INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
·
2025
·
IF 2.8
Rui Zhou,Xiuzhu Wang,Nannan Li
Diabetic cardiomyopathy (DCM) is a cardiovascular disease specific to patients with diabetes. The pathophysiology of DCM is significantly influenced by oxidative stress and apoptosis, which are critical mechanisms underlying the disease. PBX homeobox 1 (PBX1) is a homeodomain transcription factor, which plays a crucial role in regulating various biological processes. However, the precise molecular mechanism of PBX1 in DCM is still unclear. In this study, we investigated the protective effect of PBX1 against cardiac injury. Male C57BL/6 mice subjected to streptozotocin were used to simulate DCM in vivo . Genetic manipulation of PBX1 mediated by the adeno-associated virus-based vectors was employed to overexpress PBX1 in mice. The findings indicated that PBX1 expression was significantly downregulated in the left ventricular tissues of DCM mice, and overexpression of PBX1 mitigated cardiac fibrosis and enhanced cardiac function. Additionally, our results demonstrated that PBX1 overexpression effectively reduced oxidative stress and apoptosis in DCM-affected mice. To mimic DCM in vitro , human cardiomyocytes AC16 cells were treated with high glucose (HG), and results obtained in vitro were consistent with those in vivo. Mechanistically, PBX1 could bind to the promoter region of thioredoxin interacting protein (TXNIP) and exerted a negative regulatory effect on TXNIP transcription. In conclusion, these results suggest that overexpression of PBX1 attenuates oxidative stress and apoptosis in DCM progression by transcriptionally inhibiting TXNIP expression. PBX1 may be a novel therapeutic candidate for DCM treatment.
研究领域:
生物化学
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分子生物学
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心脏病学
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遗传学
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2025
·
IF 2.2
Rongyan Zhu,Liu Yang,Yulan Li
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age and is frequently associated with impaired glucose metabolism. Thioredoxin-interacting protein (TXNIP) plays a critical role in cellular metabolic regulation; however, its involvement in PCOS pathogenesis remains unclear. Bioinformatics analysis revealed significantly increased TXNIP expression in both PCOS patients and mouse ovarian granulosa cells (GCs). In vivo experiments using dehydroepiandrosterone (DHEA)-induced PCOS mouse models showed that TXNIP knockdown restored the expression of glycolysis-related enzymes, including HK2, PFKM, and PKM2. This restoration enhanced glycolytic function by suppressing IRS-1 phosphorylation and activating the PI3K signaling pathway. In vitro, dihydrotestosterone (DHT)treatment elevated TXNIP expression and suppressed glycolytic activity in KGN cells. Silencing TXNIP restored glycolytic metabolites such as pyruvate and lactate and promoted glycolytic flux, while TXNIP overexpression further impaired these functions. Additionally, treatment with the IRS-1 inhibitor NT157 confirmed that TXNIP regulates glycolysis in GCs through the IRS-1/PI3K signaling axis. This study is the first to demonstrate that TXNIP contributes to glycolytic dysfunction in PCOS GCs via the IRS-1/PI3K pathway, highlighting a potential target for PCOS diagnosis and therapy.
研究领域:
生殖生物学
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代谢病学
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内分泌学
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PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2023
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IF 4.5
Zhihui Li,Yan Shi,Yougang Wang,Haomin Qi,Haiyu Chen,Jinquan Li,Li Li
Cadmium (Cd) is a hypertoxic heavy metal that may be exposed to environmental pollutants by humans and animals. It can lead to cognitive disfunction, and is linked to neurodegenerative diseases. Cadmium reportedly can induce endoplasmic reticulum (ER) stress, but few studies have concentrated on it in nerve cells, and the connection between ER stress and neuroinflammation. In this study, in vitro experiments on SH-SY5Y neuroblastoma cells were carried out. We aimed at exploring whether Cd attributed to the cell pyroptosis and the role of PERK in promoting this form of cell damage which can induce strong inflammatory responses. Our results demonstrated that CdCl 2 treatment induced excess reactive oxygen species (ROS) production, caused significant modifications in the expression of PERK and increased TXNIP, NLRP3, IL-1β, IL-18, and caspase1 in SH-SY5Y cells. In addition, scavenging ROS with N -acetylcysteine or inhibiting the expression of PERK by using GSK2606414, rescued the SH-SY5Y cells from cadmium-induced pyroptosis. In conclusion, the results suggest that Cd induces pyroptotic death of SH-SY5Y cells through ER stress, and this may be the potential mechanism of Cd incurring neurological diseases.
研究领域:
神经毒理学
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细胞生物学
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分子生物学
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环境毒理学
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PubMed
高影响因子
EXPERIMENTAL ANIMALS
·
2023
·
IF 2.4
Sheng LI,Gaoxiang OUYANG,Linhui YUAN,Xiaoxuan WU,Lijun ZHANG
Diabetic retinopathy (DR), a common complication of diabetes, involves excessive proliferation and inflammation of Muller cells and ultimately leads to vision loss and blindness. SRY-box transcription factor 9 (SOX9) has been reported to be highly expressed in Müller cells in retinal light-damaged rats, but the functional role of SOX9 in DR remains unclear. To explore this issue, the DR rat model was successfully constructed via injecting with streptozotocin (STZ, 65 mg/kg) and the retinal thicknesses and blood glucose levels were evaluated. Müller cells were treated with 25 mmol/L glucose to create a cell model in vitro. The results indicated that SOX9 expression was significantly increased in DR rat retinas and high glucose (HG)-stimulated Müller cells. HG treatment promoted the proliferation and migration capabilities of Müller cells, whereas SOX9 knockdown reversed those behaviors. Moreover, SOX9 knockdown protected against HG-induced inflammatory response, as evidenced by reduced tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 levels in serum and decreased NLRP3 inflammasome activation. Notably, SOX9, acted as a transcription factor that positively regulated thioredoxin-interacting protein (TXNIP), a positive regulator of Müller cells gliosis under HG conditions. Dual luciferase assay demonstrated that SOX9 could enhance TXNIP expression at the transcriptional level through binding to the promoter of TXNIP. Moreover, TXNIP overexpression restored the effects caused by SOX9 silencing. In conclusion, these findings demonstrate that SOX9 may accelerate the progression of DR by promoting glial cell proliferation, metastasis, and inflammation, which involves the transcriptional regulation of TXNIP, providing new theoretical fundamentals for DR therapy.
研究领域:
眼科学
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细胞生物学
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糖尿病
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转录调控
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DOI
PubMed
高影响因子
Nutrients
·
2022
·Vol. 14
·期 15
·3102
·
IF 6.706
Ning Li,Liuding Wen,Tiange Li,Huijie Yang,Mingwu Qiao,Tianlin Wang,Lianjun Song,Xianqing Huang,Mingming Li,Erkigul Bukyei,Fangyu Wang
Many researchers have found that Pb exposure can cause oxidative stress damage to the body’s tissue. Black soybean peptide (BSP) has a variety of physiological functions, especially in terms of oxidative stress. Nevertheless, the mitigation function of BSPs on Pb-induced oxidative stress damage in PC12 cells has not been clearly defined. In this study, cell viability was detected by CCK8. Oxidative stress indicators, such as ROS, GSH/GSSG, MDA, SOD, CAT, GPx, and GR, were tested with biochemical kit. Protein expression of Keap1, Nrf2, and TXNIP was measured by Western blot. Compared with the control group, Pb reduced the cell viability of PC12 cells. However, BSP treatment significantly increased the viability of PC12 cells induced by lead exposure (p< 0.05). Lead can enrich the contents of MDA and ROS, but decrease the amount of CAT, SOD, GR, GPx, and GSH/GSSG in PC12 cells, while BSP can alleviate it (p< 0.05). Lead can enhance the expression of Keap1 and TXNIP proteins, but reduce Nrf2 expression. In contrast, BSPs reversed this phenomenon (p< 0.05). BSPs can alleviate oxidative stress injury induced by lead in PC12 cells through the Keap1/Nrf2/TXNIP signaling pathway.Keywords:black soybean peptide;Pb;PC12 cells;Keap1/Nrf2/TXNIP;oxidative stress
研究领域:
毒理学
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细胞生物学
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药理学
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Zhihong Zhuo,Yao Wang,Huimin Kong,Tianjiao Fu
Neuroinflammation is a major component of epilepsy. Gut-enriched Kruppel-like factor (GKLF), a transcription factor of Kruppel-like factor family, has been reported to promote microglia activation and mediate neuroinflammation. However, the role of GKLF in epilepsy remains poorly characterized. This study focused on the function of GKLF in neuron loss and neuroinflammation in epilepsy and the molecular mechanism underlying microglia activation induced by GKLF upon lipopolysaccharides (LPS) treatment. An experimental epileptic model was induced by an intraperitoneal injection of 25 mg/kg kainic acid (KA). Lentivirus vectors (Lv) carrying Gklf CDS or short hairpin RNA targeting Gklf (shGKLF) was injected into the hippocampus, resulting in Gklf overexpression or knockdown in the hippocampus. BV-2 cells were co-infected with Lv-shGKLF or/and Lv carrying thioredoxin interacting protein ( Txnip ) CDS for 48 h and treated with 1 μg/mL LPS for 24 h. Results showed that GKLF enhanced KA-induced neuronal loss, pro-inflammatory cytokine secretion, activation of NOD-like receptor protein-3 (NLRP3) inflammasomes and microglia, and TXNIP expression in the hippocampus. GKLF inhibition showed negative effects on LPS-induced microglia activation, as evidenced by reduced pro-inflammatory cytokine secretion and activation of NLRP3 inflammasomes. GKLF bound to Txnip promoter and increased TXNIP expression in LPS-activated microglia. Interestingly, Txnip overexpression reversed the inhibitory effect of Gklf knockdown on microglia activation. These findings indicated that GKLF was involved in microglia activation via TXNIP. This study demonstrates the underlying mechanism of GKLF in the pathogenesis of epilepsy and uncovers that GKLF inhibition may be a therapeutic strategy for epilepsy treatment.
研究领域:
神经科学
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
MECHANISMS OF AGEING AND DEVELOPMENT
·
2024
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IF 5.3
Qingqiu Chen,Rong Hu,Hongmei Qiu,Shan Li,Peng Xiang,Yining Lu,Xianmin Wang,Tongchuan Wang,Lan Zhou,Wanping Zhang,E Wen,Limei Ma,Chao Yu
Endothelial cell senescence characterized by reactive oxygen species (ROS) accumulation and chronic inflammation is widely recognized as a key contributor to atherosclerosis (AS). Regulated in development and DNA damage response 1 (REDD1), a conserved stress-response protein that regulates ROS production, is involved in the pathogenesis of various age-related diseases. However, the role of REDD1 in endothelial cell senescence is still unclear. Here, we screened REDD1 as a differentially expressed senescence-related gene in the AS progression using bioinformatics methods, and validated the upregulation of REDD1 expression in AS plaques, senescent endothelial cells, and aging aorta by constructing AS mice, D-galactose (DG)-induced senescent endothelial cells and DG-induced accelerated aging mice, respectively. siRNA against REDD1 could improve DG-induced premature senescence of endothelial cells and inhibit ROS accumulation, similar to antioxidant N-Acetylcysteine (NAC) treatment. Meanwhile, NAC reduced the upregulation of REDD1 induced by DG, supporting the positive feedback loop between REDD1 and ROS contributes to endothelial cell senescence. Mechanistically, the regulatory effect of REDD1 on ROS might be related to the TXNIP-REDD1 interaction in DG-induced endothelial cell senescence. Collectively, experiments above provide evidence that REDD1 participates in endothelial cell senescence through repressing TXNIP-mediated oxidative stress, which may be involved in the progression of atherosclerosis.
研究领域:
心血管生物学
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分子生物学
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细胞衰老
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衰老研究
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PubMed
高影响因子
FISH & SHELLFISH IMMUNOLOGY
·
2022
·
IF 4.622
Zhiying Miao,Zhiruo Miao,Xiaohua Teng,Shiwen Xu
Lead (Pb) has been concerned as one of the most severe hazardous contaminants, because it can cause pyroptosis in multiple tissues of mammals and birds. Melatonin (Mel) has attracted much interest for its role in governing intestinal injury via microRNAs (miRNAs). To explore the effect of Mel on Pb exposure-induced intestinal epithelial cell pyroptosis in common carps by regulating miR-17-5p/TXNIP axis, the Pb exposure and Pb-Mel treated models were constructed in vivo . The results elucidated that the suppressed expression of miR-17-5p and intensified level of TXNIP were primarily detected in Pb-exposed gut tissues, and both abolished with Mel addition, along with downregulated Pb-mediated elevated expression of NLRP3, CASP1, IL1β and GSDMD. Additionally, the targeting relationship between miR-17-5p and TXNIP were demonstrated by dual-luciferase reporter assay, and on this basis, miR-17-5p NC, mimic and inhibitor cell models were established. Thereby, Thereby, the expression of TXNIP in the miR-17-5p mimic groups was significant lower in the Pb-exposure but still elevated than the Control group, and the expression of NLRP3 and NLRP3-dependent pyrotposis-related genes performed consistent alterations. Noticeably, the expression of TXNIP suppressed with Mel addition even in the miR-17-5p inhibitor cell model, resulting in the inactivation of NLRP3 inflammasome-dependent pyroptosis. Overall, we draw the conclusion as Mel attenuates Pb-induced intestinal epithelial cell pyroptosis via miR-17-5p/TXNIP axis. The present study provides a novel perspective for toxicological mechanism of Pb, and new insights for the detoxification mechanism of Mel.
研究领域:
毒理学
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分子生物学
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水生生物学
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环境科学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Hongtao Duan,Rui Zhang,Aiminuer Asikaer,Liang Pan,Shui Wang,Kuilong Huang,Deshuai Lou,Yuanqiang Wang,Zhihua Lin,Yan Shen
Background & Aims: Acute pancreatitis (AP) is a life-threatening condition, and hypertriglyceridemia (HTG) is recognized as a factor exacerbating AP and impeding pancreatic regeneration. Nicotinamide mononucleotide (NMN), a precursor in the biosynthesis of nicotinamide adenine dinucleotide (NAD + ), is extensively utilized to restore NAD + levels. However, the impact of NMN on HTG-AP has not been previously addressed, which prompted our investigation into its effects and underlying mechanisms in this study. Methods & Results: Here, through bioinformatics analysis and in vivo experiments, we identified abnormalities in the thioredoxin system. In vitro studies revealed that NMN rescued oleic acid (OA)- and palmitic acid (PA)-induced mitochondrial dysfunction and cellular injury in pancreatic acinar cells by suppressing thioredoxin-interacting protein (TXNIP) through NAD + /sirtuin 1 (SIRT1) signaling. Repeated administration of NMN significantly ameliorated P407 and caerulein (CER)-induced pancreatic injury and dysfunction in mice. Consistently, NMN exhibited the potential to reduce inflammatory responses, lower serum lipid levels, and mitigate the accumulation of reactive oxygen species (ROS). More importantly, sustained NMN treatment inhibited the NOTCH pathway and promoted M2-type macrophage dominance during the pancreatic repair phase, influencing early or late macrophage polarization, which significantly enhanced inflammation resolution. As expected, in vitro models using mouse bone marrow-derived macrophage (BMDM), RAW 264.7, and THP-1 cells confirmed that NMN influences macrophage phenotype through the NOTCH pathway. Conclusions: Therefore, NMN ameliorates pancreatic acinar cell injury via NAD + /SIRT1-mediated TXNIP suppression and may influence macrophage polarization by inhibiting NOTCH activation, offering a novel therapeutic strategy for the treatment and repair of HTG-AP.
研究领域:
医学
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生物化学
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分子生物学
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PubMed
高影响因子
CELL BIOLOGY AND TOXICOLOGY
·
2024
·Vol. 40
·期 1
·1-25
·
IF 5.3
Wu Wentong,Li Jinjin,Yin Yiming,Zhou Yourong,Huang Xiangliang,Cao Yashi,Chen Xueqin,Zhou Yunfang,Du Jiangxia,Xu Zhifei,Yang Bo,He Qiaojun,Yang Xiaochun,Hu Yuhuai,Yan Hao,Luo Peihua
Ensartinib, an approved ALK inhibitor, is used as a first-line therapy for advanced ALK-positive non-small cell lung cancer in China. However, the hepatotoxicity of ensartinib seriously limits its clinical application and the regulatory mechanism is still elusive. Here, through transcriptome analysis we found that transcriptional activation of TXNIP was the main cause of ensartinib-induced liver dysfunction. A high TXNIP level and abnormal TXNIP translocation severely impaired hepatic function via mitochondrial dysfunction and hepatocyte apoptosis, and TXNIP deficiency attenuated hepatocyte apoptosis under ensartinib treatment. The increase in TXNIP induced by ensartinib is related to AKT inhibition and is mediated by MondoA. Through screening potential TXNIP inhibitors, we found that the natural polyphenolic flavonoid rutin, unlike most reported TXNIP inhibitors can inhibit TXNIP by binding to TXNIP and partially promoting its proteasomal degradation. Further studies showed rutin can attenuate the hepatotoxicity of ensartinib without antagonizing its antitumor effects. Accordingly, we suggest that TXNIP is the key cause of ensartinib-induced hepatotoxicity and rutin is a potential clinically safe and feasible therapeutic strategy for TXNIP intervention. Graphical Abstract
研究领域:
肿瘤学
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药理学
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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
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
·
2023
·Vol. 64
·期 3
·16-16
·
IF 4.4
Lili Lian,Zhenmin Le,Zhenzhen Wang,Ying-ao Chen,Xiaodong Jiao,Hang Qi,J. Fielding Hejtmancik,Xiaoyin Ma,Qinxiang Zheng,Yueping Ren
Purpose:To determine whether SIRT1 regulates high glucose (HG)–induced inflammation and cataract formation through modulating TXNIP/NLRP3 inflammasome activation in human lens epithelial cells (HLECs) and rat lenses.Methods:HG stress from 25 to 150 mM was imposed on HLECs, with treatments using small interfering RNAs (siRNAs) targeting NLRP3, TXNIP, and SIRT1, as well as a lentiviral vector (LV) for SIRT1. Rat lenses were cultivated with HG media, with or without the addition of NLRP3 inhibitor MCC950 or SIRT1 agonist SRT1720. High mannitol groups were applied as the osmotic controls. Real-time PCR, Western blots, and immunofluorescent staining evaluated the mRNA and protein levels of SIRT1, TXNIP, NLRP3, ASC, and IL-1β. Reactive oxygen species (ROS) generation, cell viability, and death were also assessed.Results:HG stress induced a decline in SIRT1 expression and caused TXNIP/NLRP3 inflammasome activation in a concentration-dependent manner in HLECs, which was not observed in the high mannitol–treated groups. Knocking down NLRP3 or TXNIP inhibited NLRP3 inflammasome-induced IL-1β p17 secretion under HG stress. Transfections of si-SIRT1 and LV-SIRT1 exerted inverse effects on NLRP3 inflammasome activation, suggesting that SIRT1 acts as an upstream regulator of TXNIP/NLRP3 activity. HG stress induced lens opacity and cataract formation in cultivated rat lenses, which was prevented by MCC950 or SRT1720 treatment, with concomitant reductions in ROS production and TXNIP/NLRP3/IL-1β expression levels.Conclusions:The TXNIP/NLRP3 inflammasome pathway promotes HG-induced inflammation and HLEC pyroptosis, which is negatively regulated by SIRT1. This suggests viable strategies for treating diabetic cataract.
研究领域:
眼科学
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细胞生物学
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糖尿病
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炎症
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2023
·
IF 7.5
Zhangnian Liu,Shiquan Gan,Lingyun Fu,Yini Xu,Shengquan Wang,Guangqiong Zhang,Di Pan,Ling Tao,Xiangchun Shen
1,8-Cineole, the main component of volatile oil in aromatic plants, has diverse pharmacological properties, including antioxidant, anti-inflammatory, and anti-cancer properties. Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus (DM). Here, we investigated the protective effect of 1,8-cineole on DR and found that 1,8-cineole treatment could alter the expression of several genes in both high glucose (HG)-induced ARPE-19 cells and retinal tissues of DM mice, as well as inhibit ferroptosis. Subsequent investigations into the molecular mechanisms underlying this inhibition revealed that expression of thioredoxin-interacting protein (TXNIP) was significantly upregulated while that of peroxisome proliferator-activated receptor γ (PPAR-γ) was significantly downregulated in HG-induced ARPE-19 cells, and treatment with 1,8-cineole could effectively reverse these changes. Treatment with a PPAR-γ pharmacological agonist (rosiglitazone), alone or combined with 1,8-cineole, significantly inhibited the transcription of TXNIP and ferroptosis in HG-induced ARPE-19 cells. Conversely, pretreatment with GW9662, a PPAR-γ inhibitor, upregulated the transcription and expression of TXNIP in HG-induced ARPE-19 cells; 1,8-cineole failed to reverse this upregulated expression. To explore these relationships, we constructed a PPAR-γ adenovirus shRNA to elucidate the effect of 1,8-cineole on the negative regulation of TXNIP by PPAR-γ. Taken together, the present findings indicate that HG-induced ferroptosis in retinal tissue plays an essential role in the pathogenesis of DR, which can be ameliorated by 1,8-cineole.
研究领域:
药理学
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眼科学
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分子生物学
·
糖尿病研究
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产品关联
DOI
PubMed
高影响因子
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