CELL BIOLOGY AND TOXICOLOGY
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2025
·Vol. 41
·期 1
·1-17
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IF 5.9
Mao Shitao,Yu Na,Wang Wei,Mao Yikai,Du Ying,Zhao Qihe,Gu Xiu,Kang Jian
Idiopathic pulmonary fibrosis (IPF), characterized by fibroblast activation and collagen deposition, is a progressive lung disease that lacks effective interventions. Ubiquitin-specific peptidase 10 (USP10) acts as a multifunctional player in inflammatory response and progression of cancers, the effect on pulmonary fibrosis is unknown. Here, we demonstrated downregulated expression of USP10 in fibrotic lung tissues of IPF patients. In the current study, lung tissues were collected at the end of weeks 1, 2, or 3 post bleomycin (BLM)-intratracheal delivery. Consistently, USP10 expression levels were reduced after BLM challenge in a time-dependent manner. Mice treated with lentivirus overexpressing USP10 exhibited mitigative lung injury and reduced collagen deposition. USP10 overexpression enhanced autophagy in BLM-treated mouse lungs. Interestingly, the protective effect of USP10 was attenuated as the pulmonary autophagy flux was blocked by autophagy inhibitor 3-methyladenine (3-MA). Primary human and mouse lung fibroblasts were treated with pro-fibrotic TGF-β1 to verify the role of USP10 in vitro. Mechanically, the deubiquitinating enzyme USP10 interacted with Sirtuin 6 (Sirt6) and inhibited its degradation. Furthermore, USP10 overexpression inhibited the activation of Sirt6-mediated AKT/mTOR pathway in both lung tissues and fibroblasts. Our findings suggest that USP10 might attenuate pulmonary fibrosis through the promotion of Sirt6/AKT/mTOR-mediated autophagy. These data prioritize USP10 as a therapeutic target for treating IPF. Graphical
研究领域:
医学
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分子生物学
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PubMed
高影响因子
Cancer Medicine
·
2025
·Vol. 14
·期 9
·e70872
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IF 3.1
Haitao Xu,Dangui Chen,Jia Lu,Long Zhong,Lihong Wang,Jian Ge
Background Acute myeloid leukemia (AML) represents a highly aggressive hematological malignancy characterized by a poor prognosis and a pressing demand for innovative diagnostic and prognostic biomarkers. Recent studies have indicated that ADP-ribosylation factor 6 (ARF6) is overexpressed across various cancer types; however, its specific role and implications in AML have yet to be thoroughly investigated. Methods To elucidate the clinical relevance and functional mechanisms of ARF6 in AML, we conducted an integrated analysis utilizing RNA sequencing data from The Cancer Genome Atlas (TCGA) alongside clinical samples and AML cell lines. The diagnostic potential of ARF6 was assessed through receiver operating characteristic curve analysis, and logistic regression was employed to identify factors correlating with elevated ARF6 expression. Functional assays were performed to elucidate the effects of ARF6 modulation on apoptosis, cell cycle progression, and AML cell proliferation, while mechanistic investigations focused on the PI3K/AKT/mTOR signaling pathway, particularly in the context of pharmacological PI3K inhibition. Results Our findings revealed a significant upregulation of ARF6 in AML compared to normal controls, with diagnostic efficacy indicated by an AUC of 0.793. Logistic regression analysis identified older age (> 60 years) and a higher white blood cell count (> 20 × 10 9 /L) as significant predictors of high ARF6 expression. Moreover, elevated ARF6 levels were independently associated with shorter overall survival (HR = 1.634, p = 0.045). Notably, ARF6 knockdown induced apoptosis and G0/G1 cell cycle arrest, whereas its overexpression yielded contrary effects. In addition, ARF6 activated the PI3K/AKT/mTOR pathway, which was abrogated by pharmacological PI3K inhibition. Conclusion Collectively, our findings establish ARF6 as a valuable diagnostic and prognostic marker in AML, driving disease progression through the activation of the PI3K/AKT/mTOR pathway. These insights not only enhance our understanding of AML pathology but also underscore the potential of targeting ARF6 for therapeutic intervention in AML treatment paradigms. Future research should aim at evaluating the therapeutic implications of targeting ARF6 in combination with existing treatment modalities.
研究领域:
血液学
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肿瘤学
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分子生物学
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PubMed
高影响因子
TOXICOLOGY LETTERS
·
2022
·
IF 4.271
Rongzhe Zhu,Xiaochen Liu,Qiupeng Xue,Xiaoru Dong,Tianyi Zhang,Yan Jiang
Previous surveys have revealed that mirtazapine (MIR), one of the most commonly prescribed antidepressants, is associated with a higher risk of adverse cardiac events compared with other newer antidepressants. Chronic ethanol (EtOH) abuse could also lead to myocardial injuries. Concerning the common comorbidity of major depression and alcohol dependence, combined consumption of MIR and EtOH might be prevalent in patients with depression, resulting in an additive or synergistic cardiotoxic effect. To this end, the present study evaluated cardiotoxicity induced by MIR-plus-EtOH in vivo (male C57BL/6J mice) and in vitro (H9c2 cardiomyoblasts), Further research on the role of autophagy and underlying signaling pathway were carried out in H9c2 cells. We found that EtOH exacerbated MIR-induced cardiotoxicity both in vivo and in vitro . Furthermore, EtOH significantly potentiated MIR-induced dysfunctional autophagy as reflected by upregulated protein levels of LC3-II, p62, Beclin1 and LAMP-1. Pharmacological inhibition of autophagy by 3-methyladenine alleviated MIR-plus-EtOH-induced myocardial injury. High mobility group box 1 (HMGB1) is a positive regulator of autophagy. In our work, HMGB1 knockdown decreased autophagosome accumulation and boosted viability in H9c2 cells. Additionally, HMGB1 blockage markedly upregulated p-Akt/Akt and p-mTOR/mTOR levels which were suppressed in MIR-plus-EtOH treated cells. In general, the present study demonstrates that EtOH potentiates MIR-induced cardiotoxicity which might be attributed to dysfunctional autophagy via inhibiting Akt/mTOR signaling pathway, while HMGB1 knockdown might contribute to improve autophagy flux.
研究领域:
药理学
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心脏病学
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细胞生物学
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毒理学
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PubMed
高影响因子
JOURNAL OF DRUG TARGETING
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2019
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IF 3.277
Jun Ma,Di Du,Jia Liu,Lei Guo,Yongchuan Li,Aimin Chen,TianWen Ye
Hydrogen sulphide (H2S), a gasotransmitter, plays an important role in the regulation of bone homeostasis. However, the precise effect of H2S on osteoclasts was still elusive. The goal of this study was to determine the potential role of H2S in regulation of osteoclasts and the underlying mechanisms by which H2S affected osteoclastogenesis. The present study applied western blot, quantitative real-time PCR, tartrate-resistant acid phosphatase staining, pit formation assay, immunofluorescence confocal microscopy, transmission electron microscopy and annexin V-fluorescein isothiocyanate/propidium iodide double-staining assay. The results showed that the expressions of cystathionine b-synthase (CBS) and cystathionine c-lyase (CSE) were obviously increased in osteoclast differentiation induced by the receptor activator of nuclear factor kappa-β ligand (RANKL). In addition, H2S promoted RANKL-induced osteoclastogenesis and inhibited apoptosis of mature osteoclasts. Mechanistically, H2S inhibited autophagy in Raw 264.7 cells. Autophagy activator (rapamycin) alleviated the induction of osteoclast differentiation by H2S. Further studies showed that H2S inhibited autophagy by activating the PI3K/AKT/mTOR signalling pathway. Taken together, our results implicated that exogenous H2S could promote osteoclastogenesis by activating the PI3K/AKT/mTOR pathway to downregulate autophagy.
研究领域:
骨骼生物学
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细胞信号传导
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分子生物学
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PubMed
高影响因子
Acta Biomaterialia
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2025
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IF 9.6
Shiyi Yao,Hui Yuan,Luqi Yang,Yin Zhang,Hanyu Wang,Renxuan Li,Tingjun Ye,Wenguo Cui,Lei Wang
Interface friction impedes tissue healing and stimulates interface cells to produce matrix metalloproteinases (MMPs); however, the precise mechanisms underlying matrix degradation, and the formation of fibrous scars remain unclear. This research involved the development of interface lubricating microspheres that inhibit the PI3K/AKT/mTOR signaling pathway in tenocytes. This inhibition significantly decreased MMP-13 expression and increased COL-1 production, thereby facilitating interface repair and regeneration. In vitro experiments demonstrated that interface friction activates the PI3K/AKT/mTOR/MMP-13 signaling pathway, while the use of interface lubricating microspheres reduced friction by 78 %, resulting in a threefold decrease in MMP-13 expression through pathway inhibition. Animal studies showed that the application of interface lubricating microspheres reduced friction at the tendon-bone interface, mitigating MMP-13-mediated matrix degradation and effectively reducing fibrous scar formation (as evidenced by decreased α-SMA expression), thus promoting interface healing following ACLR surgery in rats. Consequently, this study suggests that interface friction can trigger the PI3K/AKT/mTOR signaling pathway in tenocytes, leading to increased MMP-13 expression, matrix degradation, and fibrous scar formation. The use of interface lubricating microspheres can enhance interface healing by inhibiting this pathway, offering strategies for improving interface healing and minimizing fibrous scar formation. Statement of significance Interface healing plays a crucial role following tendon-bone surgeries, yet it is often hindered by challenges such as interface friction and scar formation. In this study, we propose a combined approach in which lubricating microspheres and an anti-matrix degradation drug are used to enhance interface healing. We fabricated novel lubricating microspheres that exhibit outstanding biocompatibility and degradability; these microspheres serve as lubricants for the tendon-bone interface and facilitate the delivery of doxycycline to reduce excessive matrix metalloproteinase (MMP) secretion. The experimental results demonstrated that this method could enhance tendon-bone interface healing in rats, resulting in increased bone formation and higher histological scores than those of the control group. This study represents a preliminary effort to integrate lubrication and anti-matrix degradation in interface healing, potentially offering new insights into the mechanism between interface friction and fibrous scar healing, while promoting interface healing by reducing interfacial friction.
研究领域:
生物医学工程
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分子生物学
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再生医学
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PubMed
高影响因子
npj Breast Cancer
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2024
·Vol. 10
·期 1
·1-15
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IF 6.5
Rossetti Stefano,Broege Aaron,Sen Adrish,Khan Salmaan,MacNeil Ian,Molden Jhomary,Kopher Ross,Schulz Stephen,Laing Lance
The PI3K, AKT, and mTOR (PAM) pathway is frequently dysregulated in breast cancer (BC) to accommodate high catabolic and anabolic activities driving tumor growth. Current therapeutic options for patients with hormone receptor (HR) + / HER2- advanced BC (ABC) include PAM inhibitors that selectively inhibit only one PAM pathway node, which can lead to drug resistance as cells rapidly adapt to maintain viability. We hypothesized that gedatolisib, which potently inhibits all Class I PI3K isoforms, as well as mTORC1 and mTORC2, may be more effective in BC cells than single-node PAM inhibitors by limiting adaptive resistances. By using multiple functional assays, a panel of BC cell lines was evaluated for their sensitivity to four different PAM inhibitors: gedatolisib (pan-PI3K/mTOR inhibitor), alpelisib (PI3Kα inhibitor), capivasertib (AKT inhibitor), and everolimus (mTORC1 inhibitor). Gedatolisib exhibited more potent and efficacious anti-proliferative and cytotoxic effects regardless of the PAM pathway mutational status of the cell lines compared to the single-node PAM inhibitors. The higher efficacy of gedatolisib was confirmed in three-dimensional culture and in BC PDX models. Mechanistically, gedatolisib decreased cell survival, DNA replication, cell migration and invasion, protein synthesis, glucose consumption, lactate production, and oxygen consumption more effectively than the other PAM inhibitors tested. These results indicate that inhibition of multiple PAM pathway nodes by a pan-PI3K/mTOR inhibitor like gedatolisib may be more effective at inducing anti-tumor activity than single-node PAM inhibitors. A global Phase 3 study is currently evaluating gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2− ABC.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
高影响因子
BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH
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2025
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IF 1.5
Han Wang,Guan Mengtong,Liao Bo,Han Xiaoyu,Li Kaiting,Chen Qing,Guo Xiya,Niu Yajuan,Zhu Ying,Bai Dingqun
Cellular senescence is an important cause of age-related degenerative diseases, including osteoarthritis (OA). Chondrocyte senescence is crucial in OA onset and progression. As a non-invasive, safe, and widely used physical rehabilitation factor, the effect and mechanism of low intensity pulsed ultrasound (LIPUS) on chondrocyte senescence remain unclear. This study evaluated the inhibitory effect of LIPUS on OA chondrocyte senescence in vitro and in vivo. The effect of LIPUS on chondrocyte senescence was examined by RT-qPCR, enzyme-linked immunosorbent assay (ELISA), and western blotting. Changes in levels of reactive oxygen species (ROS) and γ-h2ax foci in senescent chondrocytes were detected using fluorescent staining. Chondrocyte senescence was evaluated by senescence-associated β-galactosidase (SA-β-gal) staining. The PI3K inhibitor LY294002 and the PI3K agonist 740Y-P were used to investigate whether PI3K/AKT/mTOR signalling was involved in the effect of LIPUS in senescent chondrocytes. Chondrocyte senescence and cartilage degeneration were analyzed in a destabilization of the medial meniscal (DMM) mouse model by immunohistochemistry, hematoxylin and eosin staining, and safranin-O/fast green staining. LIPUS inhibited the expression of the senescence-associated secretory phenotype (SASP) factors CCL4 and CCL2 and the senescence phenotype in doxorubicin-treated chondrocytes by inhibiting the PI3K/AKT/mTOR pathway. LIPUS alleviated chondrocyte senescence and attenuated OA progression in the DMM mice. These results demonstrated a novel role for LIPUS in inhibiting chondrocyte senescence and the SASP by modulating PI3K/AKT/mTOR signalling. Our findings expanded the clinical application of LIPUS and provide a new, non-invasive, and safe treatment approach to prevent and treat age-related degenerative joint disorders.
研究领域:
医学
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生物学
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PubMed
高影响因子
TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE
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2025
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IF 1.6
Shaohao Luo,Yunfei Bai,Boqian Wang,Haixia Xu,Shu Zhang,Gang Guo,Xin Li,Hongyang Sun,Xiaobo Cui
Homeobox A1 (HOXA1) is implicated in the progression of various cancers, but its biological function in laryngeal cancer (LC) remains undefined, which is the foothold of our study. Bioinformatics analysis and survival analysis were performed to predict HOXA1 expression in LC tissues, and the prognostic relationship between high HOXA1 expression and LC. Whether high HOXA1 expression correlated with the clinical characteristics and prognosis of LC patients was analyzed. LC cell viability and sensitivity to cisplatin were determined by Methyl thiazolyl tetrazolium assay. The cell migration, invasion, and cell cycle after transfection were examined by Wound healing, Transwell, and flow cytometry assays, respectively. The corresponding mRNA and protein expressions were measured by quantitative real-time PCR or Western blot. A higher expression of HOXA1 was detected in LC tissues, which was found to be relevant to poor prognosis of LC patients. The association of high expression of HOXA1 with lymph node and clinical stage was also confirmed. Silencing of HOXA1 in LC cells enhanced the cell sensitivity to cisplatin, inhibited viability, migration, invasion and cell cycle, and reduced N-Cadherin, Vimentin, PCNA, p-AKT and p-mTOR expressions, while overexpression of HOXA1 had the opposite effects. Collectively, HOXA1 boosts migration, invasion and cell cycle, while suppressing cisplatin sensitivity of LC cells by mediating AKT/mTOR pathway, hinting that HOXA1 is a promising biomarker for diagnosis and prognosis of LC in clinical practice.
研究领域:
肿瘤学
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分子生物学
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PubMed
高影响因子
Experimental and Therapeutic Medicine
·
2018
·Vol. 17
·期 1
·393-397
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IF 1.41
Rendong Wei,Haidong Liu,Ru Chen,Yunjian Sheng,Tao Liu
Astragaloside Ⅳ (AS‑Ⅳ) in improving liver cirrhosis injury in rats and its effect on the phosphoinositide 3‑kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) signaling pathway were observed. Rat model of liver cirrhosis was induced by injection of carbon tetrachloride (CCl4). A total of 36 Sprague‑Dawley (SD) rats were randomly divided into three groups: the normal control group (n=10), the model control group (n=13), and the AS‑Ⅳ group (n=13). The normal control group was injected with olive oil and given carboxymethyl cellulose (CMC)‑Na (10 ml/kg/day), the model control group was given CMC‑Na (10 ml/kg/day), and the AS‑Ⅳ group underwent intragastric administration of AS‑Ⅳ (20 ml/kg/day). The content of alanine transaminase (ALT) and aspartate transaminase (AST) of rats was detected. The levels of tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑6 and IL‑1β in serum were detected via enzyme‑linked immunosorbent assay (ELISA). Hematoxylin and eosin (H&E) staining was applied to observe morphological changes in liver tissues. The expression of collagens in liver tissues was detected via Masson's trichrome staining. Additionally, the expression of proteins in liver tissues was detected via western blotting. Compared with those in the blank group, the levels of AST, ALT, TNF‑α, IL‑6 and IL‑1β were higher, the expression level of collagens in liver tissues was increased, and the expression ratios of phosphorylated (p)‑PI3K/PI3K, p‑Akt/Akt and p‑mTOR/mTOR proteins were increased in the model group. Compared with the model group, AS‑Ⅳ could significantly decrease the content of AST, ALT, TNF‑α, IL‑6 and IL‑β in serum of rats, obviously inhibit the expression of collagens in liver tissues and decrease the expression ratios of p‑PI3K/PI3K, p‑Akt/Akt and p‑mTOR/mTOR proteins in liver tissues. AS‑Ⅳ can inhibit the inflammatory response so as to reduce the expression of collagens, and its mechanism may play a key role by inhibiting the PI3K/Akt/mTOR signaling pathway.
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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PubMed
高影响因子
NEUROCHEMICAL RESEARCH
·
2020
·Vol. 45
·期 12
·2926-2938
·
IF 3.038
Tian Jun,Yang Lei,Wang Pengfei,Yang Lijun,Fan Zhenzeng
With millions of traumatic brain injury (TBI) patients every year, TBI is regarded as one of the leading causes of human death and disability. Calcitonin gene-related peptide (CGRP) has been domenstrated to be a potential therapeutic target for TBI. However, the detailed effect and underlying mechanism of CGRP on the injured brain after TBI has hardly been investigated. In this work, we established TBI models of mice and injected CGRP before and after modelling to study its effects on the brain lesion, neurological functions and behaviours, neuron apoptosis and autophagy after TBI. Impacts of introduced CGRP on the activation of Akt/mTOR signalling in the cortical tissues surrounding injured areas after TBI were also evaluated. It was found that CGRP was reduced after TBI, and gradually restored over time. CGRP administration significantly restored the brain lesion induced by TBI. The permeability of blood–brain barrier and brain edema was increased dramatically after TBI, which was ameliorated by exogenous CGRP. Moreover, several neurological behaviour tests were performed, showing that CGRP introduction also relieved the cognitive abilities of mice which were impaired after TBI. Enhancing apoptosis and autophagy of neurons in the cortical tissues of injury sites following TBI were also alleviated by CGRP administration. Besides, CGRP-treated brain cortical tissues showed increased activation of Akt/mTOR signalling after TBI. Therefore, the results suggest that exogenous CGRP plays a neuroprotective role in the injuryed brain after TBI, to relieve cell apoptosis and autophagy, at least partially through Akt/mTOR signalling pathway. This finding also provides more evidence for the treatment of TBI through introducing exogenous CGRP or its related drugs.
研究领域:
神经科学
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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
EXPERIMENTAL CELL RESEARCH
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2022
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IF 4.145
Feng Chi,Long Chen,Xiaoming Jin,Guijin He,Zhen Liu,Sijia Han
Cytoskeleton-associated protein 2-like (CKAP2L) is a mitotic spindle protein and its high expression is reported to be associated with the poor prognosis of cancer patients. Interestingly, TNMplot website analysis indicated that CKAP2L expression was significantly higher in breast cancer (BC) tissues than in normal breast tissues ( P < 0.001). Thus, this study was conducted to investigate the role of CKAP2L in breast carcinogenesis and its underlying molecular mechanisms. The mRNA and protein expression levels of CKAP2L in 40 paired fresh BC and para-carcinoma specimens were first analyzed, and the results confirmed the high expression of CKAP2L in BC tissues. Functional studies revealed that CKAP2L silencing dramatically suppressed the proliferation, migration, and invasion, induced cell cycle arrest and apoptosis of BC cells in vitro , and inhibited the growth of xenografted tumors in vivo . However, CKAP2L overexpression produced the opposite results. Mechanically, CKAP2L could activate the AKT/mTOR signaling pathway in BC cells accompanied by increased phosphorylation levels of AKT, mTOR , and p70S6K in CKAP2L-overexpressed cells. Forkhead box protein P3 (FOXP3), a transcription factor with tumor-suppressive properties, was proved to negatively regulate CKAP2L expression in BC cells through binding to the promoter of CKAP2L and inhibiting its transcription. In summary, the present study demonstrates that CKAP2L, transcriptionally regulated by FOXP3 , activates the AKT/mTOR signaling pathway and promotes breast carcinogenesis. CKAP2L may serve as a promising target of therapeutic intervention for BC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Journal of Orthopaedic Surgery and Research
·
2023
·Vol. 18
·期 1
·1-13
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IF 2.6
Zhang Yang,Liu Wenguang,Liu Zhonghao,Liu Yi
Background Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degeneration and intra-articular inflammation. Daurisoline (DAS) is an isoquinoline alkaloid isolated from Rhizoma Menispermi, whose antitumor and anti-inflammatory pharmacological effects have been demonstrated, but the effects of DAS on OA have rarely been researched. In this study, we aimed to explore the potential role of DAS in OA and its partial mechanism.
Materials and methods The cytotoxicity of H 2 O 2 and DAS toward chondrocytes was detected by the Cell Counting Kit-8 assay. Safranin O staining was used to detect chondrocyte phenotype changes. Cell apoptosis was measured by both flow cytometry and quantitative analysis of the protein levels of the apoptosis-related factors Bax, Bcl-2 and cleaved caspase-3 by western blot. Western blotting and immunofluorescence were used to assess the expression of the autophagy-related proteins LC3, Beclin-1 and p62. In addition, key signal pathway targets and matrix-degrading indicators were measured by western blot. Results Our results indicated that H 2 O 2 induced human chondrocyte apoptosis and activated autophagy in a dose-dependent manner. DAS treatment dose-dependently reversed the expression of apoptosis-related proteins (Bax, Bcl-2 and cleaved caspase3) and the apoptosis rate induced by H 2 O 2 . Western blot and immunofluorescence analyses showed that DAS decreased the H 2 O 2 -induced upregulation of the autophagy marker Beclin-1 and the LC3 II/LC3 I ratio and upregulated the p62 protein level. Mechanistically, DAS inhibited autophagy through the activation of the classical PI3K/AKT/mTOR signaling pathway and protected chondrocytes from apoptosis. In addition, DAS alleviated the H 2 O 2 -induced degradation of type II collagen and the high expression of matrix metalloproteinase 3 (MMP3) and MMP13. Conclusion Our research demonstrated that DAS alleviated chondrocyte autophagy caused by H 2 O 2 through activation of the PI3K/AKT/mTOR signaling pathway and protected chondrocytes from apoptosis and matrix degradation. In conclusion, these findings suggest that DAS may serve as a promising therapeutic strategy for OA.
研究领域:
药理学
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细胞生物学
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风湿病学
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骨科
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）