Cell Death & Disease
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2021
·Vol. 12
·期 5
·1-17
·
IF 8.469
Wang Ruoqin,Sun Linqing,Xia Suhua,Wu Hongya,Ma Yanchao,Zhan Shenghua,Zhang Guangbo,Zhang Xueguang,Shi Tongguo,Chen Weichang
Emerging evidence suggests that cellular senescence induced by chemotherapy has been recognized as a new weapon for cancer therapy. This study aimed to research novel functions of B7-H3 in cellular senescence induced by a low dose of doxorubicin (DOX) in colorectal cancer (CRC). Here, our results demonstrated that B7-H3 knockdown promoted, while B7-H3 overexpression inhibited, DOX-induced cellular senescence. B7-H3 knockdown dramatically enhanced the growth arrest of CRC cells after low-dose DOX treatment, but B7-H3 overexpression had the opposite effect. By RNA-seq analysis and western blot, we showed that B7-H3 prevented cellular senescence and growth arrest through the AKT/TM4SF1/SIRT1 pathway. Blocking the AKT/TM4SF1/SIRT1 pathway dramatically reversed B7-H3-induced resistance to cellular senescence. More importantly, B7-H3 inhibited DOX-induced cellular senescence of CRC cells in vivo. Therefore, targeting B7-H3 or the B7-H3/AKT/TM4SF1/SIRT1 pathway might be a new strategy for promoting cellular senescence-like growth arrest during drug treatment in CRC.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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PubMed
高影响因子
EXPERIMENTAL NEUROLOGY
·
2016
·
IF 4.657
Ranran Han,Juan Gao,Hui Zhai,Jinting Xiao,Ya'nan Ding,Junwei Hao
Guillain–Barre' syndrome (GBS) is an acute, postinfectious, immune-mediated, demyelinating disease of peripheral nerves and nerve roots. As a classical animal model of GBS, experimental autoimmune neuritis (EAN) has become well-accepted. Additionally, the potent immune modulation exerted by mammalian target of rapamycin (mTOR) inhibitors has been used to treat cancers and showed beneficial effects. Here we demonstrate that the mTOR inhibitor RAD001 (everolimus) protected rats from the symptoms of EAN, as shown by decreased paralysis, diminished inflammatory cell infiltration, reductions in demyelination of peripheral nerves and improved nerve conduction. Furthermore, RAD001 shifted macrophage polarization toward the protective M2 phenotype and modified the inflammatory milieu by downregulating the production of pro-inflammatory cytokines including IFN-γ and IL-17as well as upregulating the release of anti-inflammatory cytokines such as IL-4 and TGF-β. Amounts of the mTOR downstream targets p-P70S6K and p-4E-BP1 in sciatic nerves decreased, whereas the level of its upstream protein p-Akt was elevated. This demonstrated that RAD001 inhibited the mTOR pathway and encouraged the expression of p-Akt, which led to M2 macrophage polarization, thus improved the outcome of EAN in rats. Consequently, RAD001 exhibits strong potential as a therapeutic strategy for ameliorating peripheral poly-neuropathy.
研究领域:
神经病学
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免疫学
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药理学
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高影响因子
CELL BIOLOGY INTERNATIONAL
·
2020
·Vol. 44
·期 7
·1503-1513
·
IF 2.571
Peng Yuan,Aidong Zheng,Qing Tang
Tripartite motif protein 25 (TRIM25) expression was altered in various human cancers. Herein, we found that the expression of TRIM25 was elevated in hepatocellular carcinoma (HCC) tissues and cell lines. Knockdown of TRIM25 increased the sensitivity of HCC HepG2 cells to epirubicin (EPI), as indicated by reduced cell viability, enhanced cell apoptosis, and downregulated P-glycoprotein (P-gp) and multiple drug-resistance protein 1 (MRP1). Moreover, TRIM25 knockdown strengthened the effects of EPI on phosphatase and tensin homolog (PTEN) and phosphorylated (p)-AKT. However, overexpression of TRIM25 exerted an opposite effect, weakening the sensitivity of Huh7 to EPI, and obviously increasing PTEN and reducing p-AKT. Most important, all the changes induced by TRIM25 overexpression in Huh7 were reversed with additional treatment of LY294002 (an AKT pathway inhibitor). Notably, coimmunoprecipitation experiments confirmed the interaction between TRIM25 and PTEN. Knockdown of TRIM25 resulted in reduced ubiquitination of PTEN protein. Collectively, our data suggested that TRIM25 enhanced EPI resistance via modulating PTEN/AKT pathway, and targeting TRIM25 may enhance the sensitivity of HCC cells toward chemotherapy drugs.
研究领域:
肿瘤学
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分子生物学
·
癌症研究
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PubMed
高影响因子
CELL AND TISSUE RESEARCH
·
2019
·Vol. 378
·期 1
·113-125
·
IF 3.36
Zheng Rongzong,Huang Shuming,Zhu Junkun,Lin Wei,Xu Huan,Zheng Xiang
Rotator cuff tears (RCTs), the most common tendon injury, are always accompanied by muscle atrophy, which is characterized by excessive protein degradation. Autophagy–lysosome systems are the crucial proteolytic pathways and are activated in atrophying muscle. Thus, inhibition of the autophagy–lysosome pathway might be an alternative way to minimize skeletal muscle atrophy. In this present study, combined with a tendon transection-induced rat model of massive rotator cuff tears, HE staining and transmission electron microscopy methods, we found leucine supplementation effectively prevented muscle atrophy, muscle injury and autophagosome formation. Utilizing immunoblotting, we discovered that leucine supplementation is able to inhibit the rise in autophagy-related protein expression (including LC3, Atrogin-1, MuRF1, Bnip3 and FoxO3) driven by tendon transection. The PI3K/AKT/mTOR pathway that was essential in autophagosome formation and autophagy was blocked in atrophying muscle and reactivated in the presence of leucine. Once administrated with LY294002 (PI3K inhibitor) and Rapamycin (mTOR inhibitor), leucine mediated by the anti-atrophic effects was nearly blunted. These results suggest that leucine potentially attenuates tendon transection-induced muscle atrophy through autophagy inhibition via activating the PI3K/AKT/mTOR pathway.
研究领域:
骨骼肌生物学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
ONCOLOGY REPORTS
·
2016
·Vol. 36
·期 4
·2160-2168
·
IF 2.486
Ming Liu,Jiwei Wang,Qichao Qi,Bin Huang,Anjing Chen,Xingang Li,Jian Wang
Recent studies have demonstrated that nitidine chloride (NC), a natural bioactive alkaloid, displays potent antitumor activity in various types of cancer. In the present study, NC was examined for efficacy in the treatment of human glioblastoma multiforme (GBM) as well as the molecular basis for its more general inhibitory effects in cancer. U251 and U87 GBM cell lines were exposed to three concentrations of NC (5, 25 and 50 µM) in vitro, and tumor cell growth was assessed on the basis of proliferation, migration and energy metabolism. Decreases in viability and proliferation reached ~50% for both cell lines with 50 µM NC at 24 h as assessed by cell viability Cell Counting Kit-8 (CCK-8) and EdU assays. In wound closure and Transwell assays, migration and invasion were inhibited at 50 µM after 24 h (~20 and 80%, respectively; P<0.05). ATP and L-lactate levels were also decreased after treatment with NC (50 µM, 24 h; P<0.05 and P<0.01, respectively). Finally, in western blot analysis, phosphorylation of Akt and mTOR was suppressed by NC, but partially restored when cells were treated simultaneously with a novel Akt activator, SC79. Partial restoration was also observed in viability/proliferation (U251 and U87, ~15 vs. 40%; NC vs. NC + SC79; P<0.05) and invasion (U251 and U87, ~30 vs. 60%; NC vs. NC + SC79; P<0.05). Our results demonstrated that NC inhibits development of GBM by targeting the PI3K/Akt/mTOR signaling pathway and provides a potential therapeutic agent for the treatment of GBM.
研究领域:
肿瘤学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
Quantitative Imaging in Medicine and Surgery
·
2025
·Vol. 16
·期 1
·18
·
IF 2.3
Xi Weizhe,Liu Fenfang,Zhong Guangen,Chen Fen,Xie Yin,Lai Meilian,He Qiting,Lu Yiqing,Zhang Jiping,Chen Ying,Meng Luo,Yang Lu
Background Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that leads to cartilage degradation and bone destruction, significantly impacting daily life. Melittin acupoint injection (MAI) is a promising traditional Chinese medicine treatment, but its molecular mechanisms are not fully understood. This study aimed to investigate the therapeutic effects of MAI on RA and elucidate its underlying mechanisms. Methods A collagen-induced arthritis (CIA) mouse model was established using bovine type II collagen, administered every other day for 28 days. The mice were randomly divided into a CIA model group (MO group), melittin acupoint subcutaneous injection group (ST group), melittin acupoint intramuscular injection group (IT group), and methotrexate group (MTX group), with an additional normal control group (NC group) established. Each group contained 8 mice, all of which were treated for 28 days. Therapeutic outcomes were assessed by measuring body weight, swollen joint count (SJC), arthritis index (AI), ankle circumference, and plantar thickness. Radiological and histological changes were analyzed with micro-computed tomography (CT) imaging and pathological staining. Cytokine levels were measured via enzyme-linked immunosorbent assay (ELISA), and autophagy levels were assessed using immunofluorescence staining. The phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway and autophagy status were examined through western blot (WB) and immunofluorescence techniques. Results MAI significantly improved clinical symptoms in CIA mice by reducing plantar thickness, AI scores, and swollen joints (P<0.05). Histopathological analysis showed decreased inflammatory cell infiltration, synovial proliferation, and cartilage damage (P<0.01). Micro-CT and immunohistochemistry revealed reduced inflammation, bone destruction, and cartilage erosion, along with decreased tumor necrosis factor-α (TNF-α) expression (P<0.05). MAI also lowered serum levels of interleukin (IL)-1β (P<0.05), IL-17A, and TNF-α (P<0.01), while increasing IL-10 levels (P<0.05). Immunofluorescence indicated increased microtubule-associated protein 1 light chain 3 beta (LC3B) fluorescence intensity (P<0.05). WB analysis showed elevated levels of Unc-51-like autophagy activating kinase 1 (ULK1), beclin-1 (P<0.01), and microtubule-associated protein 1 light chain 3 II (LC3II) (P<0.05), and reduced phosphorylation of PI3K, AKT, and mTOR (P<0.05). Conclusions MAI alleviates RA symptoms by inhibiting the PI3K/AKT/mTOR pathway and promoting autophagy.
研究领域:
风湿病学
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分子医学
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中医中药
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免疫学
·
信号转导
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产品关联
DOI
PubMed
高影响因子
BEHAVIOURAL BRAIN RESEARCH
·
2026
·
IF 2.9
Xinyao Zhang,Xu Yang,Dongpei Zhuang,Zhiyi Mu,Chuanxia Ju
Neuronal hyperexcitability is crucial to the pathogenesis of Alzheimer's disease (AD). Activating the Kv7 channel is an effective way to reduce neuronal excitability. The Kv7 channel opener retigabine (RTG) has been demonstrated to alleviate spatial memory deficits in APP/PS1 transgenic mice. However, the mechanism by which RTG reduces cognitive deficits in APP/PS1 mice remains unclear. In this study, we revealed that RTG could ameliorate learning and spatial memory deficits in APP/PS1 mice during novel object recognition and Morris water maze tests. Meanwhile, RTG increased NeuN neuronal fluorescence intensity, increased the expression of the synaptic proteins postsynaptic density protein 95 (PSD95) and synaptophysin (SYN), improved synaptic plasticity, increased insulin-degrading enzyme (IDE) expression, decreased beta-secretase 1 (BACE1) expression, reduced Aβ 1–40 and Aβ 1–42 levels, and increased pAKT (ser473) and pGSK-3β (ser9) expression. These results indicated that RTG alleviates learning and spatial memory deficits in APP/PS1 mice, with potential mechanisms involving a reduction in neuronal loss, attenuation of synaptic damage, a decrease in β-amyloid (Aβ) deposition, and activation of the AKT/GSK-3β pathway.
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高影响因子
Journal of Inflammation Research
·
2026
·
IF 4.6
Jianglong Chen,Yunfei Cui,Rujie Zhou,Yu Zhu,Meijia Chen,Jinhua Su,Jinhui Wang,Guang Li
Objective To explore the therapeutic effect and molecular mechanism of Arundina graminifolia (D.Don) Hochr (BYJ) on renal fibrosis in chronic kidney disease (CKD) mice.Methods Phytochemical profiles of the methanol extract BYJ were analyzed using ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS), while network pharmacology and molecular docking were employed to predict the core active components and therapeutic targets. For experimental validation, a CKD mouse model was established via adenine induction. Mice were randomly assigned to normal control, model, and three BYJ treatment groups (low-dose: 2 g/kg·d, middle-dose: 4 g/kg·d, and high-dose: 8 g/kg·d, crude drug equivalent). Assessments included renal function parameters, histopathological changes, inflammatory markers, and oxidative stress indicators. The associated molecular mechanisms were analyzed using immunohistochemistry staining and Western blot.Results In silico analysis identified five core targets—PIK3R1, AKT1, SRC, MTOR, and EGFR—and suggested esculetin as a key active component with strong binding affinity to these targets. Experimentally, BYJ administration significantly reduced in serum creatinine (SCr), blood urea nitrogen (BUN), and the kidney index, and ameliorated glomerular atrophy and tubular dilation. Furthermore, BYJ treatment downregulated pro-inflammatory factors (eg, IL-1β), elevated superoxide dismutase (SOD) activity, and decreased malondialdehyde (MDA) content. The intervention suppressed the epithelial-mesenchymal transition (EMT) process, as evidenced by the upregulation of E-cadherin and downregulation of α-SMA expression. Mechanistic verification indicated that BYJ treatment was associated with attenuated the overactivated of TGF-β/PI3K-AKT/mTOR pathway in renal tissues.Conclusion The methanolic extract of BYJ effectively attenuates CKD progression in mice, which is associated with by modulated the overactivation of the TGF-β/PI3K-AKT/mTOR pathway, inhibited the EMT process, and ameliorated inflammatory response and oxidative stress. These findings provide a preliminary theoretical basis for the development of BYJ as a potential candidate agent for CKD treatment.
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高影响因子
Cell Death & Disease
·
2026
·Vol. 17
·期 1
·750
·
IF 12.2
Luomeng Qian,Ping Chen,Bo Wang,Qing Zhang,Yuan Guo,Jie Cui,Ran Ding,Hongkai Zhang,Sihe Zhang
Sorafenib is a widely used targeting drug for hepatocellular carcinoma (HCC) patients; however, sorafenib resistance poses a significant clinical challenge. Hypoxia and extracellular vesicles (EVs) induce vasculogenic mimicry (VM) which is linked to sorafenib resistance in HCC. Migrasomes (Migs), the newly discovered large EVs, foster HCC malignant phenotypes by facilitating the intercellular transfer of functional molecules. Despite these advancements, the precise mechanism by which Migs cause sorafenib resistance is still unknown. In this study, we found that hypoxia upregulates the Migs release and CD147 expression on Migs surface, which is related to sorafenib resistance in HCC. Further investigations revealed that hypoxia-induced migrasomes (hypo-Migs) induce VM formation, thereby promoting sorafenib resistance in HCC. Notably, hypo-Migs are internalized into HCC cells through macropinocytosis, which depends on the expression of lysophosphatidic acid receptor 6 (LPAR6). Mechanistically, CD147-positive (CD147 + ) hypo-Migs activate the PI3K/AKT/TWIST1 signaling pathway, subsequently inducing VM formation and promoting sorafenib resistance. Importantly, dual blockade of CD147 + -hypo-Migs macropinocytosis and VM formation enhances the sorafenib-killing efficacy to HCC. Conclusively, our findings uncover a novel sorafenib resistance mechanism induced by CD147 + -hypo-Migs, and highlight dual-targeting of macropinocytosis and VM as a promising strategy to overcome the sorafenib resistance in HCC.
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高影响因子
Communications Biology
·
2026
·
IF 5.8
He Mingli,Yang Cheng,Shi Haiyuan,Xuan Xunrong,Li Juan,Zhang Chunyang,Zhang Han
Cryptochrome 2 (CRY2) has been implicated in blood perfusion recovery. This study aims to explore its effects on the repair of the blood-brain barrier (BBB) during chronic cerebral hypoperfusion (CCH). Human cortical microvessels endothelial cells/D3 (hCMEC/D3) are induced with hypoxia and co-cultured with microvascular pericytes and astrocytes. Mice are induced by bilateral common carotid artery stenosis (BCAS). In hypoxia-induced hCMEC/D3 cells and vascular endothelial cells from BCAS-induced mice, CRY2 is downregulated. CRY2 overexpression ameliorates hCMEC/D3 injury and inhibits BBB disruption and cognitive dysfunction in mice. rs10838524 (A > G) resulted in the CRY2 reduction and correlated with more severe CCH. CRY2 mediates the time-dependent expression of insulin-like growth factor 2 (IGF2). The ameliorative effect of CRY2 on CCH is dependent on the IGF2/Phosphoinositide 3-Kinase (PI3K)/Protein Kinase B (AKT). The findings demonstrate that the rs10838524 (A > G) of CRY2 represses enhancer-mediated transcription of CRY2 , thereby attenuating activation of IGF2 and impairing PI3K/AKT signaling.
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高影响因子
MATERIALS & DESIGN
·
2026
·
IF 8.2
Yue Peng,Cuiman Tang,Mingcong Niu,Tianyi Xu,QingYu Meng,Xinran Li,Rongheng Ma,Huimin Yu
A traditional medicine-inspired strategy provides a logical framework for constructing carrier-free hybrids. • Precise structural modifications successfully circumvent the inherent bioaccessibility limitations of natural products. • The covalent integration of diverse functional modules enables synergistic therapeutic efficacy against arthritis. • The therapeutic action is closely associated with the modulation of protein kinase B and hypoxia-inducible factor signaling. Curcumin (Cur) possesses potent anti-inflammatory activity but faces clinical challenges due to poor aqueous dispersibility, insufficient membrane affinity, and low bioavailability. Borneol (Bor), a classic “envoy” component in Traditional Chinese Medicine (TCM), exhibits prominent membrane-penetrating properties. Inspired by the “monarch-envoy” compatibility theory, we rationally designed carrier-free hybrids by covalently conjugating Cur (“monarch”) with Bor (“envoy”). Systematic characterization confirmed the successful synthesis and controllable optimization of key properties, including enhanced dispersibility, improved cellular uptake, and favorable biocompatibility. Using rheumatoid arthritis (RA) as a disease model, we identified SCBMS as the optimal formulation owing to its superior dispersibility and uptake, which directly translated into the most potent anti-RA efficacy. The hybrids exerted synergistic multifunctional effects—including robust anti-inflammatory and antioxidant activities—effectively reducing the arthritis index and ameliorating synovial hyperplasia and joint destruction in vivo . Mechanistically, our results indicate a close correlation between the therapeutic effects and the downregulation of the AKT/mTOR/HIF-1α signaling pathway, supporting the involvement of this pathway in the observed anti-RA activity. This study provides a generalizable framework for developing functional hybrids guided by TCM principles and validates their translational potential. Download: Download high-res image (152KB) Download: Download full-size image
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高影响因子
Frontiers in Physiology
·
2026
·
IF 4.3
Yu Xin,Chenyu Yang,Gege Wang,Huiping Ma,Linlin Jing
IntroductionCognitive impairment is a common symptom for these people entering high altitude. Unfortunately, the potential molecular mechanisms are not totally clear. This study aimed to identify the genes and signaling pathways associated with high-altitude cognitive dysfunction (HACD) in mice.MethodsMale C57BL/6 J mice were allocated into two groups: control group and hypobaric hypoxia (HH) group. The cognitive function was assessed using novel object recognition test and Morris water maze test. The histological analysis was performed using Hematoxylin-Eosin (HE) staining and Nissl staining. Evans blue (EB) assay was performed to evaluate the integrity of the blood-brain barrier (BBB). The gene levels in hippocampal tissue were assessed via RNA-Seq technique. Differentially expressed genes (DEGs) were identified using the DESeq2 R package, followed by functional and pathway enrichment analyses. The protein-protein interaction (PPI) network was established for screening hub genes, which were subsequently validated by qRT-PCR. The related proteins were detected by Western blot.ResultsHH exposure led to pathological changes in hippocampal tissue, accompanied by increased oxidative stress, inflammatory response, and BBB disruption, and then induced impaired cognitive function in mice. In the HACD mice, 178 DEGs (70 upregulated and 108 downregulated genes) were found, in comparison to the control, and 8 hub genes were identified. GO and KEGG enrichment analysis demonstrated that PI3K/AKT signaling pathway is a significantly enriched pathway, suggesting its potential involvement in the pathogenesis of HACD. Then, we performed validation experiments via qRT-PCR for four hub genes (Vwf, Vegfa, Kdr, Spp1) closely related to the PI3K/AKT signaling pathway, and the results aligned with the RNA-seq data. Furthermore, Western blot analysis indicated that the PI3K/AKT pathway was substantially inhibited following HH exposure. Downstream analysis revealed significantly decreased expression of antioxidant proteins Nrf2 and HO-1, accompanied by increased phosphorylation of NF-κB, indicating enhanced neuroinflammation and impaired antioxidant defenses.ConclusionsOur results reveal a significant association between PI3K/AKT signaling pathway inhibition and HACD and offer potential therapeutic targets for developing novel treatment strategies for HACD.
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高影响因子
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