BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
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2022
·
IF 5.011
Xijie Yu,Xiaoxiao Xu,Wei Dong,Chang Yang,Yao Luo,Ying He,Chenxi Jiang,Yanru Wu,Jiawei Wang
Endoplasmic reticulum (ER) stress is an evolutionarily conserved cellular stress response related to multiple diseases, including temporomandibular joint (TMJ) cartilage-related diseases. Recent studies have indicated that DDIT3/CHOP (a downstream transcription factor of ER stress) is an important effector in mediating ER stress to inhibit chondrogenesis . However, the underlying mechanism by which DDIT3 regulates chondrogenesis remains unclear. In this study, tunicamycin (an ER stress agonist)-induced ER stress inhibited chondrocyte differentiation and matrix synthesis in vitro and led to an osteoarthritis-like phenotype in mouse TMJ cartilage. Meanwhile, DDIT3 expression in chondrocytes was robustly upregulated. Loss-of-function experiments validated the inhibiting effect of DDIT3 on chondrocyte differentiation and matrix synthesis. Mechanistically, the inhibiting effect was attributed to the direct and indirect regulatory effect of DDIT3 on SIRT1 (sirtuin1, silent mating type information regulation protein type 1, a member of NAD+ dependent class III histone deacetylases). On one hand, DDIT3 directly promoted the transcription of SIRT1. On the other hand, DDIT3 indirectly increased the expression of SIRT1 by promoting AMPKα phosphorylation and activation. Furthermore, activation of AMPKα or SIRT1 with the corresponding agonist AICAR or resveratrol in the DDIT3-knockdown cells partially restored the inhibiting effect of DDIT3 on chondrocyte differentiation and matrix synthesis. Collectively, these novel findings indicate that DDIT3 regulates the inhibitory effect of ER stress on chondrocyte differentiation and matrix synthesis partially via the AMPKα-SIRT1 pathway. A thorough understanding of ER stress in regulating chondrocyte homeostasis and its role in the onset of osteoarthritis may be promising to develop therapeutic targets and prevent condyle cartilage destruction.
研究领域:
细胞生物学
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分子生物学
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骨科
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病理学
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DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2023
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IF 3.8
Yixin Sun,Danyang Guo,Saiding Yue,Mingyan Zhou,Dongxu Wang,Fengjiao Chen,Lingling Wang
Background Doxorubicin (DOX), a chemotherapeutic drug, could relieve the progressions of various diseases. However, its clinical application is limited due to its cardiotoxicity. This study aimed to investigate the effects of afzelin (a flavonol glycoside found in Houttuynia cordata ) on the cardiotoxicity induced by DOX. Methods In ex-vivo, H9C2 cells were incubated with 20, 40, or 80 μM afzelin for 12 h, followed by the treatment with 1 μM DOX for 12 h. In vivo, C57BL/6 J mice were intraperitoneally injected with 4 mg/kg/day DOX on days 1, 7, and 14. Meanwhile, starting from day 1, mice were intragastrically administrated with 5 mg/kg/day or 10 mg/kg/day afzelin for 20 days. The cardiac function of mice was evaluated by detecting hemodynamic parameters using the M-mode echocardiography. Results DOX decreased the cell survival rate, and elevated apoptotic rate, as well as induced the oxidative stress and mitochondrial dysfunction in H9C2 cells. All these changes were alleviated by afzelin treatment in a concentration-dependent manner. The results were further proven by the mitigation of cardiac injury in vivo, as evidenced by the elevation of fractional shortening, heart weight/tibia length, and the rate of the increase/decrease of left ventricular pressure in mice subjected to DOX-induced cardiotoxicity. Furthermore, afzelin upregulated the expression of p-AMP-activated protein kinase alpha (AMPKα) and sirtuin1 (SIRT1). Dorsomorphin (an AMPKα inhibitor) abrogated the anti-cardiotoxicity effects of afzelin in H9C2 cells induced by DOX. Conclusion Afzelin protected against DOX-induced cardiotoxicity by promoting the AMPKα/SIRT1 signaling pathway.
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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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
·
2020
·Vol. 236
·期 3
·1889-1902
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IF 5.546
Wenhui Yao,Kai Wang,Xiniao Wang,Xinran Li,Jieyan Dong,Yusheng Zhang,Xuansheng Ding
Icariin (ICA), as a flavonoid glycoside, is associated with the improvement of vascular complications in diabetes. However, its protective mechanisms remain to be well-established. Here, we tested the hypothesis that ICA attenuates vascular endothelial dysfunction by inhibiting endoplasmic reticulum (ER) stress in type 1 diabetes. In streptozotocin-induced diabetic rats, ICA positively affected acetylcholine-induced vasodilation and phenylephrine-induced vasoconstriction in aortas. ICA treatment significantly attenuated ER stress in diabetic rats and high-glucose induced human umbilical vein endothelial cells. Incubation with ICA in vitro attenuated vascular reactivity in diabetic rats, which was blocked by the ER stress inducer, and peroxisome proliferator-activated receptor α (PPARα), sirtuin1 (Sirt1), or AMP-activated protein kinase-α (AMPKα) inhibitors. Western blot showed that ICA activated the PPARα/Sirt1/AMPKα pathway, which contributed to reducing ER stress and activating endothelial nitric oxide synthase in vivo and vitro. Our results implicate that ICA normalizes ER stress to attenuate endothelial dysfunction by the regulation of the PPARα/Sirt1/AMPKα pathway.
研究领域:
药理学
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糖尿病
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心血管疾病
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分子生物学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2020
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IF 4.225
Li Shaoguang,Wang Xuewen,Wang Gang,Shi Peiying,Lin Shilan,Xu Dafen,Chen Bing,Liu Ailin,Huang Liying,Lin Xinhua,Yao Hong
Colorectal cancer is one type of cancer with high incidence rate and high mortality worldwide. Thus, developing new chemotherapeutic drugs is important. The Selaginella doederleinii Hieron ethyl acetate (SDEA) extract showed good anti-colon cancer effect in vitro and in vivo, but its mechanism is unclear. This study aimed to further reveal the anti-colon cancer effect of SDEA and its possible mechanism. The effects on cell viability, apoptosis, autophagy, and cell cycle in colorectal cells (HT29 and HCT116) were studied using MTT assay, fluorescence microscopy, transmission electron microscopy, and flow cytometry. The mechanisms were further studied using cell transfection, Western blot, and real-time quantitative polymerase chain reaction assay. The effect of xenotransplantation in vivo was observed using immunohistochemistry. Results showed that SDEA inhibited cell proliferation and induced cell morphological changes, cell cycle arrest, autophagy, and apoptosis. It also induced loss of mitochondrial membrane potential, increased the autophagic flux, raised the ratio of Bax/Bcl-2, activated caspases, and inhibited PI3K-Akt-mTOR signaling pathways. Furthermore, SDEA inhibited the growth of xenograft tumors in a dose-dependent manner. Immunohistochemistry analysis confirmed the alteration of autophagy- and apoptosis-related proteins and immunohistochemical microvascular density in xenografts, which were consistent with the results in vitro. Therefore, SDEA is important for developing candidate drugs against colorectal cancers.
研究领域:
肿瘤学
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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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DOI
PubMed
高影响因子
Microbial Biotechnology
·
2024
·Vol. 17
·期 4
·e14455
·
IF 4.8
Xuke Yang,Jichao Yang,Mengyu Lyu,Yaqiong Li,Anqi Liu,Bang Shen
Toxoplasma gondii is a zoonotic parasite infecting humans and nearly all warm-blooded animals. Successful parasitism in diverse hosts at various developmental stages requires the parasites to fine tune their metabolism according to environmental cues and the parasite's needs. By manipulating the β and γ subunits, we have previously shown that AMP-activated protein kinase (AMPK) has critical roles in regulating the metabolic and developmental programmes. However, the biological functions of the α catalytic subunit have not been established. T. gondii encodes a canonical AMPKα, as well as a KIN kinase whose kinase domain has high sequence similarities to those of classic AMPKα proteins. Here, we found that Tg KIN is dispensable for tachyzoite growth, whereas Tg AMPKα is essential. Depletion of Tg AMPKα expression resulted in decreased ATP levels and reduced metabolic flux in glycolysis and the tricarboxylic acid cycle, confirming that Tg AMPK is involved in metabolic regulation and energy homeostasis in the parasite. Sequential truncations at the C-terminus found an α-helix that is key for the function of Tg AMPKα. The amino acid sequences of this α-helix are not conserved among various AMPKα proteins, likely because it is involved in interactions with Tg AMPKβ, which only have limited sequence similarities to AMPKβ in other eukaryotes. The essential role of the less conserved C-terminus of Tg AMPKα provides opportunities for parasite specific drug designs targeting Tg AMPKα.
研究领域:
寄生虫学
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分子生物学
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医学
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产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
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2026
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IF 8.1
Yi-wen Qian,Yao Lu,Miao-miao Chang,Qian-qian Niu,Jia-xin Fan,Shi-ying Xing,Peng Li,Ling Liu
Cardiomyocyte senescence contributes to the progression of multiple cardiac diseases, with oxidative stress identified as a central pathophysiological mechanism. Previous animal experiments demonstrated that citronellal (CT), administered at 200 mg/kg in rats, exerted significant cardioprotective effects. However, the molecular mechanisms underlying these effects remain unclear. This study aimed to investigate the role of CT in mitigating myocardial senescence and to elucidate its mechanistic pathways. Doxorubicin-induced myocardial senescence mouse models and H9C2 cardiomyocyte senescence models were established. SA-β-gal staining, Western blotting, immunofluorescence, and immunohistochemistry were employed to evaluate senescence and oxidative stress markers. Network pharmacology analysis and molecular docking were conducted to predict CT targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to identify potential mechanisms of action. CT treatment significantly reduced myocardial oxidative stress levels, ameliorated senescent phenotypes in both in vivo and in vitro models, and enhanced mitophagy by activating the AMPKα-mediated PINK1/Parkin pathway. Bioinformatics analyses further supported the involvement of oxidative stress resistance and mitophagy regulation as central mechanisms underlying CT's cardioprotective effects. Citronellal effectively alleviates cardiomyocyte senescence by reducing oxidative stress and promoting mitophagy through activation of the AMPKα–PINK1/Parkin signaling pathway. These findings provide experimental evidence supporting CT as a promising cardioprotective agent and highlight a novel mechanism of action that may inform future therapeutic strategies for cardiac aging and related diseases.
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产品关联
DOI
PubMed
高影响因子
CELLULAR ONCOLOGY
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2026
·Vol. 49
·期 2
·55
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IF 5.6
Xin Qi,Zhang Henan,Zhao Zheng,Xu Gang,Zhang Jihong
Purpose This study aims to investigate the role of AGAP2 in acute myeloid leukemia (AML), particularly its involvement in lipid metabolic reprogramming and AML progression, and to explore the underlying regulatory mechanisms. Methods AGAP2 expression was analyzed in CD34⁺ cells from AML patients stratified by cytogenetic risk. Functional assays, including knockdown and overexpression of AGAP2, were performed in KG-1 and HL-60 AML cell lines to assess effects on proliferation, apoptosis, differentiation, and lipid metabolism. mRNA sequencing and KEGG pathway analysis were used to identify relevant signaling pathways. Lipid accumulation was evaluated via Filipin III staining. The AMPK pathway activator GSK621 was applied to examine lipid deposition. In vivo tumor growth and survival were studied in a mouse model, and bone marrow infiltration of CD45⁺ cells was analyzed. The transcriptional regulation of AGAP2 by NR2F2 was assessed through promoter binding and functional rescue experiments. Results AGAP2 was highly expressed in CD34⁺ cells from AML patients, with higher levels in the poor-risk group compared to favorable- and intermediate-risk groups. Knockdown of AGAP2 induced apoptosis and differentiation, while its overexpression promoted cell proliferation. KEGG analysis indicated enrichment of differentially expressed genes in the AMPK pathway. AGAP2 was found to inhibit AMPK/ACC pathway activation. Overexpression of AGAP2 increased lipid deposition whereas GSK621 treatment reversed it. In vivo, AGAP2 knockdown suppressed tumor growth, improved survival, and reduced CD45⁺ cell infiltration in bone marrow. Furthermore, NR2F2 bound to the AGAP2 promoter and suppressed its transcription. NR2F2 overexpression reduced lipid accumulation, an effect reversed by AGAP2 overexpression. Conclusion AGAP2 promotes lipid deposition and AML progression by inhibiting the AMPKα/ACC pathway. NR2F2 acts as a transcriptional repressor of AGAP2, thereby attenuating AML development. These findings reveal a novel NR2F2/AGAP2/AMPK/ACC regulatory axis in AML, highlighting potential therapeutic targets for lipid metabolism-based interventions in leukemia. Graphical
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PubMed
高影响因子
IMMUNITY
·
2024
·
IF 25.5
Jun Xiao,Shuang Wang,Longlong Chen,Xinyu Ding,Yuanhao Dang,Mingshun Han,Yuxiao Zheng,Huan Shen,Sifan Wu,Mingchang Wang,Dan Yang,Na Li,Chen Dong,Miao Hu,Chen Su,Weiyun Li,Lijian Hui,Youqiong Ye,Huiru Tang,Bin Wei,Hongyan Wang
Macrophages are critical to turn noninflamed “cold tumors” into inflamed “hot tumors”. Emerging evidence indicates abnormal cholesterol metabolites in the tumor microenvironment (TME) with unclear function. Here, we uncovered the inducible expression of cholesterol-25-hydroxylase (Ch25h) by interleukin-4 (IL-4) and interleukin-13 (IL-13) via the transcription factor STAT6, causing 25-hydroxycholesterol (25HC) accumulation. scRNA-seq analysis confirmed that CH25H hi subsets were enriched in immunosuppressive macrophage subsets and correlated to lower survival rates in pan-cancers. Targeting CH25H abrogated macrophage immunosuppressive function to enhance infiltrating T cell numbers and activation, which synergized with anti-PD-1 to improve anti-tumor efficacy. Mechanically, lysosome-accumulated 25HC competed with cholesterol for GPR155 binding to inhibit the kinase mTORC1, leading to AMPKα activation and metabolic reprogramming. AMPKα also phosphorylated STAT6 Ser564 to enhance STAT6 activation and ARG1 production. Together, we propose CH25H as an immunometabolic checkpoint, which manipulates macrophage fate to reshape CD8 + T cell surveillance and anti-tumor response.
研究领域:
免疫学
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肿瘤学
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代谢生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PEDIATRIC RESEARCH
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2024
·
IF 3.1
Hu Yingying,Nan Yan,Lin Hongzhou,Zhao Qianlei,Chen Tingting,Tao Xiaoyue,Ding Bingqing,Lu Liying,Chen Shangqin,Zhu Jianghu,Guo Xiaoling,Lin Zhenlang
Background Hypoxic-ischemic encephalopathy (HIE) is caused by perinatal hypoxia and subsequent reductions in cerebral blood flow and is one of the leading causes of severe disability or death in newborns. Despite its prevalence, we currently lack an effective drug therapy to combat HIE. Celastrol (Cel) is a pentacyclic triterpene extracted from Tripterygium Wilfordi that can protect against oxidative stress, inflammation, and cancer. However, whether Cel can alleviate neonatal hypoxic-ischemic (HI) brain damage remains unclear. Methods Here, we established both in vitro and in vivo models of HI brain damage using CoCl 2 -treated PC12 cells and neonatal rats, respectively, and explored the neuroprotective effects of Cel in these models. Results Analyses revealed that Cel administration reduced brain infarction size, microglia activation, levels of inflammation factors, and levels of oxidative stress markers by upregulating levels of p-AMPKα, Nrf2, HO-1, and by downregulating levels of TXNIP and NLRP3. Conversely, these beneficial effects of Cel on HI brain damage were largely inhibited by AMPKα inhibitor Compound C and its siRNA. Conclusions We present compelling evidence that Cel decreases inflammation and oxidative stress through the AMPKα/Nrf2/TXNIP signaling pathway, thereby alleviating neonatal HI brain injury. Cel therefore represents a promising therapeutic agent for treating HIE. Impact
We firstly report that celastrol can ameliorate neonatal hypoxic-ischemic brain injury both in in vivo and in vitro, which represents a promising therapeutic agent for treating related brain injuries.
Celastrol activates the AMPKα/Nrf2/TXNIP signaling pathway to relieve oxidative stress and inflammation and thereby alleviates neonatal hypoxic-ischemic brain injury.
研究领域:
神经科学
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药理学
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儿科
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 3.9
Yi Zhou,Yawen Chen,Yuanyuan Zhao,Qiaohui Lu,Shihao Li,Wen-song Tan,Yan Zhou
Hydrostatic pressure (HP) is one of the important mechanical stimuli to maintain the structure and function of bone tissue. Under non-physiological conditions, abnormal increases or decreases in HP can lead to loss of bone tissue function. Although HP has been proven to affect osteogenic differentiation, the rules and mechanisms of its regulatory effect are still unclear. In this study, the HP showed a marginal effect on promoting osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). The regulation of osteogenic differentiation by HP is closely related to the Piezo1 ion channel. On the one hand, the activity of mTOR is inhibited by HP through the CaMKK2/AMPKα/mTOR signaling axis, thereby promoting the osteogenic differentiation. On the other hand, the cell morphology is also regulated by HP and tends to be round, which is not conducive to osteogenesis. The two regulatory modes jointly control the ultimate osteogenic differentiation ability of BMSCs in a complex way. This study provides new insights into the mechanism by which HP regulates osteogenic differentiation, suggesting the need to consider the role of signaling cascades and physical changes simultaneously.
研究领域:
生物力学
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干细胞生物学
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骨组织工程
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DOI
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Dan Wang,Yimeng Zou,Tianqi Zhao,Weiyue Cao,Jiachi Han,Qing Wu,Zhitong Li,Xinyu Li,Peijing Liu,Lin Bai,Guiping Ren
Background The blood FGF21 expression has been previously suggested to increase in patients developing atopic dermatitis (AD) and asthma. However, its impact on atopic march is rarely analyzed. The present work focused on investigating the role of Fibroblast Growth Factor 21(FGF21) in atopic march mice and its underlying mechanisms. Methods The models were induced with Diisononyl phthalate (DINP) and OVA in wild-type C57BL/6 and FGF21 −/− mice. RAW264.7 cells were induced by LPS with/without FGF21 or KLB-SiRNA for in vitro analyses. Results The data indicated that there were more severe allergic reactions including IgE levels and the proportion of mast cells in the blood of FGF21 −/− mice in relative to WT model mice during the progression from AD to asthma. However, exogenous administration of FGF21 inhibited allergies. In this study, we reported that FGF21 mitigated AD-like lesions and Th1/2 or Th17/Treg cell imbalance in AD mice, and significantly decreased TSLP, IL-33, IL-4, IL-5, IL-13 and IL-17A expression on skin. During the asthma phase, FGF21 improved airway remodeling by downgrading inflammatory factors IL-4, IL-5, IL-13 and IL-17A; fibrotic markers α-SMA and Collagen I; and oxidative products MDA and ROS in wild-type model mice. Compared with WT model mice, the adverse consequences were aggravated in FGF21 −/− asthmatic mice. From the mechanistic perspective, FGF21 suppressed NF-κB/NLRP3, TGF-β1/Smad3 and JNK signaling pathways and increased Nrf2 expression in vivo and in vitro. In addition, β-Klotho knockdown attenuated the ameliorative impact of FGF21 on cellular damage. Blocking AMPKα in the LPS-treated RAW264.7 cells inhibited the reduction of FGF21 and the phosphorylation of JNK. Conclusions To conclude, FGF21 alleviated atopic march by inhibiting Th2/17 immune response, and reduced airway remodeling by regulating NF-κB/NLRP3, TGF-β1/Smad3 and AMPKα/JNK pathways. Moreover, this study provides a rationale and novel ideas for applying FGF21 in treating AD and asthma.
研究领域:
免疫学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
·
2019
·Vol. 234
·期 10
·17999-18016
·
IF 4.522
Zhida Shen,Qi Chen,Tingting Jin,Meihui Wang,Hangying Ying,Jiangting Lu,Ming Wang,Wenbin Zhang,Fuyu Qiu,Chongying Jin,Yanbo Zhao,Guosheng Fu
Theaflavin 3,3′-digallate (TF3), is reported to protect cardiomyocytes from lipotoxicity and reperfusion injury. However, the role of TF3 in the protection of high-glucose injury is still poorly understood. This study investigated the protective effects of TF3 on gap junctions and autophagy in neonatal cardiomyocytes (NRCMs). NRCMs preincubated with high glucose were coincubated with TF3. The expression of connexins and autophagy-related proteins was determined. The functioning of gap-junctional intercellular communication (GJIC) was measured by a dye transfer assay. Adenosine monophosphate-activated protein kinase (AMPK) activity was determined by western blot. Moreover, AMPK was activated with aminoimidazole-4-carboxamide-1-β- d -ribofuranoside (AICAR) or inhibited by AMPKα small interfering RNA (siRNA) to explore the role of AMPK in the modulation of connexin 43 (Cx43) and autophagy. Meanwhile, autophagy was activated or blocked to observe the change in Cx43 expression. It was found that the protein expression of Cx43 and autophagy-related proteins was increased in a TF3 dose- and time-dependent manner under high glucose. TF3 also recovered the reduced GJIC function induced by high glucose concentrations. TF3 activated phosphorylated AMPK in a time-dependent way. AMPKα siRNA abrogated the protection of TF3, while AICAR showed similar results compared to the TF3 treatment. Meanwhile, autophagy activation caused decreased Cx43, while cotreatment with baf A1 enhanced Cx43 expression further compared with the TF3 treatment alone under high glucose. We concluded that TF3 partly reversed the inhibition of Cx43 expression and autophagy induced by high glucose in NRCMs, partly by restoring AMPK activity. Inhibition of autophagy might be protective by preserving Cx43 expression in NRCMs stimulated by high glucose.
研究领域:
心脏病学
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分子生物学
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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
危险品化学品经营许可证（带存储）