FASEB JOURNAL
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2025
·Vol. 39
·期 20
·e71141
·
IF 4.2
Mingxing Sui,Shuying Wu,Qingqing Song,Siyao Chen,Yingli Lu
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder with complex pathophysiology and limited therapeutic options. To elucidate potential biomarkers and molecular mechanisms underlying PCOS, we analyzed gene expression profiles in ovarian tissues from dehydroepiandrosterone (DHEA)-induced PCOS mice and control mice by conducting mRNA sequencing. Transcription factor forkhead box O6 (FOXO6) drew our focus, as it exhibited higher expression in PCOS ovarian tissues (fold change ≈1.71, p < 0.05). Functional validation revealed that FOXO6 knockdown alleviated ovarian dysfunction accompanied by attenuated mitochondrial damage and reduced apoptosis in the ovarian tissues of PCOS mice. Meanwhile, high expression of FOXO6 was also observed in dihydrotestosterone (DHT)-treated granulosa cells. Post-FOXO6 downregulation, DHT-induced apoptosis and mitochondrial dysfunction were suppressed. Notably, the RNA level of FOXO6 was upregulated by the methyltransferase METTL3, which inhibited the decay of FOXO6 RNA by increasing the m6A modification of FOXO6 RNA. The inhibitory effects of METTL3 knockdown on apoptosis and mitochondrial dysfunction in granulosa cells were weakened by FOXO6 overexpression. Furthermore, transcriptomic profiling of DHT-treated granulosa cells with or without FOXO6 overexpression was conducted. This analysis yielded 386 upregulated genes and 582 downregulated genes, among which thioredoxin-interacting protein (TXNIP) was prominently upregulated in FOXO6-overexpressing cells (fold change ≈4.5, p < 0.05). FOXO6 transcriptionally activated TXNIP by binding to its promoter, and TXNIP knockdown reversed the effects of FOXO6 overexpression. Collectively, our findings highlight the METTL3/FOXO6/TXNIP axis as a vital regulator of ovarian dysfunction in PCOS, offering novel insights for therapeutic intervention. Graphical To elucidate PCOS biomarkers and mechanisms, mRNA-sequencing of ovarian tissues from DHEA-induced PCOS and control mice identified highly expressed FOXO6 (FC ≈1.71, p < 0.05). FOXO6 knockdown alleviated PCOS ovarian dysfunction, mitochondrial damage, and apoptosis, and suppressed DHT-induced granulosa cell defects. METTL3 upregulated FOXO6 via m6A modification to inhibit its RNA decay. FOXO6 activated TXNIP transcription by binding its promoter. This highlights the METTL3/FOXO6/TXNIP axis as a key PCOS ovarian dysfunction regulator, offering new insights for PCOS therapy.
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IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL
·
2025
·
IF 1.7
Wang Ying,Liu Jiahui,Jiang Yiqun,Liu Yanzuo,Kuang Hongying,Feng Xiaoling
Polycystic ovary syndrome (PCOS), a common endocrine disorder affecting over 10% of women, is characterized by hyperandrogenism and ovarian dysfunction. While linked to chronic inflammation and granulosa cell apoptosis, its molecular mechanisms remain unclear. In this study, we elucidated the novel role of Krüppel-like factor 5 (KLF5) in the pathogenesis of PCOS and its regulatory role with thioredoxin interacting protein (TXNIP). In a mouse model of PCOS induced by dehydroepiandrosterone (DHEA), KLF5 expression was significantly elevated in ovarian tissues (up-regulated 2.62-fold, P < 0.001), correlating with hyperandrogenism (testosterone: up-regulated 2.83-fold, P < 0.001) and cystic follicle formation. The proliferative capacity of testosterone-treated KGN cells was reduced to 59% after KLF5 was knocked down ( P < 0.01), attenuated apoptosis by inhibiting the increase of Bax and Cleaved-caspase 3 proteins and thus attenuated inflammation by down-regulating NLRP3 and Interleukin- (IL-) 1β. Most importantly, dual luciferase assay showed that KLF5 transcriptionally activated TXNIP, resulting in a 3.04-fold enhancement of its promoter activity ( P < 0.001). Meanwhile, overexpression of TXNIP reversed the silencing effect of KLF5, resulting in a significant increase in apoptosis and secretion of inflammatory factors. These results reveal a previously unrecognized KLF5/TXNIP axis driving granulosa cell (GC) dysfunction in polycystic ovary syndrome, in which KLF5 transcriptionally upregulates TXNIP to promote apoptosis and NLRP3 inflammasome activation. Our findings provide the first evidence linking KLF5 to the pathogenesis of PCOS and establish this pathway as a potential therapeutic target, bridging a significant gap in understanding the molecular basis of the disease and providing compelling evidence for clinical drug development.
研究领域:
生殖内分泌学
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分子生物学
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病理生理学
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转化医学
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妇科疾病
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高影响因子
EXPERIMENTAL EYE RESEARCH
·
2026
·
IF 3.1
Meiyu Wang,Xiangyu Liu,Zhenzhen Ji,Yingxin Chen,Jun Cai,Mei Dong,Ziwen Xu,Jingxin Ju,Zhijian Li
Background As the predominant cause of blindness, cataract pathogenesis centrally involves oxidative stress-induced damage and apoptosis in lens epithelial cells. Although resveratrol possesses recognized antioxidant and antiapoptotic activities, its functional role in cataract development and its specific impact on TXNIP require further elucidation. This study aimed to investigate whether resveratrol delays cataract progression by regulating the TXNIP/Trx2 pathway, improving mitochondrial function, and inhibiting apoptosis. Methods In vitro , an oxidative stress model was established using the hydrogen peroxide (H 2 O 2 )-induced human lens epithelial cell line B3 (HLE-B3), whereas in vivo , a cataract model was constructed in sodium selenite-induced SD rats. Evaluations included cell viability, ROS levels, mitochondrial function (mitoROS and ΔΨm), antioxidant markers (GSH, SOD, and CAT), expression of TXNIP, Trx2, and apoptosis-related proteins (cleaved-caspase-3, Bax, Bcl-2), and apoptosis detection. Lenticular opacity and histopathological changes were assessed in vivo . Results In vitro experiments demonstrated that resveratrol and SRI37330 comparably suppressed H 2 O 2 -induced TXNIP expression and mitochondrial translocation, thereby upregulating Trx2, reducing ROS production, improving mitochondrial membrane potential, enhancing antioxidant capacity, and attenuating apoptosis. In vivo experiments revealed that resveratrol alleviated lens opacity and tissue abnormalities in rats, restored antioxidant function, regulated the expression of TXNIP, Trx2, and apoptosis-related proteins, and inhibited apoptosis. Conclusion Resveratrol delays cataract formation and progression by inhibiting TXNIP expression and mitochondrial translocation, restoring the mitochondrial antioxidant protein Trx2 expression, thereby reducing mitochondrial oxidative stress-related damage and blocking the mitochondrial apoptotic pathway.
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JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
·
2023
·
IF 5.6
Aiyun Li,Li Guan,Wanzhen Su,Ning Zhao,Xuwen Song,Jin Wang,Xiaoxiao Tang,Weize Li,Xiangying Jiao
Thioredoxin interacting protein (TXNIP) is a potential drug target for type 2 diabetes mellitus (T2DM) treatment. A series of quinazoline derivatives were designed, synthesised, and evaluated to inhibit TXNIP expression and protect from palmitate (PA)-induced β cell injury. In vitro cell viability assay showed that compounds D-2 and C-1 could effectively protect β cell from PA-induced apoptosis, and subsequent results showed that these two compounds decreased TXNIP expression by accelerating its protein degradation. Mechanistically, compounds D-2 and C-1 reduced intracellular reactive oxygen species (ROS) production and modulated TXNIP-NLRP3 inflammasome signalling, and thus alleviating oxidative stress injury and inflammatory response under PA insult. Besides, these two compounds were predicted to possess better drug-likeness properties using SwissADME. The present study showed that compounds D-2 and C-1, especially compound D-2, were potent pancreatic β cell protective agents to inhibit TXNIP expression and might serve as promising lead candidates for the treatment of T2DM.
研究领域:
药理学
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糖尿病研究
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药物化学
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细胞生物学
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高影响因子
JOURNAL OF DRUG TARGETING
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2024
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IF 4.3
Xiaoli Li,Duanfang Zhou,Mingpu Liu,Hongfang Zeng,Xiaoping Yu,Yi Song,Qichen He,Xu Liu,Huan Zhang,Zhengze Shen,Zeng Zhu,Mingyan Gu,Xiangnan Hu,Weiying Zhou
Emerging data suggest that cocrystal of two compounds may have a different pharmacological effect from two compounds alone or their physical combination. Glimepiride (Gli) and metformin (Met) are two types of anti-diabetic drugs. Previously we generated the glimepiride/metformin cocrystal (GM). In this study, we evaluated the anti-diabetic effects of GM and explored the underlying mechanisms. Our result showed that GM reduced the blood glucose and HbA1c levels in db/db mice, and low doses of GM can achieve the hypoglycemic effect as Gli or Met alone, and high dose of GM was better than Gli and Met alone in improving the pathological changes of liver. In vivo studies showed that GM activated AMPK and STAT3 signaling, downregulated TXNIP expression and upregulated MaFA expression. Moreover, GM promoted the secretion of insulin in pancreas of db/db mice and in high glucose-treated INS-1 and MIN-6 cells. Together, GM possesses slightly better anti-diabetic effects than Met or Gli alone in db/db mice, and the mechanism of GM protecting β-cell dysfunction induced by glucotoxicity may be associated with activation of the AMPK/TXNIP/MaFA pathway.
研究领域:
药理学
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糖尿病研究
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分子生物学
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Diabetology & Metabolic Syndrome
·
2023
·Vol. 15
·期 1
·1-13
·
IF 4.8
Li Tianrong,Yang Jingjing,Tan Anjun,Chen Hewen
Background Irisin plays a key role in metabolic diseases, including type 2 diabetes mellitus (T2DM). However, the mechanism underlying the link between irisin and the development of T2DM, particularly in pancreatic islet β-cells, remains unknown.Methods In vitro, Min6 cells were treated with high glucose (HG) to generate T2DM cell models. GSDMD-N staining, Western blotting assays, and ELISA were performed to measure the expression levels of GSDMD, caspase 1, IL-1β, and IL-18. Next, the NLRP3 stimulator, ATP, was used to assess the effect of irisin on NLRP3 inflammasome. To evaluate the function of the Nrf2-TrX/TXNIP signaling axis, the Nrf2 inhibitor ML385 was used. For in vivo assessment, we first established T2DM model mice. Then, hematoxylin and eosin (H&E) staining was performed to observe the islet morphology, and the immunofluorescence technique was used to examine the mass of α and β cells. To confirm the role of the Nrf2-TrX/TXNIP signaling axis, ML385 was injected into the mice. Immunofluorescence of Nrf2, caspase 1, and GSDMD was detected in the islet cells of the model mice to verify the results.Results We found that irisin treatment significantly decreased the expression of GSDMD-N (P31) and cleaved caspase-1 (p20), decreased caspase1 activity, and inhibited the secretion of IL-1β and IL-18 in HG-treated Min6 cells. We also found that irisin inhibited oxidative stress and NLRP3 expression by activating the Nrf2-TrX/TXNIP signaling axis. Additionally, in the T2DM model mice, irisin enhanced the function of islet cells, decreased insulin resistance, and preserved the morphology of pancreatic islets.Conclusion We showed in this study that irisin can be used for treating pyroptosis in HG-induced islet β-cells and T2DM model mice. We also found that irisin inhibits pyroptosis and oxidative stress by inhibiting the NLRP3-GSDMD pathway and activating the Nrf2-TrX/TXNIP signaling axis.
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MOLECULAR AND CELLULAR ENDOCRINOLOGY
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2016
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IF 3.859
Aiyun Li,Shuihong Zhang,Jia Li,Kang Liu,Fang Huang,Baolin Liu
Objective This study was designed to investigate the hypothesis that metformin and resveratrol exhibited the same effect on inhibition of NLRP3 inflammasome activation with regulation of AMPK in adipose tissue exposed to high glucose. Methods To induce adipose tissue dysfunction, we treated epididymal adipose tissue of mice or differentiated 3T3-L1 adipocytes with high glucose (33 mM) for 24 h. Meanwhile, mice were injected with streptozotocin STZ to induce diabetes and followed by oral administration of metformin (200 mg/kg), resveratrol (50 mg/kg) or ER stress inhibitor TUDCA (50 mg/kg) for 7 days. The effects of metformin and resveratrol on ROS production, mitochondrial fission , ER stress, TXNIP/NLRP3 inflammasome activation, inflammation and apoptosis were observed. Results Metformin and resveratrol inhibited ROS-associated mitochondrial fission by upregulating Drp1 phosphorylation (Ser 637) in an AMPK-dependent manner, and then suppressed ER stress indicated by dephosphorylation of IRE1α and eIF2α in the adipose tissue. As a result from suppressing TXNIP/NLRP3 inflammasome activation, metformin and resveratrol inhibited inflammation and reduced cell apoptosis in adipose tissue or adipocytes exposed to high glucose. Conclusion Metformin and resveratrol protected mitochondrial integrity by inhibiting Drp1 activity and prevented NLRP3 inflammasome activation by suppressing ER stress, and thereby protected adipose function from high glucose insult.
研究领域:
药理学
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内分泌学
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分子生物学
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糖尿病研究
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高影响因子
PeerJ
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2023
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IF 2.7
Liang Chen,Yi Xu
Scalp cooling is the most approved treatment for preventing chemotherapy-induced alopecia (CIA). However, the protective mechanism of scalp cooling has rarely been reported. The goal of the present study was to study the relationship between paclitaxel concentration and temperature and the inhibitory effect of low temperature on paclitaxel-induced alopecia. The results showed that the dose of paclitaxel should not exceed 60–70 mg/mL during scalp cooling treatment, and the optimal cooling temperature under different paclitaxel concentrations was determined. Normal human epidermal keratinocytes (NHEK) cells were analyzed by global transcriptome analysis, functional annotation and pathway analysis of differentially expressed genes (DEGs) and ELISA kit to analyze the mechanism of low temperature therapy. The expression of HSPA8, HSPA1A and HSPA1B, which belongs to HSP70, was up-regulated by low temperature. These genes are important target genes of low temperature treatment, which were confirmed by ELISA. The up-regulation of PLK2 and the down-regulation of TXNIP expression are the upstream of mitochondrial dysfunction and ROS, inhibiting the accumulation of ROS and up-regulating the mitochondrial membrane potential. Our research partially elucidates the therapeutic mechanism of scalp cooling, which provides a new idea on the drug research and development in CIA.
研究领域:
肿瘤学
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细胞生物学
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药理学
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分子生物学
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高影响因子
Nutrients
·
2022
·Vol. 14
·期 13
·2591
·
IF 6.706
Cuicui Zhang,Hai Niu,Chengyu Wan,Xiuxian Yu,Guang Xin,Yuda Zhu,Zeliang Wei,Fan Li,Yilan Wang,Kun Zhang,Shiyi Li,Yuman Dong,Yangying Li,Wen Huang
Acute pancreatitis (AP) is one of the most common causes of hospitalization for gastrointestinal diseases, with high morbidity and mortality. Endoplasmic reticulum stress (ERS) and Gasdermin D (GSDMD) mediate AP, but little is known about their mutual influence on AP. Diosgenin has excellent anti-inflammatory and antioxidant effects. This study investigated whether Diosgenin derivative D (Drug D) inhibits L-arginine-induced acute pancreatitis through meditating GSDMD in the endoplasmic reticulum (ER). Our studies were conducted in a mouse model of L-arginine-induced AP as well as in an in vitro model on mouse pancreatic acinar cells. The GSDMD accumulation in ER was found in this study, which caused ERS of acinar cells. GSDMD inhibitor Disulfiram (DSF) notably decreased the expression of GSDMD in ER and TXNIP/HIF-1α signaling. The molecular docking study indicated that there was a potential interaction between Drug D and GSDMD. Our results showed that Drug D significantly inhibited necrosis of acinar cells dose-dependently, and we also found that Drug D alleviated pancreatic necrosis and systemic inflammation by inhibiting the GSDMD accumulation in the ER of acinar cells via the TXNIP/HIF-1α pathway. Furthermore, the level of p-IRE1α (a marker of ERS) was also down-regulated by Drug D in a dose-dependent manner in AP. We also found that Drug D alleviated TXNIP up-regulation and oxidative stress in AP. Moreover, our results revealed that GSDMD-/-mitigated AP by inhibiting TXNIP/HIF-1α. Therefore, Drug D, which is extracted from Dioscorea zingiberensis, may inhibit L-arginine-induced AP by meditating GSDMD in the ER by the TXNIP /HIF-1α pathway.Keywords:acute pancreatitis;L-arginine;Gasdermin D;endoplasmic reticulum stress;TXNIP
研究领域:
药理学
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炎症
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分子生物学
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细胞生物学
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高影响因子
Neuroscience Bulletin
·
2020
·Vol. 36
·期 4
·346-358
·
IF 4.326
Su Cun-Jin,Shen Zhu,Cui Ru-Xiao,Huang Ya,Xu De-Lai,Zhao Feng-Lun,Pan Jie,Shi Ai-Ming,Liu Tong,Yu Yun-Li
Patients with diabetes mellitus have a higher risk of developing Parkinson’s disease (PD). However, the molecular links between PD and diabetes remain unclear. In this study, we investigated the roles of thioredoxin-interacting protein (TXNIP) in Parkin/PINK1-mediated mitophagy in dopaminergic (DA) cells under high-glucose (HG) conditions. In streptozotocin-induced diabetic mice, TXNIP was upregulated and autophagy was inhibited in the midbrain, while the loss of DA neurons was accelerated by hyperglycemia. In cultured PC12 cells under HG, TXNIP expression was upregulated and the intracellular reactive oxygen species (ROS) levels increased, leading to cell death. Autophagic flux was further blocked and PINK1 expression was decreased under HG conditions. Parkin expression in the mitochondrial fraction and carbonyl cyanide 3-chlorophenylhydrazone (CCCP)-induced co-localization of COX IV (marker for mitochondria) and LAMP1 (marker for lysosomes) were also significantly decreased by HG. Overexpression of TXNIP was sufficient to decrease the expression of both PINK1 and Parkin in PC12 cells, while knockdown of the expression of TXNIP by siRNA decreased intracellular ROS and attenuated cellular injury under HG. Moreover, inhibition of TXNIP improved the CCCP-induced co-localization of COX IV and LAMP1 in PC12 cells under HG. Together, these results suggest that TXNIP regulates Parkin/PINK1-mediated mitophagy under HG conditions, and targeting TXNIP may be a promising therapeutic strategy for reducing the risk of PD under hyperglycemic conditions.
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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糖尿病研究
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神经退行性疾病
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PubMed
高影响因子
CELL STRESS & CHAPERONES
·
2020
·Vol. 26
·期 2
·367-375
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IF 2.892
Chen Jun,Li Lihua,Zhou Yun,Zhang Jiahua,Chen Lei
Diabetic retinopathy (DR) is a serious microvascular complication of diabetes. Gambogic acid has been reported to have anti-inflammatory effect. However, the effect of GA on inflammatory response of ARPE-19 cells remains unclear. In our study, ARPE-19 cells were stimulated by palmitic acid (PA) induction in the presence of 30 mM glucose and then treated with 0.5, 1, 2, 5, 10, or 20 μM GA. CCK-8 assay showed that cell viability was increased by GA treatment at doses of 0.5, 1, and 2 μM instead of higher doses. ELISA analysis found that GA dose-dependently reduced the production of pro-inflammatory mediators TNF-α and IL-1β. Western blot indicated that GA downregulated the expression of NLRP3 inflammasome components including TXNIP, NLRP3, ASC, cleaved-caspase-1, and cleaved-IL-1β in a dose-dependent manner. In addition, Western blot and immunofluorescence analysis suggested that GA effectively increased the protein level of nuclear factor E2-related factor-2 (Nrf2). RT-qPCR showed that GA significantly increased the mRNA levels of Heme oxygenase-1 (HO-1) and NADPH:quinone oxidoreductase1 (NQO1). Furthermore, Nrf2 siRNA transfection confirmed the above effects of GA. In total, subtoxic doses of GA significantly flattened the inflammatory response induced by HG and PA in ARPE-19 cells via modulating the Nrf2 signaling pathway.
研究领域:
药理学
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细胞生物学
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糖尿病研究
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炎症
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高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
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2024
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IF 6.8
Bing Shang,Yaqiong Dong,Bo Feng,Jingyan Zhao,Zhi Wang,Debbie C. Crans,Xiaoda Yang
Background and Purpose Metal-based therapeutic agents are limited by the required concentration of metal-based agents. Hereby, we determined if combination with 17β-oestradiol (E2) could reduce such levels and the therapy still be effective in type 2 diabetes mellitus (T2DM). Experimental Approach The metal-based agent (vanadyl acetylacetonate [VAC])– 17β-oestradiol (E2) combination is administered using the membrane-permeable graphene quantum dots (GQD), the vehicle, to form the active GQD–E2–VAC complexes, which was characterized by fluorescence spectra, infrared spectra and X-ray photoelectron spectroscopy. In db / db type 2 diabetic mice, the anti-diabetic effects of GQD–E2–VAC complexes were evaluated using blood glucose levels, oral glucose tolerance test (OGTT), serum insulin levels, homeostasis model assessment (homeostasis model assessment of insulin resistance [HOMA-IR] and homeostasis model assessment of β-cell function [HOMA-β]), histochemical assays and western blot. Key Results In diabetic mice, GQD–E2–VAC complex had comprehensive anti-diabetic effects, including control of hyperglycaemia, improved insulin sensitivity, correction of hyperinsulinaemia and prevention of β-cell loss. Co-regulation of thioredoxin interacting protein (TXNIP) activation by the combination of metal complex and 17β-oestradiol contributed to the enhanced anti-diabetic effects. Furthermore, a potent mitochondrial protective antioxidant, coniferaldehyde, significantly potentiates the protective effects of GQD–E2–VAC complexes. Conclusion and Implications A metal complex–E2 combinatorial approach achieved simultaneously the protection of β cells and insulin enhancement at an unprecedented low dose, similar to the daily intake of dietary metals in vitamin supplements. This study demonstrates the positive effects of combination and multi-modal therapies towards type 2 diabetes treatment. Graphical
研究领域:
药理学
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糖尿病
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治疗学
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纳米技术
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分子生物学
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PubMed
高影响因子
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