MOLECULAR MEDICINE
·
2025
·Vol. 31
·期 1
·1-23
·
IF 6.4
Wang Qiuhong,Wei Dong,Li Chunman,Yang Xiawei,Su Kun,Wang Tao,Zou Renchao,Wang Lianmin,Cun Dongyun,Tang Bo,Wu Tao
Section
Background
Pancreatic cancer is highly lethal, and METTL3 plays a crucial role in the regulation of m6A. However, the therapeutic potential of METTL3 in pancreatic cancer is unclear.
Section
Methods
By means of functional gain and loss experiments, the relationship between METTL3 and gemcitabine resistance as well as ferroptosis was explored. The target genes of METTL3 were screened, and the influence of O-GlcNAcylation on the stability and ubiquitination modification of METTL3 was dissected.
Section
Results
We found that METTL3 is highly expressed in pancreatic cancer and regulates ferroptosis and gemcitabine resistance by promoting the degradation of HMGB1 in an m6A-YTHDF2-dependent manner. O-GlcNAcylation modulates the METTL3’s stability. The interaction between the deubiquitinase EIF3H and METTL3 is influenced by O-GlcNAcylation.
Section
Conclusion
METTL3 affects pancreatic cancer progression by promoting degradation of HMGB1. The O-GlcNAcylation of METTL3 not only stabilizes METTL3 but also augments EIF3H-mediated deubiquitination. These findings uncover potential mechanisms underlying gemcitabine resistance in pancreatic cancer and offer potential therapeutic strategies for the treatment of this disease.
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ENVIRONMENTAL POLLUTION
·
2026
·
IF 7.2
Zixu Li,Muge Xu,Yahan Zhang,Yao Chen,Weiwei Feng,Ting Zhao,Liuqing Yang,Guanghua Mao,Xiangyang Wu
The widespread presence of plastic pollutants, particularly phthalate esters such as dibutyl phthalate (DBP), poses a significant threat to both ecosystems and human health. Despite the accumulating evidence of DBP toxicity, the mechanisms driving DBP-induced hepatotoxicity remain poorly understood. In this study, an integrated approach combining network toxicology, molecular docking, and multidimensional experimental validation was applied to elucidate the molecular pathways through which DBP causes liver damage. Ferroptosis was identified as a central player in DBP-induced hepatotoxicity. The results showed that DBP activates the aryl hydrocarbon receptor (AhR), regulating the NRF2/HO-1 signaling axis, which in turn induces iron overload and lipid peroxidation. Furthermore, ferroptotic hepatocytes release high-mobility group box 1 (HMGB1), activating the TLR4/NF-κB pathway in macrophages and amplifying inflammatory responses that exacerbate liver injury. Crucially, inhibition of either AhR expression or ferroptosis significantly attenuated these changes, highlighting the potential of AhR and ferroptosis as therapeutic targets. Together, these findings establish a novel mechanistic framework for DBP-induced hepatotoxicity: the AhR–NRF2/HO-1–ferroptosis–HMGB1/TLR4 axis. This study advances our understanding of plasticizer toxicity and offers insights for risk assessment and intervention strategies for combating environmental hepatotoxins.
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Research
·
2026
·
IF 12.9
Lishi Jie,Jun Mao,Li Zhang,Houyu Fu,Xiaochen Li,Taiyang Liao,Yibao Wei,Deren Liu,Jiaojiao Du,Peng Wu,Songjiang Yin,Nongshan Zhang,Meng Cao,Peimin Wang
Knee osteoarthritis (KOA) is clinically characterized by recurrent and progressively worsening episodes;however, its underlying pathological mechanisms remain incompletely understood. Phenotypic changesand the specific migration of circulating monocytes may be key factors contributing to the recurrenceand progressive exacerbation of synovial inflammation in KOA. In this study, we report a specificsubtype of circulating monocytes in KOA that highly express IL1A, IL1R1, TNF, CXCL12, CXCL3,CXCL2, CCL20, and G0S2. These monocytes exhibit a trained immune phenotype, and their CXCR4-dependent migration to the synovium exacerbates synovial inflammation. HMGB1 (high mobility groupprotein B1) primes the trained immunity of this subtype, resulting in increased chromatin accessibility,and the transcriptional storage of multiple pro-inflammatory factors enables them to exhibit a morepositive inflammatory response when restimulated by HMGB1. In addition, we find that MyD88,downstream of HMGB1, recruits cytoplasmic IRF1 to the nucleus, and then stabilizes IRF1 in chromatinthrough SUMOylation of TRIM28 to exert transcriptional activity and epigenetic enhancement of pro-inflammatory factor expression. Finally, we found that KOA inflammation was effectively attenuated byblocking HMGB1. Taken together, this study reveals the mechanism by which trained immunity ofcirculating monocyte promote the progression of synovial inflammation, support a future therapeuticapproach in the management of KOA.Keywordsknee osteoarthritis; trained immunity; HMGB1; IRF1; SUMOylation; CXCL12; CXCR4
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EUROPEAN JOURNAL OF MEDICAL RESEARCH
·
2025
·Vol. 30
·期 1
·1-13
·
IF 3.4
Luo Liling,Jiang Chao,Xie Songxi
Background Previous studies showed that high mobility group box-1 (HMGB1) facilitates the initiation and progression of esophageal squamous cell carcinoma (ESCC), and the current research investigated the detailed mechanisms implicated.Methods The impact of HMGB1 and IGFBP3 levels on the survival of ESCC was examined by plotting Kaplan–Meier (KM) curves based on the data collected from The Cancer Genome Atlas (TCGA). Quantitative real-time PCR (qRT-PCR) was performed to detect the expressions of HMGB1 in both human esophageal epithelial cells (HEEC) and ESCC cells. After cell transfection, the proliferation of ESCC cells was measured, and the cell metastasis was determined based on the levels of cadherins (CDHs) and Vimentin (VIM). Macrophage polarization was determined by calculating the mean fluorescence intensity (MFI) of CD206 and CD86. In addition, co-immunoprecipitation and immunoblotting were applied to evaluate the interaction between insulin-like growth factor binding protein 3 (IGFBP3)/DNA-dependent protein kinase catalytic subunit (DNA–PKcs) and HMGB1.Results A high level of HMGB1 was predictive of an unfavorable prognosis of ESCC (p < 0.05). HMGB1 showed a higher expression in ESCC cells (p < 0.05), while knockdown of HMGB1 inhibited ESCC cell proliferation, downregulated the levels of CDH2 and VIM and upregulated the level of CDH1 (p < 0.05). In contrast, overexpressed HMGB1 showed the opposite effects (p < 0.05), suggesting the role of HMGB1 in the epithelial–mesenchymal transition (EMT) of ESCC. After the knockout of HMGB1, the MFI of CD86 was increased but that of CD206 was reduced, indicating the polarization towards M1 macrophages (p < 0.05). However, the results were reversed when HMGB1 was overexpressed (p < 0.05). Meanwhile, HMGB1 could interact with the IGFBP3/DNA–PKcs complex (p < 0.05). Low-expressed IGFBP3 was predictive of an unfavorable prognosis of ESCC, and IGFBP3 silencing promoted the proliferation of ESCC cells (p < 0.05). Besides, HMGB1 and IGFBP3 could act antagonistically in influencing the proliferation of ESCC cells and macrophage polarization.Conclusion sThrough in vitro experiments, this study found that HMGB1 was linked to the proliferation and polarization of macrophages in ESCC, providing novel evidence for the role of HMGB1 in ESCC development.
研究领域:
肿瘤学
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分子生物学
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免疫学
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癌症研究
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FREE RADICAL BIOLOGY AND MEDICINE
·
2023
·
IF 7.4
Daohui Gong,Xueping Liu,Pengfei Wu,Yue Chen,Yuhang Xu,Zhan Gao,Hang Qian,Guansong Wang,Binfeng He
Macrophage dysfunction is a significant contributor to more than 70 % of sepsis-related deaths, specifically secondary bacterial infections, during the immunosuppression stage of sepsis. Nevertheless, the role of Rab26 in this context remains unclear. In this study, we observed a substantial decrease in Rab26 expression in macrophages during the immunosuppressive phase of sepsis, which was also found to be suppressed by high extracellular levels of HMGB1 . During the progression of sepsis, Rab26 deficiency promotes a polarization shift from the M1 to the M2-like phenotype in macrophages, rendering them susceptible to ferroptosis . Subsequent experimentation has revealed that Rab26 deficiency facilitates the degradation of GPX4, thereby aggravating macrophage ferroptosis through the upregulation of levels of lipid ROS , MDA , and ferrous iron induced by RSL3, a ferroptosis inducer. Additionally, Rab26-deficient mice in the immunosuppressed phase of sepsis exhibit heightened susceptibility to secondary infections, leading to exacerbated lung tissue damage and increased mortality rate. Overall, these findings indicate that Rab26 plays a crucial role in sepsis-induced macrophage immunosuppression by regulating macrophage ferroptosis and polarization. Hence, it represents a potential novel target for sepsis therapy.
研究领域:
免疫学
·
细胞生物学
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传染病学
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FREE RADICAL BIOLOGY AND MEDICINE
·
2024
·
IF 7.1
Qi Wei,Fuxia He,Jiangyan Rao,Xiaoxia Xiang,Li Li,Hongyi Qi
Given the substantial risks associated with ultraviolet B radiation (UVB)-induced solar dermatitis, enhancing current strategies to combat UVB regarding skin diseases is imperative. The cross-talk between ferroptosis and inflammation has been proven to be an essential factor in UVB-induced skin inflammation, whereas detailed process of how their interaction contributes to this remains unclear. Therefore, further investigation of ferroptosis-mediated processes and identification of corresponding inhibitory approaches hold promise for repairing skin damage. Senkyunolide I (Sen I), a bioactive component mainly extracted from the traditional Chinese medicinal plants, Ligusticum chuanxiong Hort. and Angelica sinensis (Oliv.) Diels, has demonstrated efficacy in combating oxidative stress and inflammation. In this study, we utilized UVB-irradiated HaCaT cells as an in vitro model and C57BL/6J mice as an in vivo model of solar dermatitis. Our findings revealed the pivotal roles of autophagy and ferroptosis in inducing skin inflammation, particularly emphasizing the activation of ferroptosis through macroautophagy. Surprisingly, this mechanism operated independently of ferritinophagy, a classical autophagy-driven ferroptosis pathway. Instead, our results highlighted Transferrin Receptor 1 (TfR1), tightly controlled by autophagy, as a crucial mediator of ferroptosis execution and amplifier of subsequent lethal signals. Furthermore, extracellular High Mobility Group Box 1 protein (HMGB1), released following UVB-induced ferroptotic cells from activated autophagic flux, initiated a feedback loop with TfR1, propagating ferroptosis to neighboring cells and exacerbating damage. Remarkably, Sen I administration showed a significant protective effect against UVB damage in both in vitro and in vivo models by interrupting this cascade. Consequently, we have illuminated a novel therapeutic pathway post-UVB exposure and identified Sen I as a potent natural molecule that safeguarded against UVB-induced solar dermatitis by suppressing the autophagy-ferroptosis-HMGB1-TfR1 axis, highlighting a new frontier in photoprotection.
研究领域:
药理学
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皮肤病学
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分子生物学
·
细胞生物学
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JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·
IF 15
Lei Jin,Cao Kun,Chen Huimin,Hou Jinhuan,Li Taiqin,Zhang Ya,Chen Chengxin,Ma Huaxing,Jin Jiliang,Qian Junxue,Li Zhi,Zhang Tian,Zuo Shi,Linghu Kegang,Li Haiyang
Chronic liver fibrosis remains a major healthcare burden with no approved pharmacotherapies currently available that directly target the fibrotic process. Although apoptotic vesicles (apoVs) derived from human umbilical cord mesenchymal stem cells (hUMSCs) hold great therapeutic potential for tissue repair, their mechanisms in alleviating liver fibrosis and their feasibility as siRNA carriers remain unclear. Here, we demonstrate that systemically administered apoVs exhibit robust liver tropism, efficiently delivering miR-6869-5p to both hepatic stellate cells (HSCs) and macrophages. Mechanistically, miR-6869–5p directly targets fibroblast growth factor 1 (FGF1) to suppress the PI3K/AKT/mTOR signaling pathway, thereby inhibiting HSC activation and reducing collagen deposition. Simultaneously, it targets high-mobility group box 1 (HMGB1) to attenuate NF-κB activity and establish an antifibrotic microenvironment through HSC-macrophage crosstalk. In clinical cohorts ( n = 100), serum miR-6869 − 5p levels were inversely correlated with fibrosis indices. Leveraging these unique properties, we engineered apoVs loaded with antifibrotic TANGO1 siRNA (si-apoVs), which blocks collagen secretion; this achieves enhanced antifibrotic efficacy in CCl₄-induced liver fibrosis models while mitigating the pro-inflammatory side effects associated with free siRNA. This study identifies hUMSC-derived apoVs as a liver-targeted, dual-action therapeutic platform, and si-apoVs represent a potent, translation-ready strategy for the treatment of liver fibrosis. Graphical abstract The alternative text for this image may have been generated using AI.
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CNS Neuroscience & Therapeutics
·
2023
·Vol. 29
·期 6
·1667-1677
·
IF 5.5
Yuhua Chen,Wei He,Hong Wei,Cuicui Chang,Lingjian Yang,Jiao Meng,Tianlin Long,Quanhua Xu,Chi Zhang
Aim Ferroptosis is increasingly becoming to be considered as an important mechanism of pathological cell death during stroke, and specific exogenous ferroptosis inhibitors have the ability to reverse cerebral ischemia/reperfusion injury. However, research on Srs11-92 (AA9), a ferrostatin-1 (Fer-1) analog, in preclinical studies is limited. Methods In the middle cerebral artery occlusion-reperfusion (MCAO/R) mice model or oxygen–glucose deprivation/reperfusion (OGD/R) cell model, Fer-1, AA9, and/or ML385 were administered, and brain infarct size, neurological deficits, neuronal damage, oxidative stress, and neuroinflammation were determined after the damage, in vitro and in vivo. Results Fer-1 and AA9 improved brain infarct size, neuronal damage, and neurological deficits in mice model of MCAO/R, and inhibited the overloaded iron deposition, ROS accumulation, and neuroinflammation response: it also increased the expression of GPx4, Nrf2, and HO-1 and suppressed the expression of HMGB1 and NF-κB p65 in the epicenter of injured hippocampal formation. However, Nrf2 inhibitor ML385 reversed the neuroprotective effect of AA9, including the oxidative stress and neuroinflammation. In vitro studies showed that AA9 relieved OGD/R-induced neuronal oxidative stress and neuroinflammation via the Nrf2 pathway, which was impaired by ML385 in primary neurons. Conclusion The findings imply that Fer-1 analog AA9 may be suitable for further translational studies for the protection of neuronal damage via Nrf2 signal pathway-mediated oxidative stress and neuroinflammation in stroke and others neurological diseases.
研究领域:
神经科学
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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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神经病学
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Biomaterials Science
·
2023
·Vol. 11
·期 7
·2531-2542
·
IF 6.6
Zongjian Sun,Mingxin Zhang,Yanjun Wei,Mengshuang Li,Xianggen Wu,Meng Xin
A simple but novel ophthalmic solution based on two approved drugs was developed to reposition existing drugs to treat new diseases. This nanoformulation was developed using the phytochemical drug glycyrrhizin as an amphiphilic nanocarrier to micellarly solubilize empagliflozin (EMP), an oral drug that is widely used to control high blood glucose but has poor water solubility. This novel nanoformulation, which we designated the EMP@glycymicelle ophthalmic solution, was obtained using a simple preparation process. The resulting solution was a clear solution with an EMP encapsulation efficiency of 97.91 ± 0.50%, a small glycymicelle size of 6.659 ± 0.196 nm, and a narrow polydispersity index of 0.226 ± 0.059. The optimized formulation demonstrated that EMP was soluble in water up to 18 mg ml−1 because of its encapsulation within glycymicelles. The EMP@glycymicelle ophthalmic solution exhibited excellent characteristics, including good storage stability, fast in vitro release profiles, improved in vitro antioxidant activity, and no ocular irritation. Ocular permeation evaluation showed that the EMP@glycymicelle ophthalmic solution had strong ocular permeation of EMP, and it reached the posterior segment of mouse eyes after ocular topical administration. The treatment efficacy evaluation showed that the EMP@glycymicelle ophthalmic solution had a significant effect against corneal alkali burns in mice, prompting corneal wound healing, recovering corneal sensitivity, reducing corneal haze, and relieving corneal NV invasion. The mechanism of inhibiting HMGB1 signaling was involved in this strong treatment effect. These results indicated that the EMP@glycymicelle ophthalmic solution provided a new concept of drug repurposing and a promising ocular system for the nano-delivery of EMP with significantly improved in vivo profiles.
研究领域:
药学
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眼科
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纳米技术
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药物递送系统
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2019
·
IF 4.784
Qiang Chu,Shuang Zhang,Lushuang Yu,Yonglu Li,Yangyang Liu,Xiang Ye,Xiaodong Zheng
The tubers of Apios americana Medikus possess high nutritional value and have been used as food in many countries for a long time. However, few researches have focused on the tuber polysaccharides. In the present study, a purified polysaccharide (ATP-1) was isolated with the average molecular weights of 12.16 kDa. ATP-1 significantly suppressed the release of nitric oxide (NO) and inflammatory cytokines from LPS-induced RAW 264.7 cells, as well as oxidative stress and mitochondrial dysfunction. Meanwhile, ATP-1 reduced oxidative damage via the NF-κB, MAPKs and Nrf2-Keap1 signaling pathways in RAW264.7 macrophages. Furthermore, autophagy was activated by HMGB1-Beclin1, Sirt1-FoxO1 and Akt-mTOR signaling pathways, leading to a relief of oxidative stress, mitochondrial dysfunction, inflammation and an expression enhancement of autophagy-related proteins, such as LC3, Beclin1, Atg4, Atg5, and Atg7. In summary, our results suggested that ATP-1 might help to activate the anti-inflammation system，resulting in prevention of LPS-induced damage in RAW264.7 cells.
研究领域:
药理学
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免疫学
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细胞生物学
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生物化学
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JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Feifan Liu,Yuanmei Bai,Xue Wu,Yan Wan,Shifang Luo,Linao Zhang,Tao Li,Hua Tang,Xianjin Tang,Rong Chen,Qinghua Chen,Yuhuan Xie,Peixin Guo
Ethnopharmacological relevance Allergic rhinitis (AR) stands as a non-infectious inflammatory condition affecting the nasal mucosa, marked by bouts of sneezing, nasal itching, and congestion. This ailment afflicts individuals across all age groups and poses challenges for effective treatment due to its chronic nature. Cangerzisan (CEZS), documented in the Jishengfang compendium, represents a traditional Chinese medicinal formula long utilized for AR management. Aim of the study : Investigating mechanism beneath therapeutic effect of CEZS in alleviating AR. Materials and methods The main active components in CEZS were determined by High Performance Liquid Chromatography (HPLC).The active constituents of CEZS and their corresponding targets were identified through an exhaustive screening process employing TCMSP database. To identify targets relevant to AR, GeneCards, OMIM, and DisGeNET databases were thoroughly applied. Protein-protein interaction (PPI) network was assembled utilizing STRING platform. Potential signaling pathways influenced by CEZS were delineated through GO and KEGG enrichment analyses. Subsequently, an AR model was induced by administering aluminum hydroxide (Al(OH)3) and ovalbumin (OVA) for affecting basal and local sensitization, respectively, facilitating experimental validation of the principal signaling pathways. Results There were 61 active constituents identified within CEZS, targeting a pool of 129 entities associated with AR treatment. Pathways analysis of KEGG revealed that CEZS potentially inhibits AR advancement via modulating TLR4 signaling pathway. Animal experiments demonstrated that CEZS effectively alleviated symptom scores in guinea pigs with AR. Moreover, it exhibited notable improvements in serum immune and inflammatory factors levels, as well as reduced inflammatory infiltration within nasal mucosa, including goblet and mast cells. CEZS was found to enhance GATA-3 expression while reducing T-bet expression, thereby modulating the TH1/TH2 immune balance. Additionally, CEZS downregulated HMGB1, TLR4, and p–NF–κB/NF-κB protein expressions within nasal mucosa of guinea pigs. Conclusions The therapeutic mechanism of CEZS against AR involves rectifying TH1/TH2 immune imbalance and upregulating inflammatory and immune factors through modulating key proteins expression within TLR4 pathway. This targeted regulation effectively impedes AR progression.
研究领域:
民族药理学
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药理学
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免疫学
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传统中药
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生物信息学
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实验验证
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COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
·
2024
·
IF 4.9
Ziyan Hu,Zhongbing Huang,Juan Wang,Jirui Wen,Ximing Pu,Qianlei Lang,Peng Yang,Zhongxiang Shao,Jia Hu,Jiang Wu,Guangfu Yin
Typical symptoms of acute myocardial infarction (AMI) and acute aortic dissection (AAD) are similar chest pain, leading to higher clinical misdiagnosis rate, evenly the mortality rate of patients. In this work, ZrO 2 @PEI-QDs nanospheres with higher fluorescence were prepared by sequential electrostatic adsorption of branched PEI chains and CdSe/ZnS-COOH QDs on hollow ZrO 2 nanospheres. Three multi-channel LFIA strips (on sST2 and cTnI, cTnI and h-FABP, HMGB1 and sST2, respectively) based on ZrO 2 @PEI-QDs for rapid and correct distinguishing of AMI and ADD were constructed. Their visual limit of detection (vLOD for sST2 and cTnI, cTnI and h-FABP, HMGB1 and sST2) within 10–15 min reached 0.075 and 0.1 ng/mL, 0.1 and 1 ng/mL, 1 and 0.1 ng/mL, respectively, which were all lower than the normal level of healthy people. Compared with previous studies, ZrO 2 surface adsorbs more QDs, the fluorescence intensity was increased by about 2.84 times, and vLODs of three strips based on the quantitative fluorescence analysis were also increased by up to one orders of magnitude. The test results of five clinical serum samples indicated that three multi-channel LFIA strips could quantitatively detect four biomarkers of chest pain, and successfully distinguish AMI patients from AAD patients. These results indicated that this set of multi-channel LFIA strips could become an effective tool for the early and accurate detection or distinguish of ADD and AMI.
研究领域:
纳米技术
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生物传感器
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医学诊断
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心脏病学
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