Oxidative Medicine and Cellular Longevity
·
2021
·
IF 6.543
Yanzhuo Zhang,Zhe Lv,Yudong Liu,Huan Cao,Jianwang Yang,Baoshan Wang
A growing amount of evidence has confirmed the crucial role of the prolyl isomerase PIN1 in aging and age-related diseases. However, the mechanism of PIN1 in age-related hearing loss (ARHL) remains unclear. Pathologically, ARHL is primarily due to the loss and dysfunction of hair cells (HCs) and spiral ganglion cells (SGCs) in the cochlea. Therefore, in this study, we aimed to investigate the role of PIN1 in protecting hair cells and auditory HEI-OC1 cells from senescence. Enzyme-linked immunosorbent assays, immunohistochemistry, and immunofluorescence were used to detect the PIN1 protein level in the serum of ARHL patients and C57BL/6 mice in different groups, and in the SGCs and HCs of young and aged C57BL/6 mice. In addition, a model of HEI-OC1 cell senescence induced by H2O2 was used. Adult C57BL/6 mice were treated with juglone, or juglone and NAC, for 4 weeks. Interestingly, we found that the PIN1 protein expression decreased in the serum of patients with ARHL, in senescent HEI-OC1 cells, and in the cochlea of aged mice. Moreover, under H2O2 and juglone treatment, a large amount of ROS was produced, and phosphorylation of p53 was induced. Importantly, PIN1 expression was significantly increased by treatment with the p53 inhibitor pifithrin-α. Overexpression of PIN1 reversed the increased level of p-p53 and rescued HEI-OC1 cells from senescence. Furthermore, PIN1 mediated cellular senescence by the PI3K/Akt/mTOR signaling pathway. In vivo data from C57BL/6 mice showed that treatment with juglone led to hearing loss. Taken together, these findings demonstrated that PIN1 may act as a vital modulator in hair cell and HEI-OC1 cell senescence.
研究领域:
衰老
·
听力科学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MATERIALS & DESIGN
·
2023
·
IF 8.4
Mingqiao Li,Hedan Xu,Nan Zhao,Liangjun Zhang,Haihan Xia,Xiaoxun Zhang,Qiao Li,Min Liao,Qiong Pan,Zeng Yi,Jin Chai
Acute liver injury (ALI) is one of the most important causes of liver failure, and there are no FDA-approved drugs that could therapy late-stage ALI. It has been shown in this study that HA-PEI, a molecule formed by covalently combining HA and PEI, can effectively treat advanced ALI. Through the CD44 receptor, HA-PEI could target the liver actively, with the highest liver-targeting effect confirmed at 1000 K. The underlying mechanism of protection of HA-PEI is by increasing oxygen content, reducing ROS, and maintaining mitochondrial membrane potential. HA-PEI also inhibits the secretion of inflammatory factors and blocks the migration of immune cells to the liver, protecting the hepatocytes not suffer from secondary damage. More importantly, for late-stage ALI, NAC, as the only FDA-approved drug, is completely ineffective, whereas HA-PEI has an excellent therapeutic effect. This work provides a new safe therapeutic agent for ALI, which has a bright application prospect.
研究领域:
药理学
·
肝病学
·
药物递送系统
·
炎症
·
氧化应激
✓ 已验证
产品关联
DOI
高影响因子
FISH & SHELLFISH IMMUNOLOGY
·
2022
·
IF 4.622
Xiaojing Li,Ruichen Bai,Yichen Bai,Xu Shi,Yuhong Yang,Shiwen Xu
Acetochlor is a high-volume herbicide whose widespread use threatens ecosystems and affects aquaculture. Apoptosis and autophagy are important causes of hepatotoxicity caused by toxicants, which can be mediated by oxidative stress and the inhibition of PPAR/RXR pathway. However, the mechanism of acetochlor on fish hepatocyte damage still needs to be further investigated. Therefore, we treated the Ctenopharyngodon idella hepatic cell line (L8824 cells) with different concentrations (10, 20, and 40 μM) of acetochlor and/or ROS scavenger NAC (1 mM) for 24 h. The results showed that acetochlor decreased the cell viability in a dose-dependent manner. AO/EB staining and flow cytometry verified the increased apoptotic rates . Quantitative analysis of gene expression levels or protein expression levels displayed that the expression levels of Beclin1, P62, LC3B, BAX, and cleaved Casp3 were increased, and the expression of BCL2 was reduced. Besides, we detected the increased ROS contents and decreased PPAR/RXR pathway expressions after acetochlor treatment. The clearance of ROS alleviated the inhibition of the PPAR/RXR pathway and lightened apoptosis and autophagy under acetochlor stress. Overall, these results revealed that acetochlor exposure triggered BCL2/BAX/Casp3-cascaded apoptosis and Beclin1-dependent autophagy through ROS-mediated PPAR/RXR inhibition. The results partially explain the toxicological mechanism of acetochlor and provide targets for the development of its antidote.
研究领域:
毒理学
·
细胞生物学
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环境科学
·
水产养殖
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2023
·
IF 4.3
Guoliang Chen,Juan Liu,Huiyun Wang,Mingxing Wang,Guixue Wang,Tingzhang Hu
SYP-3343 is a novel strobilurin fungicide with excellent and broad-spectrum antifungal activity , and its potential toxicity raises public health concerns. However, the vascular toxicity of SYP-3343 to zebrafish embryos is still not well understood. In the present study, we investigated the effects of SYP-3343 on vascular growth and its potential mechanism of action. SYP-3343 inhibited zebrafish endothelial cell (zEC) migration, altered nuclear morphology, and triggered abnormal vasculogenesis and zEC sprouting angiogenesis , resulting in angiodysplasia . RNA sequencing showed that SYP-3343 exposure altered the transcriptional levels of vascular development-related biological processes in zebrafish embryos including angiogenesis, sprouting angiogenesis, blood vessel morphogenesis , blood vessel development, and vasculature development. Whereas, the addition of NAC exerted an improvement effect on zebrafish vascular defects owing to SYP-3343 exposure. Additionally, SYP-3343 altered cell cytoskeleton and morphology, obstructed migration and viability, disrupted cell cycle progression, and depolarized mitochondrial membrane potential, as well as promoted apoptosis and reactive oxygen species (ROS) in HUVEC. SYP-3343 also caused an imbalance of the oxidation and antioxidant systems and irritated the alterations in the cell cycle- and apoptosis-related genes in HUVECs. Collectively, SYP-3343 has high cytotoxicity, possibly by up-regulating p53 and caspase3 expressions and bax/bcl-2 ratio via ROS, leading to malformed vascular development.
研究领域:
毒理学
·
发育生物学
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分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2023
·
IF 14.5
Yue Zhang,Jingwen Gao,Na Li,Peng Xu,Shimeng Qu,Jinqian Cheng,Mingrui Wang,Xueru Li,Yaheng Song,Fan Xiao,Xinyu Yang,Jihong Liu,Hao Hong,Ronghao Mu,Xiaotian Li,Youmei Wang,Hui Xu,Yuan Xie,Tianming Gao,Guangji Wang,Jiye Aa
Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.
研究领域:
神经科学
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药理学
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精神病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·
IF 12.6
Ce Li,Yichao Yuan,Yaqing Bao,Yeling Ni,Nan Chen,Jigang Piao,Lu Wang,Zhihong Zhu
Idiopathic pulmonary fibrosis (IPF), a chronic interstitial lung disease, is characterized by progressive fibrosis and poor prognosis, with no current therapies capable of reversing the fibrotic changes. The aberrant repair driven by fibroblast activation and an inflammatory microenvironment results in irreversible IPF. In this work, a macrophage-derived apoptotic body delivery system (SA + NAC@AB) co-loaded with sodium arsenite (SA) and N-acetylcysteine (NAC) was developed to exert synergistic antifibrotic activity against IPF via coordinated regulation of TGF-β1 signaling and inflammation. Apoptotic bodies derived from macrophages inherit inflammation-homing capability, enabling targeted delivery to fibrotic lesions. In vivo evaluation in a bleomycin-induced IPF mouse model demonstrated that SA + NAC@AB effectively targeted the lungs, significantly improved body weight and survival, and alleviated pulmonary fibrosis. Immunofluorescence and Western blot analyzes revealed that SA + NAC@AB reduced Smad2/3 phosphorylation and M2 macrophage polarization, indicating regulation of the TGF-β1/Smad2/3 pathway and inflammation as part of its mechanism of action. Furthermore, in vitro studies validated the enhanced efficacy of SA + NAC@AB, which significantly promoted fibroblast uptake, thereby potentiating its inhibitory effects on fibroblast viability, as well as TGF-β1-induced migration and differentiation. In conclusion, our study demonstrates that SA + NAC@AB represents an effective therapeutic strategy for IPF, offering a promising novel approach by modulating both the TGF-β1/Smad2/3 signaling pathway and the inflammatory response.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Qian Zhang,Shuai Fan,Mengjia Tang,Chenyu Wang,Xiaoxiao Li,Yuanyuan Jin,Zhaoyong Yang
The engineered human cystathionine-γ-lyase (hCGL) resulting in enhanced activity toward both cysteine and cystine unveils a potential robust antitumor activity. However, the presence of cysteine residues has the potential to induce oligomerization or incorrect disulfide bonding, which may decrease the bioavailability of biopharmaceuticals. Through a meticulous design process targeting the cysteine residues within engineered hCGL, a set of potential beneficial mutants were obtained by virtual screening employing Rosetta and ABACUS. Experimental measurements have revealed that most of the mutants showed increased activity toward both substrates l-Cys and CSSC. Furthermore, mutants C109V and C229D demonstrated Tm value increases of 8.2 and 1.8 °C, respectively. After an 80 min incubation at 60 °C, mutant C229D still maintained high residual activity. Unexpectedly, mutant C109V, displaying activity approximately 2-fold higher than the activity of wild type (WT) for both substrates, showed disappointing instability in plasma, which suggests that computational design still requires further consideration. Analysis of their structure and molecular dynamics (MD) simulation revealed the impact of hydrophobic interaction, hydrogen bonds, and near-attack conformation (NAC) stability on activity and stability. This study acquired information about mutants that exhibit enhanced activity or thermal resistance and serve as valuable guidance for subsequent specific cysteine modifications.
研究领域:
生物化学
·
蛋白质工程
·
分子生物学
·
计算生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2021
·
IF 7.963
Weike Shaoyong,Wanrong Zhang,Chenyang Wang,Zhongyun Kou,Wenlong Yong,Junheng Jiao,Wenyong Yan,Weijun Pang
Decabromodiphenyl ether (BDE-209), a congener of polybrominated diphenyl ethers (PBDEs), is used as a flame retardant and accounts for over 82% of total PBDE usage. BDE-209 has been found to be persistent in indoor and outdoor environments and has adverse health effects on humans. This study aimed to investigate the effects of BDE-209 on mouse intestinal tissues and reveal the underlying toxicological mechanisms. In this study, C57BL/6J male mice were administered BDE-209 intragastrically (200 mg/kg bodyweight) once a day for 4 weeks, after which intestinal tissues, blood samples, and fecal samples were collected for analysis. The results showed that BDE-209 exposure significantly decreased body weight ( P < 0.01) and promoted intestinal oxidative stress, apoptosis, autophagy, and inflammation. Additionally, BDE-209 reduced the intestinal mucus barrier and increased gut permeability. Importantly, BDE-209 decreased the levels of intestinal short-chain fatty acids (SCFAs), including acetic acid ( P < 0.05) and butyric acid ( P < 0.01), which protect gut health. Mechanistically, BDE-209 triggered apoptosis by damaging mitochondrial function, increasing both the release of mitochondrial cytochrome c (Cyt c) into the cytosol and the Bax/Bcl-2 ratio, as well as inducing activation of caspase-3, caspase-9, and PARP. Moreover, BDE-209 exposure induced intestinal inflammation via the TLR4/MyD88/NF-κB signaling pathway and promoted intestinal autophagy by upregulating Beclin 1, leading to the accumulation of LC3-I to LC3-II. Therapeutically, N -acetyl-L-cysteine (NAC) attenuated the effects of BDE-209 on gut toxicity, including intestinal permeability, apoptosis, and inflammation through the oxidative stress pathway. Overall, we suggest that BDE-209 causes gut toxicity by modulating the intestinal barrier, permeability, oxidative stress, autophagy, apoptosis, and inflammation, and BDE-209 exposure could be partly reversed by antioxidant NAC supplementation. Our findings provide new insights into the intestinal response to BDE-209 exposure.
研究领域:
毒理学
·
药理学
·
分子生物学
·
环境科学
✓ 已验证
DOI
高影响因子
ACS Applied Nano Materials
·
2023
·
IF 5.9
Qiang Feng,Hongting Xu,Xiaoyu Pan,Siqi Geng,Huifeng Qian,Chujie Wang,Ying Li,Jiaying Qin,Yiting Wu,Bangyi Zhou,Xiaoyu Liu,Zhiqiu Ye,Yingchun Xu,Zhangsen Yu
Acetaminophen (APAP), a common antipyretic and analgesic drug, is considered the most common cause of drug-induced liver injury (DILI). The mechanism of liver injury induced by APAP is mainly related to oxidative stress and inflammatory reaction. Herein, we report a simple and efficient one-step synthesis of Prussian blue (PB) nanozymes with multiple antioxidant enzymatic activities that effectively treat APAP-induced DILI. At the cellular level, reaching 10 μg/mL PB nanozymes can effectively scavenge intracellular reactive oxygen species (ROS), reduce mitochondrial membrane potential drop, and inhibit hepatocyte apoptosis. According to in vivo experimental studies, the levels of serum biochemical indicators and histopathological examination of DILI mice livers showed that 12.5 mg/kg PB nanozymes could effectively inhibit liver necrosis and 25 mg/kg PB nanozymes achieved the same therapeutic effect as 300 mg/kg NAC. More importantly, compared with NAC, PB nanozymes can still attenuate APAP-induced acute liver injury in mice after APAP-induced acute liver injury in mice for 3 h. Therefore, PB nanozymes can effectively prolong the therapeutic time window, revealing the potential of PB nanozymes in clinical applications for advanced DILI treatment. Furthermore, the therapeutic mechanism studies have shown that PB nanozymes with abundant and variable valence states could not only directly scavenge ROS but also through the Keap1-Nrf2/HO-1 pathway to reduce oxidative stress. Moreover, the decreased expression levels of myeloperoxidase and F4/80 in the liver, which are markers of neutrophil and macrophage infiltration, indicated that the Prussian blue nanozymes modulates inflammation to protect against APAP-induced acute liver injury. Consequently, our findings suggested that PB nanozymes have excellent clinical application prospects for acetaminophen-induced acute liver injury.
研究领域:
药理学
·
纳米医学
·
肝病学
·
生物化学
·
毒理学
✓ 已验证
产品关联
DOI
高影响因子
AICHE JOURNAL
·
2025
·
IF 4
Hanchi Chen,Shijie Lu,Liying Zha,Yazhou Lu,Qixin Wang,Linjiang Zhu,Xiaolong Chen
This study presents an approach combining molecular dynamics (MD) simulations and near-attack conformation (NAC) analysis to mine and engineer UDP-glucosyltransferases. Using the MD-NAC strategy, we identified that Bs YjiC from Bacillus subtilis possesses menthol glycosylating activity for the first time, and it exhibited a 28% higher k cat / K M value compared to the known l- menthol glycosylating enzyme, Bl YjiC from Bacillus licheniformis . The strategy was further employed to modify Bs YjiC by preventing nonproductive substrate motion and stabilizing NACs through engineering key residues identified by MD. Based on this strategy, 14 positive mutants were identified out of 16 candidates, and the double mutant A76D/V108L (M2) demonstrated a 10.64-fold increase in k cat / K M value compared to the starting point. Whole-cell cascade reactions with sucrose synthase yield 160 mM glucoside after catalyzing for 96 h, demonstrating its application merit. This work underscores MD-driven enzyme engineering as a promising strategy to overcome limitations of static structure-based approaches.
研究领域:
结构生物学
·
计算生物学
·
酶工程
·
生物化学
·
合成生物学
✓ 已验证
产品关联
DOI
高影响因子
TALANTA
·
2023
·
IF 6.1
Guanyi Lu,Haowen Fan,Kaidong Wang,Gaonan Tian,Chaoyan Chen,Yao Wang,Lei Wang,Xiangjun Fan
Herein, a fluorescent probe, GYP , was developed for the detection of ONOO − in KA-induced epileptic brains. In solution, as a ratiometric probe, GYP indicated practical properties including steadiness under wide pH range (3.0–12.0), rapid response (within 20 s), stability over 48 h, high sensitivity (LOD = 0.27 μM) and high selectivity. In living PC12 cells, in spite of the low toxicity, GYP could achieve the time-dependent and dose-dependent imaging of ONOO − , while the generation and elimination were checked by introduction of SIN-1 and NAC, respectively. Further, GYP could cross Blood-Brain Barrier (BBB) rapidly and steadily during the imaging in KA-induced mice epileptic brain model. Thus, this work raised a practical implement for the detection of ONOO − in brain region, which might be helpful for further understanding of the epilepsy mechanism in future.
研究领域:
神经科学
·
化学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2024
·Vol. 28
·期 20
·e70127
·
IF 4.3
Ming Zhang,Guan-Chun Dai,Yuan-Wei Zhang,Pan-Pan Lu,Hao Wang,Ying-Juan Li,Yun-Feng Rui
Diabetic calcific tendinopathy is the leading cause of chronic pain, mobility restriction, and tendon rupture in patients with diabetes. Tendon stem/progenitor cells (TSPCs) have been implicated in the development of diabetic calcified tendinopathy, but the molecular mechanisms remain unclear. This study found that diabetic tendons have a hyperoxic environment, characterized by increased oxygen delivery channels and carriers. In hyperoxic environment, TSPCs showed enhanced osteogenic differentiation and increased levels of reactive oxygen species (ROS). Additionally, hypoxia-inducible factor-1a (HIF-1a), a protein involved in regulating cellular responses to hyperoxia, was decreased in TSPCs by the ubiquitin-proteasome system. By intervening with antioxidant N-acetyl-L-cysteine (NAC) and overexpressing HIF-1a, we discovered that blocking the ROS/HIF-1a signalling axis significantly inhibited the osteogenic differentiation ability of TSPCs. Animal experiments further confirmed that hyperoxic environment could cause calcification in the Achilles tendon tissue of rats, while NAC intervention prevented calcification. These findings demonstrate that hyperoxia in diabetic tendons promotes osteogenic differentiation of TSPCs through the ROS/HIF-1a signalling axis. This study provides a new theoretical basis and research target for preventing and treating diabetic calcified tendinopathy.
研究领域:
糖尿病
·
干细胞生物学
·
细胞信号传导
·
骨科
·
分子生物学
✓ 已验证
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）