary cortical neurons exposed to oxygen-glucose deprivation and reoxygenation (OGD/R) and mice suffered from transient middle cerebral artery occlusion and reperfusion (MCAO/R). The results showed that DUSP10 overexpression improved survival and reduced apoptosis in neurons subjected to OGD/R, which was manifested by decreased apoptotic proteins (cleaved caspase 3 and bax) and TUNEL+ cells, as well as increased the anti-apoptotic protein (bcl-2). DUSP10 overexpression inhibited the p38/JNK signaling pathway after OGD/R treatment, whilst DUSP10 knockdown had opposite effects. In addition, the p38 inhibitor SB203580 or JNK inhibitor SP600125 attenuated the increased apoptosis of OGD/R-stimulated neurons treated with DUSP10 silencing. Consistently, DUSP10 knockdown exacerbated infarct volume in MCAO/R injury. The data of Nissl staining and TUNEL-NeuN double staining revealed that DUSP10 interference aggravated neuronal damage in the ischemic penumbra of mice. Furthermore, DUSP10 inhibition activated the p38/JNK axis accompanied by enhanced phosphorylation of p38 and JNK in vivo. In summary, DUSP10 is a neuroprotective agent against ischemic stroke-induced neuronal damage via suppressing the p38/JNK signaling pathway.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CTS-Clinical and Translational Science
·
2020
·Vol. 14
·期 5
·2075-2084
·
IF 3.373
Hongtao He,Kuangyuan Qiao,Chao Wang,Wuhan Yang,Zhuo Xu,Zhilei Zhang,Yuming Jia,Chong Zhang,Li Peng
Hydrazinocurcumin (HZC), a synthetic derivative of curcumin (CUR), has been documented to show anticancer potential in impeding tumor growth in several cancers, including hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms remain unclear. This study aimed to explore the function and underlying mechanisms of HZC on HCC cells, which may involve the p38 mitogen activated protein kinase (MAPK) pathway. HZC was first purified and identified. HepG2 cells were then subjected to treatment with HZC or CUR of different concentrations and p38 MAPK signaling inhibitor (SB203580) to verify their effects on HCC cell apoptosis and proliferation. Furthermore, the functional relevance between HZC and the p38 MAPK pathway in HCC was examined. It was observed that 40 μM HZC exhibited the best pro-apoptosis effect in HCC cells. HZC was found to inhibit HCC cell proliferation and promote apoptosis, the effect of which was stronger than 5-fluorouracil (5-FU). More importantly, the anti-oncogenic effect of HZC and 5-FU was implicated with activation of the p38 MAPK pathway. In vivo experimental results showed that HZC inhibited tumor growth more effectively than 5-FU through the p38 MAPK pathway. These results provide evidence that HZC exerted anti-oncogenic and pro-apoptosis effects in HCC cells through activation of the p38 MAPK pathway.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2026
·Vol. 17
·期 1
·198
·
IF 12.2
Guo Chipeng,Luo Siweier,Luo Jigang,Lu Siyao,You Xiaomei,Cao Junlin,Du Yufei,Lv Haoran,Liang Hanzhi,Wang Le,Wang Liangchun,Liu Tao,Zhou Yiming
Ultraviolet B (UVB) is a well-recognized trigger of cutaneous lupus erythematosus (CLE), yet its molecular basis remains largely undefined. Here, using single-cell transcriptomics and a lupus-prone mouse model, we identify keratinocyte-derived macrophage migration inhibitory factor (MIF) as a key amplifier of cutaneous inflammation through a self-sustaining feedback loop. Single-cell RNA sequencing reveals elevated MIF expression specifically within pathogenic, interferon-high keratinocyte subclusters associated with CLE, which is further validated across major CLE subtypes in clinical skin samples. In vitro, UVB irradiation dose-dependently induces the release of MIF from keratinocytes, which in turn promotes inflammatory signaling and matrix remodeling in both keratinocytes and fibroblasts. Mechanistically, we demonstrate that UVB irradiation activates the ribotoxic stress response (RSR), leading to the p38-C/EBPβ-mediated transcriptional upregulation of NLRP3 and GSDMD cleavage in keratinocytes. The ensuing GSDMD-dependent pyroptosis facilitates the release of MIF, primarily through GSDMD pores rather than vesicular secretion, which in turn amplifies the p38-C/EBPβ signaling pathway. Therapeutic disruption of this loop either by gene silencing via AAVs or pharmacological inhibition via microneedles, markedly attenuates epidermal hyperplasia and cytokine imbalance in lupus-prone mice. These findings uncover a previously unrecognized MIF-p38-GSDMD inflammatory loop contributes to the UVB-induced cutaneous lupus, offering both mechanistic insights and translational opportunities for CLE.
✓ 已验证
DOI
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2026
·Vol. 58
·期 1
·1-25
·
IF 8.5
Hui Fang,Min Shu,Jiaju Wang,Heng Tian,Jianguo Zhang,Ying Hu,He Li,Huan Zhou,Kangsheng Gu,Zhenhua Ren
International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF PHARMACOLOGICAL SCIENCES
·
2022
·
IF 3.578
Qingxin Song,Shanxin Peng,Fengyuan Che,Xiaosong Zhu
Ferroptosis is implicated in various tumors, including glioblastoma. Artesunate (ART), an anti-malarial drug, exerted antitumor properties in several cancer types. However, the role of ferroptosis in the inhibiting effect of artesunate on glioblastoma remains unclear. The purpose of this study was to investigate the effects of ART on the ferroptosis of glioblastoma and to elucidate the underlying mechanisms. We found that ART inhibited the proliferation of glioblastoma cells in vitro and glioblastoma tumorigenesis in vivo . Characteristic changes of ferroptosis were observed in ART group, including GSH depletion, lipid peroxidation and iron overload. Meanwhile, the protein level of GPX4 were lower in ART group than that in control group. Ferrostatin-1, a ferroptosis inhibitor, could rescue the cell death induced by ART in U251 cells. Further examination of the mechanism revealed that the effect of ART on ferroptosis was partially governed by regulating iron homeostasis and p38 and ERK signaling pathway. These findings support that ART triggers ferroptosis in glioblastoma and might be a potential therapeutic agent for glioblastoma treatment.
✓ 已验证
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2020
·
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.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2020
·
IF 3.723
Meihui Chen,Dan Luo,Jiheng Zhan,Yu Hou,Shudong Chen,Xing Li,Dingkun Lin
Bone mesenchymal stem cells (BMSCs) are a well-known donor graft source due to their potential for self-renewal and differentiation into multi-lineage cell types, including osteoblasts that are critical for fracture healing. Fasudil (FAS), a Rho kinase inhibitor, has been proven to induce the differentiation of bone marrow stem cells (BMSCs) into neuron-like cells. However, its role in the osteogenesis of BMSCs remain uncertain. Herein, we for the first time studied the effects of FAS on osteogenic differentiation in a mouse fracture model and further explored the involved mechanisms in mouse BMSCs. The results showed that FAS stimulated bone formation in the fracture mouse model. Additionally, at 30 μM, FAS significantly promotes alkaline phosphatase activity, mineralization, and the expression of osteogenic markers COL-1, RUNX2 and OCN in murine BMSCs. Blocking of P38 by SB202190 significantly reversed the effects of FAS, in vitro, suggesting that P38, but not ERK or JNK activation is required for FAS-induced osteogenesis. Collectively, our results indicate that FAS may be a promising agent for promoting fracture healing.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY
·
2018
·
IF 1.792
Bo Wang,Wenyang Li,Hongyu Jin,Xinshi Nie,Hui Shen,Erran Li,Wei Wang
Chronic intermittent hypoxia (CIH) is one of the main features of obstructive sleep apnea (OSA), which is also commonly associated with neurocognitive impairments. The present study aimed to elucidate the beneficial effect of curcumin on CIH-induced brain injuries. Male balb/c mice (6 ∼ 8 weeks) were exposed to normoxia or a pattern of CIH (8 h/day, cycles of 180 s each, hypoxia: 5% O 2 for 50 s, reoxygenation: 21% O 2 for 50 s) for 10 weeks, along with daily curcumin treatment (50, 100, or 200 mg/kg, intragastrically) or its vehicle. The results showed that CIH induced significant brain edema, as well as neuronal apoptosis and astrogliosis in the cerebral cortex, brainstem, and cerebellum regions of brain. In addition, increased astrocytic AQP4 expression and activation of p38 MAPK pathway were observed after CIH exposure. Curcumin dose-dependently mitigated the brain edema and relevant cell alterations, showing a neuroprotective effect in CIH-induced brain injury. Together, these results suggest curcumin ameliorates the CIH-induced brain injuries, including brain edema, neuronal death and astrogliosis. The beneficial role of curcumin is mediated partially by regulating AQP4 and p38 MAPK pathway.
研究领域:
神经科学
·
药理学
·
睡眠医学
✓ 已验证
DOI
PubMed
高影响因子
Cell and Bioscience
·
2021
·Vol. 11
·期 1
·1-13
·
IF 7.133
Tang Ying,Zhou Mengchun,Huang Rongrong,Shen Ling,Yang Li,Zhou Zhongqiu,Ren Hui,Bai Ying
Background Astrocytes participate in innate inflammatory responses within the mammalian central nervous system (CNS). HECT domain E3 ubiquitin protein ligase 1 (HECTD1) functions during microglial activation, suggesting a connection with neuroinflammation. However, the potential role of HECTD1 in astrocytes remains largely unknown. Results Here, we demonstrated that HECTD1 was upregulated in primary mouse astrocytes after 100 ng/ml lipopolysaccharide (LPS) treatment. Genetic knockdown of HECTD1 in vitro or astrocyte-specific knockdown of HECTD1 in vivo suppressed LPS-induced astrocyte activation, whereas overexpression of HECTD1 in vitro facilitated LPS-induced astrocyte activation. Mechanistically, we established that LPS activated σ-1R-JNK/p38 pathway, and σ-1R antagonist BD1047, JNK inhibitor SP600125, or p38 inhibitor SB203580 reversed LPS-induced expression of HECTD1, thus restored LPS-induced astrocyte activation. In addition, FOXJ2 functioned as a transcription factor of HECTD1, and pretreatment of primary mouse astrocytes with BD1047, SB203580, and SP600125 significantly inhibited LPS-mediated translocation of FOXJ2 into the nucleus. Conclusions Overall, our present findings suggest that HECTD1 participates in LPS-induced astrocyte activation by activation of σ-1R-JNK/p38-FOXJ2 pathway and provide a potential therapeutic strategy for neuroinflammation induced by LPS or any other neuroinflammatory disorders.
研究领域:
神经科学
·
免疫学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL DENTAL JOURNAL
·
2026
·Vol. 76
·期 5
·109799
·
IF 5.2
Xinda Li,Zhijia Liu,Xinzhu Liu,Jianing Wang,Jinlai Bao,Wuwei Li
Background To explore the osteogenic promotion of carboxymethyl chitosan (CMCS), clarify the signalling pathways involved and preliminarily evaluate the translational potential of CMCS in transcrestal sinus floor elevation. Methods Overlapping targets were identified by integrating potential CMCS targets and bone regeneration-related genes, and protein-protein interaction and GO/KEGG enrichment analyses were conducted. The GEO dataset GSE50743 was externally validated. Bone marrow-derived mesenchymal stem cells from mice were induced to osteogenic differentiation in vitro and treated with CMCS alone or in combination with the p38 inhibitor SB203580 or the VEGFR2 inhibitor SU5416. The osteogenic phenotypes and mechanism-related changes were determined by ALP, Alizarin Red S staining, RUNX2 immunofluorescence, qPCR and Western blotting. A retrospective comparative clinical study further evaluated radiographic, functional and patient-reported outcomes after transcrestal sinus floor elevation. Results We identified 187 common targets of CMCS-bone regeneration. Enrichment analyses revealed that these targets were primarily involved in cell adhesion, inflammatory and immune regulation, extracellular matrix remodelling, and osteogenesis-related pathways, including MAPK and VEGF signalling. Validation with GSE50743 confirmed significant positive enrichment of candidate gene set under osteogenic conditions. In vitro, CMCS increased ALP activity, mineralised nodule formation and the expression of RUNX2, ALP and OPN, whereas inhibition of p38 or VEGFR2 partially reduced these effects. Clinical findings showed that the two groups were generally similar in terms of safety, implant stability and patient-reported outcomes, whereas the CMCS group had better volume maintenance. Conclusions CMCS promotes osteogenesis and mineralisation, at least partly via p38 MAPK and VEGF–VEGFR2 signalling. Retrospective clinical findings also indicate its potential utility in transcrestal sinus floor elevation.
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2026
·
IF 6.8
Jingjing Xia,Jiawei Huang,Xiaobing Hou,Haibing Hua,Ming Chen
TMF was prioritized from Wendan Decoction by network analysis. • TMF reduced cochlear inflammation and injury in experimental EH. • TMF suppressed p38 MAPK/AQP2 signaling and restored DUSP3/ZO-1. • DUSP3 knockdown weakened TMF regulation in vitro and in vivo. Ethnopharmacological relevance Wendan Decoction is a classical traditional Chinese medicine formula historically used for phlegm-related dizziness and vertigo. Recent studies have shown that Wendan Decoction can ameliorate experimental endolymphatic hydrops (EH), a characteristic pathological correlate of Ménière's disease. However, the bioactive constituents responsible for these effects and their molecular targets remain incompletely defined. Aim of the study This study aimed to identify and quantify a pharmacologically relevant constituent of Wendan Decoction and to investigate its molecular target and mechanism of action in experimental EH. Materials and methods Candidate constituents and regulatory targets were prioritized through ADME-guided screening, target prediction, MD-associated transcriptomic analysis, protein–protein interaction network analysis, pathway enrichment, MAPK pathway mapping, and molecular docking. Targeted UPLC-ESI-MS/MS was used to verify and quantify 5,6,7,4′-tetramethoxyflavone (TMF) in Wendan Decoction granules. The interaction between TMF and DUSP3 was examined using surface plasmon resonance (SPR) and a cell lysate-based cellular thermal shift assay (CETSA). The effects of TMF were evaluated in LPS-stimulated HEI-OC1 cells and a DDAVP-induced guinea pig model of EH. DUSP3 knockdown and pharmacological inhibition of p38 MAPK with SB203580 were used to investigate the functional relationships among DUSP3, p38 MAPK, AQP2, and ZO-1. Results TMF was detected in Wendan Decoction granules at 0.0379% (w/w). SPR showed micromolar binding between TMF and recombinant DUSP3, while CETSA showed that TMF increased the thermal stability of DUSP3. In LPS-stimulated HEI-OC1 cells, TMF reduced inflammatory mediator production, increased DUSP3 and ZO-1 expression, inhibited p38 MAPK activation, and decreased AQP2 expression. SB203580 attenuated AQP2 upregulation, ZO-1 reduction, and pro-inflammatory cytokine production, including after DUSP3 silencing, supporting p38 MAPK as a downstream component of DUSP3-associated signaling. In DDAVP-treated guinea pigs, TMF reduced morphometrically quantified cochlear hydrops, alleviated cochlear ultrastructural injury and vestibular-associated behavioral impairment, and decreased cochlear inflammatory cytokine levels. Cochlear DUSP3 knockdown was confirmed at both the mRNA and protein levels and partially weakened TMF-mediated regulation of the p38 MAPK/AQP2 axis. Conclusions TMF is a quantified Wendan Decoction-derived constituent with protective activity against experimental EH. The findings support a direct interaction between TMF and DUSP3 and suggest that TMF alleviates EH-associated pathological changes, at least in part, through DUSP3-associated regulation of p38 MAPK activation and downstream AQP2 and ZO-1 expression. Download: Download high-res image (263KB) Download: Download full-size image
✓ 已验证
DOI
高影响因子
Scientific Reports
·
2026
·
IF 4.9
Wang Xiang,Luo Kai,Bai He,Zhang Xudong,Qu Jialin,Wang Xiaoqing,Sun Xu,Zhao Yuting,Wang Bin,Zhang Guixin
Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive liver malignancy with rising global incidence and poor prognosis. Despite recent advances in treatment strategies, effective therapeutic options for ICC remain limited. Solamargine (SM), a natural steroidal alkaloid, has demonstrated anticancer activity, yet its mechanisms in ICC are not fully understood. This study shows that SM inhibits ICC progression by inducing both apoptosis and ferroptosis in vitro and in vivo. SM significantly suppressed proliferation, migration, and invasion of ICC cells (HUCCT-1 and HCCC-9810), with minimal cytotoxicity toward normal biliary epithelial cells (HIBEC). Mechanistically, SM induced mitochondrial dysfunction, ROS accumulation, and lipid peroxidation, leading to apoptosis and ferroptosis. Transcriptome sequencing and gene set enrichment analysis (GSEA) revealed that SM treatment activated apoptosis- and ferroptosis-related pathways, including MAPK signaling. Western blot analysis and pharmacological inhibition assays confirmed that p38 MAPK activation was essential for SM-induced cell death, with ROS acting as an upstream activator. In vivo, SM significantly inhibited tumor growth in both orthotopic and subcutaneous ICC mouse models and showed better tolerability than gemcitabine. Tumor tissue analysis further confirmed increased markers of apoptosis and ferroptosis, along with p38 MAPK activation. These findings suggest that SM exerts dual antitumor effects in ICC, which are associated with the induction of apoptosis and ferroptosis and may involve the ROS/p38 MAPK signaling axis, highlighting its potential as a therapeutic candidate for ICC.
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）