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
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表观转录组学
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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 Materials Chemistry B
·
2024
·
IF 6.1
Maochang Xu,Dan Ran,Jian Hu,Jingying Mao,Dehui Qiao,Zongquan Zhang,Xiaoya Liang,Li Zhang,Yu Nie,Hong Yang,Xiangyu Zhou,Chunhong Li
Atherosclerosis (AS) is a lipid-driven chronic inflammatory disease characterized by the presence of numerous proinflammatory cytokines, massive reactive oxygen species (ROS) and excess lipids, which together result in an overall inflammatory positive feedback loop in the plaque focus. Due to its excellent enzyme-like activity in ROS scavenging and inflammation inhibition, as well as its photothermal effects in the lipid efflux ability of foam cells, Prussian blue (PB) has greater potential in preventing inflammatory factor loops for enhanced treatment of AS than traditional nanozymes. In this study, the multifunctional nanozyme BSA@PB/Cur was synthesized by self-assembly of bovine serum albumin (BSA) with PB and further encapsulation of the anti-inflammatory drug curcumin (Cur). The in vitro results showed that BSA@PB/Cur could effectively scavenge ROS and inhibit the expression of the inflammatory cytokines TNF-α and IL-1β as well as enhance the expression of ABCA1 and ABCG1 in foam cells, promote cholesterol efflux and inhibit foam cell formation. The in vivo experimental results demonstrated that BSA@PB/Cur could target plaque locations, significantly efflux the lipid content, and decrease the matrix metalloproteinase expression. This research provides a potential strategy for alleviating the persistent inflammatory feedback loop within the plaque microenvironment for AS treatment.
研究领域:
医学
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生物化学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
INDUSTRIAL CROPS AND PRODUCTS
·
2024
·
IF 5.6
Ling Zhou,Qingyin Tian,Wenjie Ding,Hongmin Hu,Tingting Shi,Guogui Ning,Lianggui Wang,Yuanzheng Yue,Xiulian Yang
Osmanthus fragrans have a unique aroma, its extracts and its constituents have a wide range of biological activities, making them of great industrial value. β-ionone is a crucial factor in determining the aroma quality of O. fragrans . The synthesis mechanism of β-ionone is essential for studying the aromatic compounds in O. fragrans . This study demonstrated that the OfMYB1R114-OfSDIR1-like- OfCCD4 module regulates β-ionone synthesis in O. fragrans . A MYB-related transcription factor OfMYB1R114 increased β-ionone aroma substance and elevated OfCCD4 expression level through binding to the OfCCD4 promoter and activating its expression; this demonstrated a positive loop in β-ionone synthesis. Screening for interacting proteins using a cDNA library of O. fragrans petals, the interaction pair between OfMYB1R114 and OfSDIR1-like was validated. In addition, OfSDIR1-like negatively regulated β-ionone synthesis by ubiquitinating the OfMYB1R114 protein and decreasing the ability of OfMYB1R114 to activate its downstream target gene OfCCD4 . Interestingly, OfMYB1R114 could directly bind to the OfSDIR1-like promoter and repress its transcription, revealing a negative feedback loop between OfMYB1R114 and OfSDIR1-like. Hence, this suggests that OfSDIR1-like is a new novel regulator that functions in β-ionone synthesis via the OfMYB1R114-mediated aroma pathway. The mechanistic framework revealed by the studies is that the OfMYB1R114-mediated module OfMYB1R114-OfSDIR1-like- OfCCD4 regulates β-ionone synthesis. It sheds light on the molecular mechanisms at the basis of aroma synthesis in O. fragrans and provides theoretical basis and technical guidance for the comprehensive utilisation and industrial development of O. fragrans aroma substance.
研究领域:
植物科学
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分子生物学
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生物化学
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农学
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产品关联
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
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分子生物学
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细胞生物学
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DOI
高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-19
·
IF 15.7
Shen Xuecheng,Qiao Wenxuan,Yan Wei,Xie Hao,Zhang Chenyang,Sun Yang,Luo Qiong,Xu Qiang
IL-17 signaling contributes to the pathogenesis of psoriasis; however, IL-17 involvement in keratinocyte hyperactivation of epidermis remains unclear. Here, we describe an IL-17A-induced, skin-specific, positive feedback loop, which operates independently of canonical chemokine production, thus untangling skin inflammation and epithelial hyperproliferation in psoriasis. We show that IL-17A-induced, keratinocyte-specific KLK8 interacts with IL-17R to promote histone H4 lysine lactylation (H4K12la) catalyzed by the acetyltransferase HAT1. H4K12la further promotes IL-17A-mediated keratinocyte proliferation and the expression of KLK8 and IL-17R, creating a feedback loop that drives psoriasis progression. Importantly, excessive lactate in the microenvironment exacerbates H4K12la and psoriasis severity, thereby impairing the efficacy of anti-IL-17A antibody. Silencing KLK8, HAT1, or inhibiting lactate accumulation attenuates psoriasis in mice. Moreover, combining lactylation inhibition with anti-IL-17A therapy exhibits synergistic effects against antibody-resistant psoriasis. Thus, our findings unveil a lactylation-driven, keratinocyte-specific IL-17A signaling and offer a promising approach for psoriasis treatment, particularly in patients with comorbid metabolic syndrome.
研究领域:
皮肤生物学
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表观遗传学
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免疫学
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分子生物学
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炎症性疾病
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转化医学
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产品关联
DOI
PubMed
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
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分子生物学
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信号转导
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癌基因调控
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代谢酶功能
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蛋白质稳定性
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靶向治疗
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·Vol. 11
·期 43
·2408013
·
IF 14.3
Kaicheng Deng,Yuyan Hua,Ying Gao,Houwei Zheng,Yangzi Jiang,Yaping Wang,Changyou Gao,Tanchen Ren,Yang Zhu
HIF-1α (hypoxia induced factor-1α), a vital protective signal against hypoxia, has a short lifetime after myocardial infarction (MI). Increasing HIF-1α stability by inhibiting its hydroxylation with prolyl hydroxylases inhibitors such as DPCA (1,4-dihydrophenonthrolin-4-one-3-carboxylic acid) presents positive results. However, the optimal inhibitor administration profile for MI treatment is still unexplored. Here, injectable, thermosensitive hydrogels with programmable DPCA release are designed and synthesized. Hydrogel degradation and slow DPCA release are coupled to form a feedback loop by attaching pendant DPCA to polymer backbone, which serve as additional crosslinking points through π–π and hydrophobic interactions. Pendant carboxyl groups are added to the copolymer to accelerate DPCA release. Burst release in the acute phase for myocardial protection and extended near zero-order release across the inflammatory and fibrotic phases with different rates are achieved. All DPCA-releasing hydrogels upregulate HIF-1α, decrease apoptosis, promote angiogenesis, and stimulate cardiomyocyte proliferation, leading to preserved cardiac function and ventricular geometry. Faster hydrogel degradation induced by faster DPCA release results in a HIF-1α expression eight times of healthy control and better therapeutic effect in MI treatment. This research demonstrates the value of precise regulation of HIF-1α expression in treating MI and other relevant diseases and provides an implantable device-based modulation strategy.
研究领域:
心血管研究
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生物材料
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药学
·
组织工程
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产品关联
DOI
PubMed
高影响因子
DEVELOPMENTAL CELL
·
2024
·
IF 10.7
Xiaoxin Guo,Juanyu Zhou,La Yan,Xingzhu Liu,Yu Yuan,Jinbao Ye,Zehong Zhang,Haiou Chen,Yongxin Ma,Zhendong Zhong,Guanzheng Luo,Haiyang Chen
Peroxisome dynamics are crucial for intestinal stem cell (ISC) differentiation and gut regeneration. However, the precise mechanisms that govern peroxisome dynamics within ISCs during gut regeneration remain unknown. Using mouse colitis and Drosophila intestine models, we have identified a negative-feedback control mechanism involving the transcription factors peroxisome proliferator-activated receptors (PPARs) and SOX21. This feedback mechanism effectively regulates peroxisome abundance during gut regeneration. Following gut injury, the released free very long-chain fatty acids (VLCFAs) increase peroxisome abundance by stimulating PPARs-PEX11s signaling. PPARs act to stimulate peroxisome fission and inhibit pexophagy. SOX21, which acts downstream of peroxisomes during ISC differentiation, induces peroxisome elimination through pexophagy while repressing PPAR expression. Hence, PPARs and SOX21 constitute a finely tuned negative-feedback loop that regulates peroxisome dynamics. These findings shed light on the complex molecular mechanisms underlying peroxisome regulation in ISCs, contributing to our understanding of gut renewal and repair.
研究领域:
分子生物学
·
干细胞研究
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胃肠科学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2019
·
IF 3.845
Lin Xiao-mian,Luo Wu,Wang Heng,Li Rong-zhen,Huang Yi-shan,Chen Lian-kuai,Wu Xiao-ping
The prostaglandin-endoperoxide synthase-2 (PTGS2) plays essential roles in diverse pathological process. Although recent studies implied that PTGS2 was closely related with chemoresistance, the precise roles and the underlying mechanisms of PTGS2 in the developing process of chemoresistance in non-small cell lung cancer (NSCLC) remained elusive. In the present study, we revealed a novel molecular mechanism of PTGS2 implicated in the chemoresistance of NSCLC and proposed a model for the positive feedback regulation of PTGS2 in the process of developing resistance phenotype in NSCLC cells. Our results demonstrated that cisplatin induced PTGS2 expression through the ROS-ERK1/2-NF-κB signaling axis. The prostaglandin E2 (PGE2) derived from PTGS2 catalyzation further strengthened PTGS2 expression via the PGE2-EPs-ERK1/2 positive feedback loop, which induced multidrug resistance of NSCLC cells through up-regulation of BCL2 expression and the subsequent attenuation of cell apoptosis. Consistently, high levels of both PTGS2 and BCL2 were closely associated with poor survival in NSCLC patients. Inhibition of PTGS2 significantly reversed the chemoresistance in the resistant NSCLC in vitro and in vivo. Our results suggested that PTGS2 might be employed as an adjunctive therapeutic target for improving the response to the therapeutic agents in a subset of resistant NSCLC.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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