EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
·
IF 4.2
Liu-Gen Cui,Miao-Miao Zhai,Jian-Jian Yin,Zhi-Mo Wang,Shu-Hui Wang,Yue-Jiao Zhou,Pei-Pei Li,Yang Wang,Li Xia,Pei Wang,Xue-Xiang Cha,Li-Rong Zhang,Sheng-Na Han
Several studies have associated the epitranscriptomic RNA modification of N6-methyladenosine (m 6 A) with cardiovascular diseases; however, how m 6 A modification affects cardiomyocyte pyroptosis after myocardial infarction (MI) remains unknown. Here, we showed that AlkB homolog 5 (ALKBH5), an m 6 A demethylase, is crucial in cardiomyocyte pyroptosis after MI. We used MI rat and mouse models, a cell hypoxia model of rat primary cardiomyocytes (RCMs), and rat embryonic ventricle cell line (H9c2) to explore the functional role of m 6 A modification and ALKBH5 in the heart and cardiomyocytes. Using plasmids and small interfering RNAs, the expressions of ALKBH5 and NOD-like receptor family pyrin domain-containing 3 (NLRP3) were determined to study their functions in regulating cardiomyocyte m 6 A and pyroptosis, respectively. We characterized the role of ALKBH5, which exhibited elevated expression in the ischemic heart tissue of rats and mice and hypoxic cardiomyocytes (RCMs and H9c2 cells). ALKBH5 knockdown alleviated hypoxia-induced H9c2 cell pyroptosis by inhibiting NLRP3 inflammasome activation, whereas ALKBH5 overexpression had the opposite effect. NLRP3 knockdown alleviated hypoxia-induced H9c2 cardiomyocyte pyroptosis by inhibiting ALKBH5 expression, whereas NLRP3 overexpression had the opposite effect. Mechanistically, ALKBH5 mediated m 6 A modification of NLRP3 mRNA in an IGF2BP2-dependent manner, and NLRP3, as a nuclear transcription factor, regulated the ALKBH5 transcription process. Targeting the ALKBH5-NLRP3 loop with the small-molecule inhibitors alleviated cardiomyocyte pyroptosis. Our results highlight that ALKBH5-NLRP3 forms a positive feedback loop that promotes cardiomyocyte pyroptosis after MI. Therefore, inhibiting the ALKBH5-NLRP3 loop is a potential strategy for treating cardiovascular diseases.
研究领域:
心血管疾病
·
表观转录组学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
APPLIED CATALYSIS B-ENVIRONMENTAL
·
2024
·
IF 20.2
Hua Wang,Yunchuan Tu,Sijun Li,Yimin Jiang,Niandan Zhao,Wenbin Wang,Wei Shen,Ming Li,Rongxing He
Efficient electrocatalytic co-reduction of CO 2 and NO 3 − to urea involves simultaneous generation and stabilization of C- and N-coupling intermediates. Herein, we report positive feedback at the interfaces of an AuPd/SnO x catalyst that enables generation and stable co-adsorption of *CO and *NH 2 OH at low-potential, fostering efficient C-N coupling for urea formation. A combination of in-situ spectroscopic analyses and theoretical calculations show that *CO 2 captures electrons by bonding to the AuPd/SnO x interface, leading to positively charged Pd sites, which promote the NO 3 RR to give the key N-intermediate *NH 2 OH. The adsorbed *NH 2 OH provides electron feedback to the catalyst surface , which not only enhances the adsorption of CO 2 and promotes the conversion of *CO 2 to *CO to accelerate the CO 2 RR, but also enhances the adsorption strength of the catalyst for *CO. Owing to this positive feedback, the Faraday efficiency and yield of urea reached 21.3 % and 1280.5 μg∙h −1 ∙mg −1 at −0.2 V (versus the relative hydrogen electrode), surpassing the performance of most previously reported catalysts. This finding provides new insights into catalyst design for advancing C-N coupling systems.
研究领域:
化学
·
材料科学
·
催化反应
✓ 已验证
产品关联
DOI
高影响因子
ATMOSPHERIC ENVIRONMENT
·
2024
·
IF 4.2
Chunyan Zhang,Qingxin Ma,Peng Zhang,Tianzeng Chen,Yonghong Wang,Biwu Chu,Hao Li,Jikun Li,Chuncheng Chen,Jincai Zhao,Hong He
As the main source of atmospheric sulfate aerosol , the aqueous-phase oxidation of SO 2 has been of great concern. Traditionally, the aqueous-phase oxidation of SO 2 is considered a consumption process of atmospheric oxidation capacity; however, we report here that •OH radicals and other reactive oxygen species (ROS) can be generated in the photochemical reactions of bulk HSO 3 − solution. This •OH production pathway results in the fast sulfate formation in the photooxidation of dissolved SO 2 . The photochemical process is determined to be pH-dependent in which sulfate formation is promoted by decreasing pH. Hence, a light - driven acidic positive feedback mechanism is proposed that the oxidation of dissolved SO 2 and the formation of •OH radicals have a synergistic promoting effect. These results indicate that the photochemistry of dissolved SO 2 could be a missing source of aqueous •OH radicals as well as sulfate at regional to global scales.
研究领域:
大气科学
·
环境化学
✓ 已验证
DOI
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2024
·Vol. 28
·期 20
·e70144
·
IF 4.3
Qiying Yao,Xinrui Hu,Tiantian Bian,Qing Zhang,Zhao Xue,Yuesheng Lv,Shupeng Ren,Yue Chen,Dongmei Zhang,Liang Chen
Sialylation catalysed by sialyltransferase 7A (SIAT7A) plays a role in the development of cardiac hypertrophy. However, the regulatory mechanisms upstream of SIAT7A in this context remain poorly elucidated. Previous study demonstrated that KLF4 activates the SIAT7A gene in ischemic myocardium by binding to its promoter region. Nevertheless, the potential involvement of KLF4 in regulating SIAT7A expression in Ang II-induced hypertrophic cardiomyocytes remains uncertain. This study seeks to deepen the underlying mechanisms of the KLF4 and SIAT7A interaction in the progression of Ang II-induced cardiac hypertrophy. The results showed a concurrent increase in SIAT7A and KLF4 levels in hypertrophic myocardium of essential hypertension patients and in hypertrophic cardiomyocytes stimulated by Ang II. In vitro experiments revealed that reducing KLF4 levels led to a decrease in both SIAT7A synthesis and Sialyl-Tn antigen expression, consequently inhibiting Ang II-induced cardiomyocyte hypertrophy. Intriguingly, reducing SIAT7A levels also resulted in decreased KLF4 expression and suppression cardiomyocyte hypertrophy. Consistent with this, elevating SIAT7A levels increased KLF4 expression and exacerbated cardiomyocyte hypertrophy in both in vivo and in vitro experiments. Additionally, a time-course analysis indicated that KLF4 expression preceded that of SIAT7A. Luciferase reporter assays further confirmed that modulating SIAT7A levels directly influenced the transcriptional activity of KLF4 in cardiomyocytes. In summary, KLF4 expression is upregulated in cardiomyocytes treated with Ang II, which subsequently induces the expression of SIAT7A. The elevated levels of SIAT7A, in turn, enhance the transcription of KLF4 . These findings suggest a positive feedback loop between KLF4 and SIAT7A-Sialyl-Tn, ultimately promoting Ang II-induced cardiac hypertrophy.
研究领域:
心脏病学
·
分子生物学
·
细胞生物学
✓ 已验证
DOI
高影响因子
Synthetic and Systems Biotechnology
·
2023
·
IF 4.8
Shuting Hu,Guangbao Zhang,Xiaoqiang Jia
In this study, we designed a Cd 2+ whole-cell biosensor with both positive and negative feedback cascade amplifiers in Pseudomonas putida KT2440 (LTCM) based on our previous design with only a negative feedback amplifier (TCM). The results showed that the newly developed biosensor LTCM was greatly improved compared to TCM. Firstly, the linear response range of LTCM was expanded while the maximum linear response range was raised from 0.05 to 0.1 μM. Meanwhile, adding a positive feedback amplifier further increased the fluorescence output signal of LTCM 1.11–2.64 times under the same culture conditions. Moreover, the response time of LTCM for detection of practical samples was reduced from 6 to 4 h. At the same time, LTCM still retained very high sensitivity and specificity, while its lowest detection limit was 0.1 nM Cd 2+ and the specificity was 23.29 (compared to 0.1 nM and 17.55 in TCM, respectively). In summary, the positive and negative feedback cascade amplifiers effectively improved the performance of the biosensor LTCM, resulting in a greater linear response range, higher output signal intensity, and shorter response time than TCM while retaining comparable sensitivity and specificity, indicating better potential for practical applications.
研究领域:
生物技术
·
环境科学
·
合成生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2021
·
IF 13.273
Bing Wang,Kai Chen,Qianfeng Zhang,Lei Gu,Qiang Luo,Zhiqian Li,Qiyong Gong,Hu Zhang,Zhongwei Gu,Kui Luo
Reactive oxygen species (ROS)-responsive drug delivery systems for cancer treatment often suffer insufficient drug release. Herein, we developed a ROS-responsive amphiphilic block copolymer-drug conjugate, TA-CA-Prodrug, based on a positive feedback strategy to address this issue. Cinnamaldehyde (CA), a ROS-generation agent, was modified as a ROS-responsive linker in the copolymer to connect hydrophilic and hydrophobic segments and conjugate an anti-tumor drug (PTX) to the main copolymeric chain. A pH-sensitive moiety (DPA) was also incorporated to the copolymer. This amphiphilic prodrug self-assembled into micelles at a particle size of around 150 nm with a negative zeta potential. ROS-responsive release of PTX and CA was confirmed after TA-CA-Prodrug was incubated with H 2 O 2 , and the drug release rate was dependent on the concentration of H 2 O 2 . After endocytosis into tumor cells, TA-CA-Prodrug were mainly colocalized with mitochondria owing to the charge reversal after protonation of DPA moieties of TA-CA-Prodrug in an acidic intracellular environment (i.e., pH ≤ 6.2). A relatively high level of ROS around the mitochondria induced simultaneous release of CA and PTX from the prodrug. Then, ROS-generation was triggered by released CA, which in turn enhanced PTX release and PTX-mediated cell cycle arrest, thus resulting in remarkable apoptosis of tumor cells after treatment with TA-CA-Prodrug compared with control groups (TK-Prodrug and Prodrug). Due to a cascaded ROS-feedback strategy, i.v. injection of TA-CA-Prodrug into mice bearing 4 T1 tumors led to a greater tumor inhibition efficacy than control groups, and no obvious side effects were confirmed from negligible changes in body weight as well as H&E stained major organs of mice. Therefore, this block copolymer-drug conjugate could enhance intracellular ROS production for efficient drug release and augment its anti-tumor effect.
研究领域:
药学
·
生物医学工程
·
肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
MOLECULAR THERAPY
·
2025
·
IF 12
Di Wang,Xiao-ya Wang,Wen-jing Li,Cheng-hui Liang,Yu-xin Zou,Jin-wei Xiao,Qing-mei Kang,Jun-han Wang,Ling Mao,Jun-jie Chen,Xue-jia Zhai,Ji-tao Zhuang,Xian-Yan Yang,Hong-ying Jiang,Tian-hua Shen,Jie Liu,Qian Wen,Jiang-jie Duan,Jun Wang,Shi-cang Yu
The oncoprotein c-Myc is a prominent target in cancer therapy and modulating its stability is a promising potential treatment strategy. Phosphorylation at Ser62 is the primary mechanism by which c-Myc degradation is suppressed, which extends its half-life. Consequently, identifying kinases that regulate the phosphorylation of c-Myc at Ser62 may pave the way for novel intervention strategies. In this study, we revealed that acetaldehyde dehydrogenase 18A1 (ALDH18A1), a key enzyme in glutamate-proline metabolism, acts as a protein kinase through its γ-glutamate kinase (γ-GK) domain, which mediates the phosphorylation of the Ser62 site of c-Myc and suppresses its degradation. In turn, stabilized c-Myc directly increases the transcription of ALDH18A1 . This positive feedback loop sustains the mutual high expression of both proteins, which promotes the development of various tumors. Thonzonium bromide (TB), a small-molecule inhibitor screened from a Food and Drug Administration-approved drug library, was found to block ALDH18A1-mediated phosphorylation of c-Myc at Ser62 and attenuate tumor progression in preclinical models. Overall, these findings reveal the therapeutic potential of inhibiting the ALDH18A1 - MYC regulatory circuit in human cancers.
研究领域:
肿瘤学
·
分子生物学
·
信号转导
·
癌基因调控
·
代谢酶功能
·
蛋白质稳定性
·
靶向治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2020
·
IF 6.793
Xuying Lv,Zixuan Liu,Lei Xu,Erqun Song,Yang Song
Tetrachlorobenzoquinone (TCBQ) is a common metabolite of persistent organic pollutants pentachlorophenol (PCP) and hexachlorobenzene (HCB). Current reports on the toxicity of TCBQmainly focused on its reproductive toxicity, neurotoxicity, carcinogenicity and cardiovascular toxicity. However, the possible immunotoxicity of TCBQ remains unclear. The release of neutrophil extracellular traps (NETs) is a recently discovered immune response mechanism, however, excess NETs play a pathogenic role in various immune diseases. In an attempt to address concerns regarding the immunotoxicity of TCBQ, we adopted primary mouse neutrophils as the research object, explored the influence of TCBQ on the formation of NETs. The results showed that TCBQ could induce NETs rapidly in a reactive oxygen species (ROS)-dependent manner. Moreover, TCBQ promoted the phosphorylation of c-Jun N-terminal kinase (JNK) mitogen activated protein kinase (MAPK), but not p38 or extracellular signal related kinase (ERK) in neutrophils. Mechanistically, JNK activation enhanced the expression of NADPH oxidase enzyme 2 (NOX2), which further accelerated the generation of ROS and thus amplified the formation of NETs. The pharmacologic blockage of JNK or NOX2 effectively ameliorated TCBQ-induced ROS and NETs, implying that ROS-JNK-NOX2 positive feedback loop was involved in TCBQ-induced NETs. In conclusion, we speculated that targeting NETs formation would be a promising therapeutic strategy in modulating the immunotoxicity of TCBQ.
研究领域:
毒理学
·
免疫学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Advanced Research
·
2023
·
IF 10.7
Wenjuan Tang,Yu Hu,Kaihui Tu,Zhengyan Gong,Man Zhu,Tianfeng Yang,Ammar Sarwar,Bingling Dai,Dongdong Zhang,Yingzhuan Zhan,Yanmin Zhang
Introduction Tumor-associated calcium signal transducer 2 (Trop2) has been used as a transport gate for cytotoxic agents into cells in antibody–drug conjugate designs because of its expression in a wide range of solid tumors. However, the specific role of Trop2 itself in breast cancer progression remains unclear and small molecules targeting Trop2 have not yet been reported. Objectives To screen small molecules targeting Trop2, and to reveal its pharmacological effects and the molecular mechanisms of action. Methods Small molecule targeting Trop2 was identified by cell membrane chromatography, and validated by cellular thermal shift assay and point mutation analyses. We investigated the pharmacological effects of Trop2 inhibitor using RNA-seq, human foreskin fibroblast (HFF)-derived extracellular matrix (ECM), Matrigel drop invasion assays, colony-forming assay, xenograft tumor model, 4T1 orthotopic metastasis model and 4T1 experimental metastasis model. The molecular mechanism was determined using immunoprecipitation, mass spectrometry, immunofluorescence, immunohistochemistry and Western blotting. Results Here we identified Bruceine D (BD) as the inhibitor of Trop2, and demonstrated anti-metastasis effects of BD in breast cancer. Notably, Lys307 and Glu310 residues of Trop2 acted as critical sites for BD binding. Mechanistically, BD suppressed Trop2-induced cancer metastasis by blocking the formation of Trop2/β-catenin positive loop, in which the Trop2/β-catenin complex prevented β-catenin from being degraded via the ubiquitin-proteosome pathway. Destabilized β-catenin caused by BD reduced nucleus translocation, leading to the reduction of transcription of Trop2, the reversal of epithelial-mesenchymal transition (EMT) process, and the inhibition of ECM remodeling, further inhibiting cancer metastasis. Additionally, the inhibitory effects of BD on lung metastatic colonization and the beneficial effects of BD on prolongation of survival were validated in 4T1 experimental metastasis model. Conclusions These results support the tumor-promoting role of Trop2 in breast cancer by stabilizing β-catenin in Trop2/β-catenin positive loop, and suggest Bruceine D as a promising candidate for Trop2 inhibition.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Pingting Ye,Chunhui Wang,Yixuan Wen,Kang Fang,Qi Li,Xin Zhang,Jingxian Yang,Ruihao Li,Mengyao Chen,Xiaohan Tong,Shuo Shi,Chunyan Dong
Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer due to poor immunogenicity and limited immune cell infiltration, efficient therapeutics are still deficiency. Ferroptosis, a reactive oxygen species (ROS)-reliant cell death, can enhance cellular immunogenicity and then active immune system. To sustain a long-term “hot” tumour immune microenvironment (TIME), an immune-modulator is indispensable. Metformin (MET), a commonly used oral drug for type 2 diabetes, has played a vital role in fostering an immunostimulatory environment. Herein, we confirm the TIME can be remodeled by MET and further promotes ferroptosis via upregulating cellular concentration of l -Glutamine. In light of this, we have design a self-assembled MET-loaded Fe 3+ -doped polydopamine nanoparticle (Fe-PDA-MET NP) that can disorder the cellular redox homeostasis and induce robust ferroptosis under 808 nm irradiation, resulting in a strong immune response. Based on the function of MET, there is a marked increase in the infiltration of activated CD8 + T cells and NK cells, which subsequently augments ferroptosis to a greater extent. Taken together, Fe-PDA-MET NPs activate a ferroptotic positive-feedback loop for effectively control TNBC progression, which offers a promising therapeutic modality to enhance the immunogenicity and reshape the TIME.
研究领域:
肿瘤学
·
免疫疗法
·
纳米技术
·
癌症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2024
·Vol. 15
·期 1
·1-15
·
IF 8.1
Li Jingzhi,Guo Ming,Chen Lin,Chen Zhuchu,Fu Ying,Chen Yongheng
Nasopharyngeal carcinoma (NPC) is a malignant tumor that is highly prevalent in Southeast Asia, especially in South China. The pathogenesis of NPC is complex, and genetic alterations of tumor suppressors and proto-oncogenes play important roles in NPC carcinogenesis. p53 is unexpectedly highly expressed in NPC and possesses an uncommon mutation of R280T, which is different from a high frequency of hotspot mutations or low expression in other tumors. However, the mechanism of p53 loss of function and its correlation with R280T in NPC are still unclear. In this study, p53 amyloid aggregates were found to be widespread in NPC and can be mainly induced by the R280T mutation. Aggregated p53-R280T impeded its entry into the nucleus and was unable to initiate the transcription of downstream target genes, resulting in decreased NPC cell cycle arrest and apoptosis. In addition, NPC cells with p53-R280T amyloid aggregates also contributed aggressively to tumor growth in vivo. Transcriptome analysis suggested that p53 amyloid aggregation dysregulated major signaling pathways associated with the cell cycle, proliferation, apoptosis, and unfolded protein response (UPR). Further studies revealed that Hsp90, as a key molecular chaperone in p53 folding, was upregulated in NPC cells with p53-R280T aggregation, and the upregulated Hsp90 facilitated p53 aggregation in turn, forming positive feedback. Therefore, Hsp90 inhibitors could dissociate p53-R280T aggregation and restore the suppressor function of p53 in vitro and in vivo. In conclusion, our study demonstrated that p53-R280T may misfold to form aggregates with the help of Hsp90, resulting in the inability of sequestered p53 to initiate the transcription of downstream target genes. These results revealed a new mechanism for the loss of p53 function in NPC and provided novel mechanistic insight into NPC pathogenesis.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
·
遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2019
·
IF 10.273
Ying Zhang,Lin Lin,Liang Liu,Feng Liu,Shu Sheng,Huayu Tian,Xuesi Chen
Targeted activation or enhancement is an attractive strategy in the design of nano-theranostics. However, the responsiveness of the nanoagents is restricted by the limited levels of intra-tumor stimuli. Herein, we constructed a positive feedback nanoamplifier by encapsulating glucose oxidase (GOx) in the ferric ions contained metal organic framework (MIL-100), and coating the nanoparticles with polydopamine modified hyaluronic acid (HA-PDA). The mechanism of action of the ensuing nanoamplifiers was three pronged: 1) the high intra-tumor acidity accelerated the release of GOx, which consumed endogenous glucose and “starved” the tumors, in addition to aggravating the local acidity and H 2 O 2 levels; 2) the hydroxyl radicals (·OH) generated from the Fenton-like reaction between MIL-100 with H 2 O 2 contributed to the chemodynamic tumor therapy and augmented the O 2 microenvironment , which could be speeded up under acid condition; 3) the oxygen (O 2 ) produced in the Fenton-like reaction relieved the intra-tumor hypoxia and ensured the enzymatic reaction of GOx, along with augmenting the photoacoustic signal of nanoamplifier. Preliminary experiments in tumor bearing mice showed that the nanoamplifier not only boosted the local acidity/H 2 O 2 /O 2 levels in tumor site to successfully suppress the growth of tumors through the self-enhanced chemodynamic/starving therapy, but also achieved the photoacoustic imaging of tumors. Taken together, this novel nanoamplifier with the abilities of self-enhanced tumor imaging and therapy is a promising entrant in the field of anti-tumor theranostics.
研究领域:
纳米技术
·
癌症研究
·
诊疗学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）