Redox Biology
·
2026
·
IF 16.2
Xiaozheng Huang,Wanglin Bao,Shengming Tang,Miao Li,Yuqing Sun,Hui Ge,Yuxin Zhao,Hao Yuan,Xinyu Pan,Wei Lin,Yuanqing Wei,Shuying Han,Wenxing Wu,Rui Liu,Jin-ao Duan
Despite the established importance of hydrogen sulfide (H 2 S) in redox biology, strategies to modulate its endogenous levels remain largely unexplored. Here, we show that a keratin fraction (KF) obtained from natural sources modulates H 2 S homeostasis and protein redox state through sulfhydration. Chemoproteomic analysis identified keratin 2 (K2; UniProtKB P25691, keratin, type II microfibrillar, component 5) as the most hyperreactive keratin toward sulfhydration. Oral administration of K2 to mice alleviated lipopolysaccharide (LPS)-induced inflammatory fever and led to the generation of K2-derived peptides (K2Ps) and their sulfhydrated form (K2P-SSH) in the intestine. Compared with K2Ps, K2P-SSH showed enhanced anti-inflammatory and antioxidant activities and promoted widespread protein sulfhydration. Mechanistically, K2P-SSH induced sulfhydration of high-mobility group box 1 (HMGB1) at Cys23 and Cys106, which was associated with reduced disulfide bond formation and dimerization, impaired interaction with toll-like receptor 4 (TLR4), and attenuation of downstream inflammatory signaling. Taken together, this study reveals a previously unrecognized role of K2 in converting H 2 S into protective sulfhydration signals and identifies K2P-SSH as a bioactive intermediate that alleviates oxidative-inflammatory stress via sulfhydration of HMGB1 at Cys23 and Cys106.
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高影响因子
Artificial Cells Nanomedicine and Biotechnology
·
2019
·Vol. 47
·期 1
·3511-3516
·
IF 4.462
Shi H,Dong Z,Gao H
The aim of this study was to investigate whether lncRNA TUG1 could mediate the progression of ischemia-reperfusion injury following acute myocardial infraction. Mouse cardiomyocytes HL-1 cells were subjected to oxygen glucose deprivation followed by reperfusion (OGD/R) to induce myocardial I/R injury. The expression of TUG1 was detected by real-time PCR. Overexpression or down expression of TUG1 was performed in mouse HL-1 cardiomyocytes. The myocardial cell viability and apoptosis were respectively detected. In addition, the expression levels of inflammatory factors, apoptosis-related proteins and HMGB1 proteins were detected. Besides, an inhibitor of HMGB1 was used to treat cells to verify the relationship between TUG1 and HMGB1 protein. The expression of TUG1 was significantly up-regulated in OGD/R-induced myocardial HL-1 cells. The overexpression of TUG1-induced inflammation and apoptosis in OGD-R-induced myocardial HL-1 cells. Knock down of TUG1 protected OGD/R-induced myocardial I/R injury by inhibiting HMGB1 expression. Suppression of lncRNA TUG1 may prevent myocardial I/R injury following acute myocardial infarction via inhibiting HMGB1 expression.
研究领域:
心脏病学
·
分子生物学
·
细胞生物学
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高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 7.3
Zhang Guoyu,Cao Yi,Wu Xingxin,Liu Hanfang,Zeng Min,Sun Xiuzhong,Huang Song,Liang Jing,Li Gaofei,Shen Huimin,Wang Peng George,Wang Chaojie,Fang Dong,Wang Jiajia,Xie Songqiang,Ma Jing
Non-small-cell
lung cancer (NSCLC) is considered as a predominant
contributor to cancer-related mortality with significant infiltration
by TAMs. HMGB1 plays a key role in modulating immune evasion, but
the mechanisms of HMGB1 in anti-NSCLC immunotherapy remain unclear.
In this study, we first identified that cisplatin-resistant A549 CisR
overexpresses HMGB1 and has hyperactivated autophagy, while cisplatin-sensitive
A549 cells exhibit the opposite reaction. Using a HMGB1-targeted modulator,
Naphplatin, we show that normalizing HMGB1 in both A549 and A549 CisR
cell lines significantly triggers HMGB1-mediated inherent metabolic
plasticity in tumors, thus releasing it to the thresholds required
for macrophage activation. Mechanistically, in tumors, HMGB1 at threshold
levels can effectively translocate to the cytoplasm from the nucleus,
initiating lysosomal metabolism. Meanwhile, in macrophages, tumor-derived
HMGB1 binds to RAGE, thereby promoting polarization toward the M1
macrophage phenotype. This study uncovers a divergent metabolic program
mediated by HMGB1 and demonstrates its role in lysosomal metabolic
plasticity.
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高影响因子
CELL PROLIFERATION
·
2021
·Vol. 54
·期 6
·e13048
·
IF 6.831
Wei Feng,Jian Wang,Xin Yan,Qianqian Zhang,Limin Chai,Qingting Wang,Wenhua Shi,Yuqian Chen,Jin Liu,Zhan Qu,Shaojun Li,Xinming Xie,Manxiang Li
Objectives High-mobility group box-1 (HMGB1) and aberrant mitochondrial fission mediated by excessive activation of GTPase dynamin-related protein 1 (Drp1) have been found to be elevated in patients with pulmonary arterial hypertension (PAH) and critically implicated in PAH pathogenesis. However, it remains unknown whether Drp1-mediated mitochondrial fission and which downstream targets of mitochondrial fission mediate HMGB1-induced pulmonary arterial smooth muscle cells (PASMCs) proliferation and migration leading to vascular remodelling in PAH. This study aims to address these issues. Methods Primary cultured PASMCs were obtained from male Sprague-Dawley (SD) rats. We detected RNA levels by qRT-PCR, protein levels by Western blotting, cell proliferation by Cell Counting Kit-8 (CCK-8) and EdU incorporation assays, migration by wound healing and transwell assays. SD rats were injected with monocrotaline (MCT) to establish PAH. Hemodynamic parameters were measured by closed-chest right heart catheterization. Results HMGB1 increased Drp1 phosphorylation and Drp1-dependent mitochondrial fragmentation through extracellular signal-regulated kinases 1/2 (ERK1/2) signalling activation, and subsequently triggered autophagy activation, which further led to bone morphogenetic protein receptor 2 (BMPR2) lysosomal degradation and inhibitor of DNA binding 1 (Id1) downregulation, and eventually promoted PASMCs proliferation/migration. Inhibition of ERK1/2 cascade, knockdown of Drp1 or suppression of autophagy restored HMGB1-induced reductions of BMPR2 and Id1, and diminished HMGB1-induced PASMCs proliferation/migration. In addition, pharmacological inhibition of HMGB1 by glycyrrhizin, suppression of mitochondrial fission by Mdivi-1 or blockage of autophagy by chloroquine prevented PAH development in MCT-induced rats PAH model. Conclusions HMGB1 promotes PASMCs proliferation/migration and pulmonary vascular remodelling by activating ERK1/2/Drp1/Autophagy/BMPR2/Id1 axis, suggesting that this cascade might be a potential novel target for management of PAH.
研究领域:
心血管疾病
·
细胞生物学
·
分子生物学
·
药理学
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3 Biotech
·
2020
·Vol. 10
·期 8
·1-10
·
IF 1.798
Ge Xin,Meng Xianglin,Fei Dongsheng,Kang Kai,Wang Qiubo,Zhao Mingyan
Lung injury associated with systemic inflammatory response is a common problem affecting human health. Previous studies have shown that lycorine exerts a anti-inflammatory effect. However, whether lycorine alleviates lung injury remains unclear. To explore this issue, BALB/c mice and MLE-12 cells were treated with lipopolysaccharide (LPS) to establish lung injury mouse model and cell model, respectively. Glycyrrhizic acid, known as an inhibitor of ALI, was also used to study the effects of lycorine in vitro. Our results showed that after LPS treatment, the lung injury score, lung wet-to-dry weight ratio, and malondialdehyde (MDA) production in the lung tissues and the expression levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 in bronchoalveolar lavage fluid were significantly increased, whereas their levels were decreased by lycorine. Additionally, LPS injection activated the high-mobility group box 1 (HMGB1)/Toll-like receptors (TLRs)/NF-κB pathway. However, lycorine treatment attenuated the activity of the HMGB1/TLRs/NF-κB pathway in the lung tissues. In vitro studies showed that lycorine administration significantly decreased the levels of inflammatory cytokines and MDA and attenuated the activity of the HMGB1/TLRs/NF-κB pathway in LPS-treated cells. Moreover, the inhibitory effects of lycorine on the inflammatory response and oxidative stress in LPS-treated lung cells were similar with that of glycyrrhizic acid, and this inhibition was intensified by both lycorine and glycyrrhizic acid treatment. We suggest that lycorine could alleviate LPS-induced lung injury of inflammation and oxidative stress by blocking the HMGB1/TLRs/NF-κB pathway, which gives a new perspective for ALI therapy to treat lycorine as a potential treatment clinically.
研究领域:
药理学
·
免疫学
·
肺病学
·
分子生物学
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MOLECULAR AND CELLULAR BIOLOGY
·
2024
·
IF 3.2
Nan Yang,Yue Zhang,Peiyao Ren,Li Zhao,Danna Zheng,Lanjun Fu,Juan Jin
Although LncRNA AA465934 expression is reduced in high glucose (HG)-treated podocytes, its role in HG-mediated podocyte injury and diabetic nephropathy (DN) remains unknown. Herein, we investigated the role of AA465934 in HG-mediated podocyte injury and DN using a spontaneous type II diabetic nephropathy (T2DN) model. The model was created by injecting AA465934 overexpressed adeno-associated virus (AAV) or control into mice. The levels of renal function, proteinuria, renal structural lesions, and podocyte apoptosis were then examined. Furthermore, AA465934 and autophagy levels, as well as tristetraprolin (TTP) and high mobility group box 1 (HMGB1) expression changes were detected. We also observed podocyte injury and the binding ability of TTP to E3 ligase proviral insertion in murine lymphomas 2 (PIM2), AA465934, or HMGB1. According to the results, AA465934 improved DN progression and podocyte damage in T2DN mice. In addition, AA465934 bound to TTP and inhibited its degradation by blocking TTP-PIM2 binding. Notably, TTP knock-down blocked the ameliorating effects of AA465934 and TTP bound HMGB1 mRNA, reducing its expression. Overexpression of HMGB1 inhibited the ability of AA465934 and TTP to improve podocyte injury. Furthermore, AA465934 bound TTP, inhibiting TTP-PIM2 binding, thereby suppressing TTP degradation, downregulating HMGB1, and reversing autophagy downregulation, ultimately alleviating HG-mediated podocyte injury and DN. Based on these findings, we deduced that the AA465934/TTP/HMGB1/autophagy axis could be a therapeutic avenue for managing podocyte injury and DN.
研究领域:
分子生物学
·
肾病学
·
糖尿病研究
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BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Huangxi Fu,Feng Jiang,Anqi Xu,Taicheng Zhou,Ning Liu,Xueqin Chen,Zizheng Gao,Wentong Wu,Hao Yan,Xiaochun Yang,Bo Yang,Qiaojun He,Peihua Luo,Zhifei Xu
The cardiac complications caused by drugs, including cardiac dysfunction and heart failure, significantly limit the wide clinical application of drugs and lead to morbidity and mortality. High mobility group box 1 (HMGB1) plays an extensive role in drug-induced cardiotoxicity. However, the cardiotoxic mechanisms for most small-molecule kinase inhibitors (SMKIs) remains unknown. Here, we identify that accumulated HMGB1 is associated with the cardiac complications caused by a series of FDA-approved SMKIs, among which trametinib-induced cardiomyocyte death was most significantly reversed by HMGB1 knockout. Moreover, cardiomyocyte-specific Hmgb1 deletion in mice could improve cardiac muscle contraction, calcium regulation and cardiomyocyte apoptosis in autophagy- or inflammation-independent manner. We further show that trametinib leads to the aberrant accumulation of HMGB1 by increasing its stability via inhibiting zinc finger protein Zinc Finger MYND-Type Containing 8 (ZMYND8)-mediated ubiquitination and proteasomal degradation of HMGB1, identifying ZMYND8 as a novel negative regulator of HMGB1 stability in cardiomyocyte and a potential novel regulator of cardiac function. Glycyrrhizic acid, an HMGB1 inhibitor used in clinic, prevents trametinib-induced cardiac complications. These findings reveal the mechanism and propose an effective intervention strategy for trametinib-induced cardiac complications, which would contribute to the safe application of trametinib, cardiac safety evaluation of drugs or candidate compounds and novel drug development.
研究领域:
心血管药理学
·
分子生物学
·
毒理学
·
肿瘤学
·
药物开发
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2020
·
IF 3.943
Yu-Nan Lu,Xu-Dong Zhao,Xiang Xu,Jing Piao,Fumie Aosai,Ying-Biao Li,Long-Xie Shen,Su-Yun Shi,Guang-Hua Xu,Juan Ma,Hu-Nan Piao,Xuejun Jin,Lian-Xun Piao
Toxoplasmosis is a parasitic zoonosis with the highest incidence in humans. Severe lesions due to acute toxoplasmosis have been recorded in the visceral organs including the liver, where hepatocytes and Kupffer cells are important innate immune cells. Arctigenin (AG) is a bioactive ingredient of Arctium lappa L. and increasing evidence suggests that AG exhibits anti-oxidant, anti-inflammatory and anti- Toxoplasma gondii ( T. gondii ) effects. However, the role of AG in acute liver damage induced by T. gondii infection remains unclear. In this study, we analyzed the effects of AG against T. gondii -induced liver damage by establishing an in vitro infection model using a murine liver cell line (NCTC-1469 cells) and an in vivo mouse model with acute T. gondii infection of virulent RH strain. In the current study, AG effectively attenuated hepatocytes apoptosis and inhibited the reproduction of T. gondii . The results of in vitro and in vivo studies showed that AG significantly reduced alanine aminotransferase/aspartate aminotransferase activities and lessened pathological damage of liver. Moreover, AG suppressed T. gondii -induced inducible nitric oxide synthase production. AG also attenuated liver inflammation by inhibiting T. gondii -induced activation of the high-mobility group box1/toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-κB) signaling pathway. These findings demonstrated that AG exhibited prominent hepatoprotective activities in toxoplasmic liver injury with anti-inflammatory effects by inhibiting the HMGB1/TLR4/NF-κB signaling axis. Thus, this study provides the basis for the development of new drugs to treat toxoplasmic hepatitis.
研究领域:
药理学
·
免疫学
·
寄生虫学
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高影响因子
Autophagy
·
2025
·
IF 14.3
Zizheng Gao,Jiaqi Zhang,Huangxi Fu,Shaoyin Zhang,Jian Chen,Haiyang Zhou,Xueqin Chen,Xiaochen Zhang,Hao Yan,Bo Yang,Qiaojun He,Zhifei Xu,Peihua Luo
Entrectinib stands unparalleled as the sole neurotrophic tyrosine receptor kinase (NTRK) inhibitor that has demonstrated clinical efficacy in treating brain metastases across various cancer types. However, its potential to induce severe cardiotoxicity, compounded by the current lack of effective intervention strategies, poses a substantial risk of treatment failure, underscoring the critical need for in-depth research on the molecular mechanism. Here, we utilized proteomics analysis and a murine model with cardiomyocyte-specific atg7 deletion to reveal that entrectinib activated autophagy in cardiomyocytes, subsequently triggering apoptosis and leading to cardiac dysfunction. Mechanistically, entrectinib directly bound to the HMGB1 protein at the 103rd phenylalanine residue, enhancing its nuclear localization. In the nucleus, HMGB1 suppressed the transcription of the deubiquitinating enzyme OTUD5, a vital regulator of the MTORC1 pathway, which subsequently inhibited the MTORC1 pathway, culminating in the activation of macroautophagy/autophagy. Furthermore, our research demonstrated that HMGB1 inhibition could prevent the cardiotoxicity induced by entrectinib in both in vivo and in vitro models. Specifically, we found that tanshinone IIA could mitigate the cardiotoxic effects of entrectinib by reducing HMGB1 protein levels. Taken together, our findings elucidated the mechanism underlying entrectinib-induced cardiotoxicity, offering a theoretical foundation for the safer clinical application of this targeted therapy.Abbreviations and Acronyms: ATG7: autophagy related 7; CHX: cycloheximide; CKMB: creatine kinase myocardial band; CQ: chloroquine; c-PARP: cleaved poly (ADP-ribose) polymerase family; DAPI: 4‘6-diamidino-2-phenylindole; EF: ejection fraction; FS: fractional shortening; GSEA: gene set enrichment analysis; H&E: hematoxylin and eosin; HW:TL: ratio of heart weight to tibia length; KEGG: Kyoto Encyclopedia of Genes and Genomes; MYH6: myosin heavy polypeptide 6, cardiac muscle, alpha; MYH7: myosin, heavy polypeptide 7, cardiac muscle, beta; NPPA: natriuretic peptide type A; NPPB: natriuretic peptide type B; PI: propidium iodide; qPCR: quantitative real-time PCR; SD: standard deviation; SRB: sulforhodamine B; WGA: wheat germ agglutinin.
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FASEB JOURNAL
·
2026
·Vol. 40
·期 13
·e72080
·
IF 4.3
Pingping Zhang,Meihua Luo,Siyu Lin,Shaoju Hu,Ping Ling,Guikang Wang,You Dai,Xiaolu Cui,Yu-Si Luo,Ke Zhang
Respiratory syncytial virus (RSV) is the leading cause of acute respiratory infections globally, with particularly severe implications for infants and the elderly population. Despite the substantial burden on public health, effective therapeutic options for the treatment of RSV infections remain limited. The pathogenesis of RSV is characterized by complex inflammatory responses, while high-mobility group box 1 (HMGB1), a damage-associated molecular pattern protein, is known to play a role in amplifying inflammation. However, the specific role of HMGB1 in RSV infection has not been thoroughly investigated. This study aims to elucidate the role of HMGB1 in RSV replication and to evaluate its potential as a target for antiviral therapy. The interaction between the RSV nucleocapsid (N) protein and HMGB1 was demonstrated through co-immunoprecipitation and mass spectrometry. Knockdown or overexpression of HMGB1 by small interfering RNA or pCMV-HA-HMGB1 resulted in a significant reduction or induction in RSV replication in vitro, thereby confirming the critical role of HMGB1 in viral propagation. Moreover, structure-based molecular docking analyses identified glycyrrhizic acid (GA) and amlexanox (AMX) as high-affinity ligands for HMGB1. In cellular studies, both GA and AMX effectively inhibited RSV replication in a dose-dependent manner while selectively suppressing HMGB1's secretion to the cytoplasm or extracellular space from RSV-infected cells. AMX was found to down-regulate HMGB1 expression while GA did not. In experiments using lethal murine RSV infection models, treatment with GA and AMX significantly improved survival rates and reduced lung pathology. In conclusion, these findings suggest that HMGB1 is a promising therapeutic target for RSV infection and highlight GA and AMX as potential antiviral candidates that can modulate HMGB1-mediated immunopathology. Graphical Direct binding between RSV N protein and HMGB1 is validated via IP-MS. Silencing or overexpression of HMGB1 potently restricted or elicited viral replication. Molecular docking identified GA and AMX as HMGB1-interacting candidates with prominent in vitro and in vivo anti-RSV efficacy. Mechanistically, GA preserves nuclear HMGB1 to block its secretion, while AMX reduces total HMGB1 abundance; both approaches limit cytoplasmic and extracellular HMGB1 release, suppressing RSV replication and downstream inflammation.
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高影响因子
TOXICOLOGY
·
2020
·
IF 4.099
Xueli Lv,Yaolu Zhu,Yingguang Deng,Shichang Zhang,Qing Zhang,Boxin Zhao,Guofeng Li
Doxorubicin (DOX) is one of the most effective and irreplaceable chemotherapeutic agents but its clinical use is limited due to its cardiotoxicity. Glycyrrhizin(GL) has been applied to liver disorders for long. However, little is known that if GL could be meaningful in attenuating cardiotoxicity. The aim of this study is to investigate the cardioprotective effects of GL in DOX-induced cardiotoxicity (DIC) and the underlying mechanism. Here, H9c2 cardiomyoblasts, Neonatal rat cardiomyocytes (NRCMs), and Rats were introduced as test models. A single dose of 20 mg/kg DOX (i.p.) was applied to induce acute cardiotoxicity in vivo, as reflected by growth inhibition, increased levels of AST and CK-MB, and reduction of SOD activity, while GL (25 or 50 mg/kg/d, 14 d, i.p.) could counteract these effects. Moreover, pre-incubation with GL (0.8 mM for 12 h) in H9c2 cells protected against DOX-induced cytotoxicity, oxidative stress and depolarization of mitochondrial membrane potential (MMP). Besides, Western blot analysis showed that DOX upregulated the expression of LC3 II and p62 whereas GL reversed that both in vitro and in vivo and improved the obstructed autophagy flux in DOX-treated H9c2 cells with an autophagy inhibitor Bafilomycin A1 (Baf A1, 50 nM, 2 h). It has been previously documented that High-mobility group box 1 (HMGB1) was involved in DIC. In our work, knockdown of HMGB1 significantly increased cell viability and LC3 II level in H9c2, suggesting HMGB1 was crucial in DOX-induced autophagy-triggering cell death. Intriguingly, GL is a direct inhibitor of HMGB1. We found that GL downregulated Akt/mTOR autophagy signaling pathway in DOX-treated H9c2 cells. More importantly, in non-silencing H9c2 cells (transfected with negative control siRNA) cells, the expression of phospho-Akt, phospho-mTOR, p62, and LC3 II was significantly decreased with GL pretreament compared to DOX alone. However, in H9c2/HMGB1 － (transfected with HMGB1 siRNA) cells exposed to DOX, the expression of p-Akt, p-mTOR, p62, LC3 II had no statistical difference with or without GL, revealing that HMGB1 mediated the cardioprotective action of GL in DIC. Taken together, our findings demonstrate that improved autophagy flux via HMGB1-dependent Akt/mTOR signaling pathway might contribute to attenuate DIC and go a novel insight into the underlying mechanisms of GL’s cardioprotective action. GL could be a potential candidate for the prevention of DIC.
研究领域:
药理学
·
心脏病学
·
细胞生物学
·
分子生物学
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FOOD AND CHEMICAL TOXICOLOGY
·
2021
·
IF 6.025
Xingyao Pei,Haiyang Jiang,Xinyu Liu,Liuan Li,Cun Li,Xilong Xiao,Daowen Li,Shusheng Tang
T-2 toxin, a food-derived mycotoxin , has been identified as a neurotoxin . Nonetheless, T-2 toxin-induced neuroinflammation has never been revealed. As an important therapeutic target for inflammatory diseases and cancers, the role of high mobility group B1 (HMGB1) in mycotoxin-mediated neurotoxicity remains a mystery. In current study, we found that PC12 cells were sensitive to trace amounts of T-2 toxin less than 12 ng/mL, distinguished by decreased cell viability and increased release of lactate dehydrogenase (LDH). Oxidative stress and mitochondrial damage were observed in PC12 cells, manifested as accumulation of oxidative stress products, up-regulation of Nrf2/HO-1 pathway and decrease of mitochondrial membrane potential (MMP), leading to mitochondria-dependent apoptosis . Meanwhile, we first discovered that tiny amounts of T-2 toxin triggered neuroinflammation directly, including raising the expression and translocation of NF-κB and promoting secretion of proinflammatory cytokines such as TNF-α, IL-6, IL-8 and IL-1β. Most interestingly, the increased of HMGB1 was detected both inside and outside the cells. Conversely, HMGB1 siRNA reduced T-2 toxin-mediated oxidative stress, apoptosis and neuroinflammatory outbreak, accompanied by lessened caspase-3 and caspase-9, and decreased secretion of pro-inflammatory cytokines. Taken together, T-2 toxin-stimulated PC12 cells simultaneously displayed apoptosis and inflammation, whereas HMGB1 played a critical role in these neurotoxic processes.
研究领域:
毒理学
·
神经科学
·
细胞生物学
·
药理学
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高影响因子
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