Diabetology & Metabolic Syndrome
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2023
·Vol. 15
·期 1
·1-13
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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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高影响因子
BIOMATERIALS
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2015
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IF 8.557
Lei Zhang,Zhanzhuang Zeng,Chaohua Hu,Susan L. Bellis,Wendi Yang,Yintao Su,Xinyan Zhang,Yunkun Wu
Conventional oral vaccines with simple architecture face barriers with regard to stimulating effective immunity. Here we describe oral vaccines with an intelligent phase-transitional shielding layer, poly[(methyl methacrylate)-co-(methyl acrylate)-co-(methacrylic acid)]-poly( d , l -lactide-co-glycolide) (PMMMA-PLGA), which can protect antigens in the gastro-intestinal tract and achieve targeted vaccination in the large intestine. With the surface immunogenic protein (SIP) from group B Streptococcus (GBS) entrapped as the antigen, oral administration with PMMMA-PLGA (PTRBL)/Trx-SIP nanoparticles stimulated robust immunity in tilapia , an animal with a relatively simple immune system. The vaccine succeeded in protecting against Streptococcus agalactiae , a pathogen of worldwide importance that threatens human health and is transmitted in water with infected fish. After oral vaccination with PTRBL/Trx-SIP, tilapia produced enhanced levels of SIP specific antibodies and displayed durability of immune protection. 100% of the vaccinated tilapia were protected from GBS infection, whereas the control groups without vaccines or vaccinated with Trx-SIP only exhibited respective infection rates of 100% or >60% within the initial 5 months after primary vaccination. Experiments in vivo demonstrated that the recombinant antigen Trx-SIP labeled with FITC was localized in colon, spleen and kidney, which are critical sites for mounting an immune response. Our results revealed that, rather than the size of the nanoparticles, it is more likely that the negative charge repulsion produced by ionization of the carboxyl groups in PMMMA shielded the nanoparticles from uptake by small intestinal epithelial cells. This system resolves challenges arising from gastrointestinal damage to antigens, and more importantly, offers a new approach applicable for oral vaccination.
研究领域:
疫苗学
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免疫学
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水产养殖
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微生物学
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FOOD AND CHEMICAL TOXICOLOGY
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2021
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IF 6.025
Bangrong Cai,Mengya Liu,Jinxing Li,Dujuan Xu,Jiansheng Li
Chronic obstructive pulmonary disease (COPD) is widely recognized as a global public health problem and the third leading cause of mortality worldwide by 2020. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a dual-specificity protein and lipid phosphatase that plays an important role in COPD. However, the redox regulation of PTEN in the development of COPD was poorly studied. Our results showed that cigarette smoke extract (CSE) could oxidize PTEN in a time-dependent manner in BEAS-2B cells, whereas PTEN oxidation exposed to CSE was delayed compared to that of H 2 O 2. Additionally, we found that ROS derived from DUOX1 and 2 of NADPH oxidases were mainly responsible for oxidative inactivation PTEN, also simultaneously led to Trx-1 inactivation by dimerization . Oxidative mechanism of PTEN exposed to CSE was mediated by forming a disulfide bond between Cys 71 and Cys 124 , similar to H 2 O 2 . Inactivation of PTEN resulted in the increased phosphorylation of Akt. In conclusion, CSE exposure could elevate the intracellular ROS mainly from DUOX1 and 2 to oxidize PTEN and Trx-1 resulting in Akt activation, eventually cause the occurrence of COPD, suggesting that PTEN is a potential target for new therapies in COPD.
研究领域:
肺科学
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分子生物学
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细胞生物学
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氧化应激
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药理学
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Acta Biomaterialia
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2023
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IF 9.7
Yang Lin,Xiangwu Chen,Cancan Yu,Guixiang Xu,Xinxin Nie,Yufeng Cheng,Yuxia Luan,Qingxu Song
Ferroptosis has received increasing attentions in cancer therapy owing to its unique advantages over apoptosis. However, ferroptosis is governed by the efficiency of reactive oxygen species (ROS) production and the tumor cell antioxidant microenvironment that compromises therapeutic efficacy of ferroptosis. It is of great significance to develop a strategy that can both achieve high-efficiency ROS production and modulate tumor cell antioxidant microenvironment to amplify ferroptosis. However, until now, such a strategy has rarely been realized. Here, we, for the first time, reported a radiotherapy -mediated redox homeostasis-controllable nanomedicine for amplifying ferroptosis sensitivity in tumor therapy. The nanomedicine is constructed by co-assembling a ferroptosis inducer hemin and a thioredoxin 1 (Trx-1) inhibitor 1-methylpropyl 2-imidazolyl disulfide (PX-12) with human serum albumin . For our nanomedicine, hemin converts H 2 O 2 to ROS via Fenton reaction to induce ferroptosis while PX-12 effectively inhibits the activity of antioxidant Trx-1 to suppress ROS depletion, resulting in amplified ferroptosis. Particularly, combining radiotherapy with the nanomedicine, radiotherapy depletes the other key antioxidant glutathione and generates additional radiotherapy-induced ROS, further boosting the ferroptosis effect. Therefore, our strategy can simultaneously ensure efficient ROS production and regulation of tumor cell antioxidant microenvironment, thereby enhancing efficacy of ferroptosis in tumor therapy. Our work offers an innovative approach to amplify ferroptosis sensitivity against tumors by simultaneously promoting ROS production and regulating redox homeostasis . Statement of significance The antioxidants such as thioredoxin 1 (Trx-1) and glutathione (GSH) in tumor cells, are significantly upregulated by the innate cancer cellular redox homeostasis, severely restricting the reactive oxygen species (ROS)-based therapy and compromising the effect of Fenton reaction-induced ferroptosis against tumors. It is urgent to develop a strategy to simultaneously achieve Fenton reaction-induced ferroptosis and regulate the cancer cellular redox homeostasis against upregulated levels of Trx-1 and GSH. A radiotherapy-mediated redox homeostasis-regulatable nanomedicine was designed for amplifying ferroptosis sensitivity in tumor therapy, where the therapeutic efficacy of ferroptosis against tumors can be significantly amplified by integrating Fenton reaction-induced and radiotherapy-induced ferroptosis as well as PX-12-enabled inhibition of antioxidant Trx-1 and radiotherapy-induced downregulation of antioxidant GSH levels.
研究领域:
癌症治疗
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纳米技术
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氧化还原生物学
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药学
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高影响因子
Frontiers in Veterinary Science
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2024
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IF 2.6
Zhou Miao,Wu Zichen,Deng Donghua,Wang Bin,Zhou Xiaoling,Zhou Bingyu,Wang Chunping,Zeng Yan
Oxidative damage resulting from weaning stress significantly impacts the growth performance and health status of piglets. Taurine, a dietary antioxidant with diverse functions, was investigated in this study for its protective role against weaning stress-induced oxidative damage and its underlying mechanism. Forty 28-day-old male castrated weaned piglets were randomly assigned to four groups. The control group received the basal diet, while the experimental groups were fed the basal diet supplemented with 0.1, 0.2%, or 0.3% taurine over a 28-day period. In vitro, H2O2 was utilized to induce oxidative damage to the jejunal mucosa of piglets via IPEC-J2 cells. The results demonstrated that taurine supplementation reduced the incidence of diarrhea in piglets compared to that in the control group (p < 0.05); the addition of 0.2 and 0.3% taurine led to increased average daily gain and improved feed conversion efficiency in weaned piglets, showing a linear dose-response correlation (p < 0.05). Taurine supplementation at 0.2 and 0.3% enhanced the activities of serum CAT and GSH-Px while decreasing the levels of serum NO, XOD, GSSG, and MDA (p < 0.05). Moreover, it significantly elevated the levels of GSS, Trx, POD, complex I, mt-nd5, and mt-nd6, enhancing superoxide anion scavenging capacity and the hydroxyl-free scavenging rate in the livers of weaned piglets while reducing NO levels in the liver (p < 0.05). Additionally, 0.2 and 0.3% taurine supplementation decreased serum IL-6 levels and elevated the concentrations of IgA, IgG, and IL-10 in weaned piglets (p < 0.05). The levels of occludin, claudin, and ZO-1 in the jejunum mucosa of weaned piglets increased with 0.2 and 0.3% taurine supplementation (p < 0.05). In IPEC-J2 cells, pretreatment with 25 mM taurine for 24 h enhanced the activities of SOD and CAT; reduced the MDA content; upregulated the mRNA expression of various genes, including ZO-1, occludin, claudin-1, Nrf2, and HO-1; and reversed the oxidative damage induced by H2O2 exposure (p < 0.05). Overall, the findings suggest that the inclusion of 2 and 3% taurine in the diet can enhance growth performance, reduce diarrhea rates, ameliorate oxidative stress and inflammation, and promote intestinal barrier function in weaned piglets.
研究领域:
动物科学
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营养学
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生理学
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兽医学
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高影响因子
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