ARCHIVES OF TOXICOLOGY
·
2025
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IF 6.9
Tang Wei,Zong Shimin,Du Peiyu,Yu Xuan,Li Ting,Liu Bo,Zhong Yu,Lei Wenyang,Yu Wenting,Xiao Hongjun
Cochlear hair cell death is the primary cause of cisplatin-induced ototoxicity, currently lacking widely applicable clinical methods for effective prevention and treatment. In this study, an in vivo cisplatin-induced ototoxicity model was established by intraperitoneal injection of 12 mg/kg cisplatin. We found that ablation of SIRT3 exacerbates cisplatin-induced hearing loss and cochlear hair cell damage. An in vitro cisplatin-induced ototoxicity model was established using 5 µM cisplatin in cochlear explants and OC-1 cells. We found that the absence of SIRT3 impairs cochlear hair cell glycolytic metabolism, leading to excessive accumulation of ROS and significant reduction in MMP levels, thereby promoting apoptosis. In contrast, overexpression of SIRT3 in OC-1 cells promotes cochlear hair cell survival and reduces cochlear hair cell apoptosis. Inhibition of PFKFB3 reduces glycolytic metabolism in OC-1 cells, and the protective effect conferred by SIRT3 overexpression is lost. In summary, the protective effect of SIRT3 may be mediated by the regulation of PFKFB3-dependent glycolysis and the mitigation of cisplatin-induced excessive ROS accumulation.
研究领域:
耳鼻喉科学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2022
·Vol. 7
·期 1
·1-17
·
IF 38.104
Zeng Hao,Pan Ting,Zhan Meiling,Hailiwu Renaguli,Liu Baolin,Yang Hua,Li Ping
Endothelial-to-mesenchymal transition (EndoMT), the process wherein endothelial cells lose endothelial identity and adopt mesenchymal-like phenotypes, constitutes a critical contributor to cardiac fibrosis. The phenotypic plasticity of endothelial cells can be intricately shaped by alteration of metabolic pathways, but how endothelial cells adjust cellular metabolism to drive EndoMT is incompletely understood. Here, we identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) as a critical driver of EndoMT via triggering abnormal glycolysis and compromising mitochondrial respiration. Pharmacological suppression of PFKFB3 with salvianolic acid C (SAC), a phenolic compound derived from Salvia miltiorrhiza , attenuates EndoMT and fibrotic response. PFKFB3-haplodeficiency recapitulates the anti-EndoMT effect of SAC while PFKFB3-overexpression augments the magnitude of EndoMT and exacerbates cardiac fibrosis. Mechanistically, PFKFB3-driven glycolysis compromises cytoplasmic nicotinamide adenine dinucleotide phosphate (reduced form, NADPH) production via hijacking glucose flux from pentose phosphate pathway. Efflux of mitochondrial NADPH through isocitrate/α-ketoglutarate shuttle replenishes cytoplasmic NADPH pool but meanwhile impairs mitochondrial respiration by hampering mitochondrial iron-sulfur cluster biosynthesis. SAC disrupts PFKFB3 stability by accelerating its degradation and thus maintains metabolic homeostasis in endothelial cells, underlying its anti-EndoMT effects. These findings for the first time identify the critical role of PFKFB3 in triggering EndoMT by driving abnormal glycolysis in endothelial cells, and also highlight the therapeutic potential for pharmacological intervention of PFKFB3 (with SAC or other PFKFB3 inhibitors) to combat EndoMT-associated fibrotic responses via metabolic regulation.
研究领域:
心脏病学
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细胞代谢
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药理学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2019
·Vol. 20
·期 21
·5415
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IF 4.183
Siyuan Yan,Nan Zhou,Deru Zhang,Kaile Zhang,Wenao Zheng,Yonghua Bao,Wancai Yang
6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3), a glycolytic enzyme highly expressed in cancer cells, has been reported to participate in regulating metabolism, angiogenesis, and autophagy. Although anti-cancer drug oxaliplatin (Oxa) effectively inhibits cell proliferation and induces apoptosis, the growing resistance and side-effects make it urgent to improve the therapeutic strategy of Oxa. Although Oxa induces the autophagy process, the role of PFKFB3 in this process remains unknown. In addition, whether PFKFB3 affects the cytotoxicity of Oxa has not been investigated. Here, we show that Oxa-inhibited cell proliferation and migration concomitant with the induction of apoptosis and autophagy in SW480 cells. Both inhibition of autophagy by small molecule inhibitors and siRNA modification decreased the cell viability loss and apoptosis induced by Oxa. Utilizing quantitative PCR and immunoblotting, we observed that Oxa increased PFKFB3 expression in a time- and dose-dependent manner. Meanwhile, suppression of PFKFB3 attenuated both the basal and Oxa-induced autophagy, by monitoring the autophagic flux and phosphorylated-Ulk1, which play essential roles in autophagy initiation. Moreover, PFKFB3 inhibition further inhibited the cell proliferation/migration, and cell viability decreased by Oxa. Collectively, the presented data demonstrated that PFKFB3 inhibition attenuated Oxa-induced autophagy and enhanced its cytotoxicity in colorectal cancer cells.Keywords:PFKFB3;Oxaliplatin;autophagy;colorectal cancer;proliferation
研究领域:
癌症生物学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2026
·Vol. 58
·期 3
·1-13
·
IF 8.5
Mingkun Xu,Linhang Fu,Yulong Zhang,Xiuli Guo,Han Wu,Sijing Gao,Fei Xiao,Li Xu
International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2025
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IF 6.3
Yanhong Bu,Hong Wu,Ran Deng,Yan Wang,Peirong Gan,Xintong Dong,Jiangtao Ke
Angiogenesis driven by aerobic glycolysis in endothelial cells sustains rheumatoid arthritis (RA) progression. Geniposide (GE), an iridoid ether extracted from the Rubiaceae plant Gardenia jasminoides J. Ellis, has shown anti-angiogenic potential in experimental arthritis. However, its role in metabolic regulation of angiogenesis remains unclear. The purpose was to explore the roles of GE on metabolism in angiogenesis and potential mechanisms. Adjuvant arthritis (AA) rat models and human umbilical vein endothelial cells (HUVECs) were established. Network pharmacology predicted potential targets of GE, while metabolomics analysis was conducted on RA patient serum and AA rat synovial tissue. The role of PFKFB3, a key glycolytic enzyme, was validated by gene silencing and pharmacological interventions. The signaling axis was further explored using inhibitors, agonists, and protein interaction assays. The role of the key glycolytic enzyme PFKFB3 and the upstream–downstream relationship of the signaling axis were validated through gene silencing and pharmacological intervention. GE improved angiogenesis in vivo and in vitro models, and PFKFB3 may be a potential target. Metabolomics has shown that GE significantly inhibited the elevated levels of glycolysis metabolism in arthritis rats, which may be related to the inhibition of PFKFB3 expression. PFKFB3-siRNA down-regulated angiogenesis in HUVECs, demonstrating that PFKFB3-mediated glycolysis was involved in angiogenesis. SphK1-siRNA indicated that PFKFB3 was regulated and activated by the SphK1-PI3K-AKt signal and induced a high level of glycolytic metabolism phenotype. GE intervention significantly downregulated the levels of glycolysis metabolism in arthritis models by inhibiting the SphK1-PI3K-AKt-PFKFB3 signal. The SphK1-PI3K-Akt-PFKB3 signal is the metabolic mechanism of the natural product active ingredient GE in anti-angiogenesis, revealing the important role of glycolytic metabolism in RA angiogenesis. This provides new insights into metabolic regulation in RA treatment and potential therapeutic strategies for metabolic targeted interventions.
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产品关联
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PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2025
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IF 5.6
Reziwanguli Wusiman,Shayila Haimiti,Hanikezi Abuduaini,Miaoyan Yang,Yitian Wang,Meijun Gu,Ali Sailike,Lei Gao
Renal fibrosis is a prominent feature of diabetic nephropathy (DN), and the connection between renal fibrosis and abnormal glycolysis is not fully understood. SUMO-activating enzyme subunit 1 (SAE1) plays a crucial role in the SUMO modification process and is related to abnormal glycolysis. Despite this, the specific role of SAE1 in DN and its mechanism are not well defined. To investigate this, a streptozotocin-induced diabetic CD1 mice model was used, with SAE1 suppression achieved through systemic administration of SAE1 siRNA. In parallel, human renal proximal tubular tubule HK2 cells transfected with siSAE1 were exposed to high glucose for in vitro studies. The study revealed that SAE1 levels were elevated in diabetic kidney, and the deletion of SAE1 mitigated renal fibrosis in DN mice. Such suppression in SAE1 was associated with the lower expression of hypoxia inducible factor-1α (HIF-1α) and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), these alterations subsequently improved abnormal glycolysis and mesenchymal transformations in vivo and in vitro . Further experiments discovered that SAE1 stabilized transcription factor HIF-1α expression through SUMOylation, promoting PFKFB3 transcription, which enhanced glycolysis characterized by increased PFK1 activity and lactate production. Additionally, pharmacological inhibition of PFKFB3 reduced renal fibrosis in DN mice, while overexpression of PFKFB3 partly restored the glycolysis and mesenchymal transformations inhibited by SAE1 knockdown in vitro . These data demonstrate that SAE1 promotes abnormal glycolysis by HIF-1α/PFKFB3 which is responsible for the fibrotic phenotype of diabetic kidney. Inhibition of SAE1 could be an alternative strategy in combating diabetes associated-kidney fibrosis via improving aberrant glycolysis.
研究领域:
肾病学
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分子生物学
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糖尿病学
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DOI
PubMed
高影响因子
LIFE SCIENCES
·
2026
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IF 6.4
ShuMei Yang,XinLin Yan,YaPeng Jing,Yi Guan,GuoZhen Chen,Xuan Li
Aims Corneal fibrosis is a leading cause of blindness with limited treatment options. This study explores the role of PFKFB3-driven glycolytic reprogramming in the development of corneal fibrosis and evaluates its potential as a therapeutic target. Materials and methods An alkali burn-induced corneal injury model was established in C57BL/6 mice to investigate temporal changes in glycolysis during wound healing. Pathological alterations were assessed using slit-lamp microscopy, hematoxylin and eosin (H&E) staining, proteomic analysis, and Western blotting. Glycolytic flux was measured by determining the extracellular acidification rate (ECAR) in both injured corneas and cultured keratocytes stimulated with TGF-β1 or LPS. Further mechanistic studies were conducted to elucidate the specific role of PFKFB3 in corneal repair. Key findings Proteomic analysis revealed a significant enrichment of glycolytic pathways during corneal repair. Following alkali injury, murine corneas exhibited a time-dependent increase in glycolytic activity, peaking at day 14, coinciding with the fibrotic phase of wound healing. Pharmacological inhibition of PFKFB3 in vivo produced multiple therapeutic benefits, including accelerated wound closure, reduced corneal opacity, and suppressed myofibroblast differentiation. This intervention also decreased the ECAR and reduced the production of fibrotic extracellular matrix components. Complementary in vitro studies confirmed that PFKFB3 blockade effectively mitigated both TGF-β1-induced fibrotic transformation and LPS-mediated inflammatory activation in keratocytes. Significance In conclusion, our study identified PFKFB3-driven glycolytic reprogramming as a critical metabolic checkpoint in corneal fibrosis. Targeting this node pathway attenuates both myofibroblast transformation and inflammatory responses.
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DOI
PubMed
高影响因子
NEUROPHARMACOLOGY
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2019
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IF 4.367
Xin-Chun Zhang,Ai-Ping Gu,Chun-Ye Zheng,Ying-Bin Li,Hong-Feng Liang,Hua-Jun Wang,Xia-Lin Tang,Xiao-Xin Bai,Jun Cai
Yin-Yang 1 (YY1) has been identified as playing critical roles in multiple diseases . However, little is known regarding its roles and mechanisms in cerebral ischemia/reperfusion (I/R) injury. This study is aimed to explore the roles of YY1 in regulating neuronal apoptosis in cerebral I/R injury and its underlying mechanisms. Primary mouse cerebral cortical neurons were isolated and subjected to OGD/R to mimic cerebral I/R injury in vitro . The roles of YY1 on OGD/R-induced neuronal injury were investigated by performing western blotting , quantitative real-time polymerase chain reaction, TUNEL , RNA-binding protein immunoprecipitation , chromatin immunoprecipitation, chromatin isolation by RNA purification assay, glucose uptake assay, lactate production assay, and extracellular acidification rate assay. YY1-binding long non-coding RNAs (LncRNAs) in neurons subjected to OGD/R were identified by RIP and RNA sequencing . The roles of YY1 on cerebral I/R in vivo were detected by assessing neuronbehaviour, infarct size, and neuronal apoptosis. We found that YY1 expression is downregulated, and LncRNA GAS5 is upregulated in neurons subjected to OGD/R. OGD/R treatment promotes YY1 interacting with GAS5 in neurons, and YY1 negatively regulates GAS5 expression by binding to GAS5 promoter to repress its transcription. Besides, YY1 and GAS5 bind to the same region of PFKFB3 promoter to promote PFKFB3 expression and strengthen neuronal glycolysis, resulting in aggravating OGD/R-induced neuronal apoptosis. Knockdown of YY1 or GAS5 protects against I/R-induced ischemic brain damage and improves overall neurological functions in vivo. Overall, YY1 interacts with LncRNA GAS5 to promote PFKFB3 transcription to enhance neuronal glycolysis, resulting in aggravating cerebral I/R injury.
研究领域:
神经科学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Cell Death Discovery
·
2023
·Vol. 9
·期 1
·1-16
·
IF 7
Shi Pilong,Wu Jiawei,Li Minghui,Cao Yonggang,Wu Jiabi,Ren Ping,Liu Kai,Zhou Jiajun,Sha Yuetong,Zhang Qianhui,Sun Hongli
Research suggests that ischemic glycolysis improves myocardial tolerance to anoxia and low-flow ischemia. The rate of glycolysis during ischemia reflects the severity of the injury caused by ischemia and subsequent functional recovery following reperfusion. Histone H2AK119 ubiquitination ( H2Aub ) is a common modification that is primarily associated with gene silencing. Recent studies have demonstrated that H2Aub contributes to the development of cardiovascular diseases. However, the underlying mechanism remains unclear. This study identified Hsp27 (heat shock protein 27) as a H2Aub binding protein and explored its involvement in mediating glycolysis and mitochondrial function. Functional studies revealed that inhibition of PRC1 (polycomb repressive complex 1) decreased H2Aub occupancy and promoted Hsp27 expression through inhibiting ubiquitination. Additionally, it increased glycolysis by activating the NF-κB / PFKFB3 signaling pathway during myocardial ischemia. Furthermore, Hsp27 reduced mitochondrial ROS production by chaperoning COQ9 , and suppressed ferroptosis during reperfusion. A delivery system was developed based on PCL-PEG-MAL (PPM)-PCM-SH (CWLSEAGPVVTVRALRGTGSW) to deliver PRT4165 (PRT), a potent inhibitor of PRC1 , to damaged myocardium, resulting in decreased H2Aub . These findings revealed a novel epigenetic mechanism connecting glycolysis and ferroptosis in protecting the myocardium against ischemia/reperfusion injury.
研究领域:
心血管研究
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表观遗传学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）