Biomaterials Science
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2021
·Vol. 9
·期 5
·1872-1885
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IF 6.843
Tiantian Zuo,Jun Zhang,Jie Yang,Rui Xu,Zongwei Hu,Zhihua Wang,Huizi Deng,Qi Shen
The desmoplastic tumor microenvironment (DTME), including overexpressed stromal cells and extracellular matrix, formed the first barrier for the accumulation and penetration of nanoparticles in tumors, which compromised the therapeutic efficacy and prognosis. In some metastatic cells, overactivity of the tricarboxylic cycle could overload the electron transport chain resulting in increased mtROS production, which triggered the mitochondria-driven tumor migration and metastasis. Hence, we developed HPBC@TRP/NPs for down-regulating the mtROS-PYK2 pathway and remodeling the DTME to inhibit tumor growth and metastasis for the first time. TPP-RSV prodrugs were synthesized and targeted at mitochondria, resulting in the scavenging of mtROS, lower PYK2 expression, and activation of the mitochondria-driven apoptotic pathway. Pirfenidone fully remodeled the DTME through inhibiting the expression of CAFs, hyaluronan and collagen I, thereby reducing IFP, eliminating the immunosuppressive microenvironment by decreasing the expression of TGF-β, and increasing the infiltration of cytotoxic T lymphocytes. The combination therapy of different mechanisms via targeting the mtROS-PYK2 pathway and CAFs might provide deeper insights into the inhibition of malignant breast cancer growth and metastasis.
研究领域:
肿瘤学
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药理学
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纳米医学
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2025
·
IF 6.2
Lei Diao,Yang Ma,Liping Wang,Peng Li,Bin Zhang,Weijing Meng,Jingzeng Cai,Yan Meng,Yuxun Zhou,Jingying Zhai,Huijie Chen
Thiacloprid (THI) is a synthetic insecticide, the misuse is targeted chiefly to control aphid pest species in orchards and vegetables. Melatonin (MET) is a hormone that plays crucial physiological roles in anti-inflammatory capacities of fish. We explored the function of MET (100 μM) to mitigate the toxicity induced by THI (20 μM) in lymphocytes. Our results indicate that THI led to a notable rise in lymphocyte mortality. Lymphocytes exposed to THI exhibited a heightened incidence of pyroptosis, accompanied by upregulation in expression associated with pyroptosis (NLRP3, GSDMEA, and IL-18). Meanwhile, THI exposure led to a decrease in lymphocyte mitochondrial membrane potential, an increase in mtROS levels, and a reduction in intracellular ATP, DNA, and NADPH/NADP+ levels, indicating an imbalance in the mitochondrial metabolism within the lymphocytes. Additionally, these effects were reversed by MET treatment, where MitoQ treatment showed that the suppression of mtROS reduced the lymphocyte pyroptosis caused by THI via the mtROS/cGAS-STING/NF-κB axis. Importantly, MET provided defense against the immunotoxic impacts of THI by ameliorating pyroptosis and enhancing anti-inflammatory capability via the mtROS/cGAS-STING/NF-κB axis. Our research potentiates the safeguarding of cultured fish from biological hazards caused by THI and highlights the valuable application of MET in common carp.
研究领域:
鱼类生理学
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环境毒理学
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免疫学
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2025
·
IF 6.2
Hao Zhang,Jia-Gen Cui,Ming-Shan Chen,Jia-Xin Wang,Xiao-Han Sun,Yi Zhao,Jin-Long Li
Di(2-ethylhexyl) phthalate (DEHP), which is widely used in agricultural plastics, accumulates in humans and animals through the food chain over time, resulting in liver toxicity. Recent studies have reported that pyroptosis and mitochondrial damage are closely related to a variety of liver diseases, but the specific mechanism is still unclear. To address this issue, in vitro and in vivo hepatotoxicity models were established. The results demonstrated that exposure to DEHP caused a buildup of MEHP in livers, altered liver metabolite composition, and caused pyroptosis-like changes in hepatocytes. After DEHP treatment, REDOX homeostasis was unbalanced, and mitochondrial reactive oxygen species (mtROS) were overproduced. MEHP exposure activates pyroptosis mediated by TNF/TNFR1 signaling and upregulates the perforating protein GSDMD-N to destroy the mitochondrial membrane of hepatocytes. Above all, this study elucidates the potential involvement of TNF/TNFR1 signaling-mediated pyroptosis in mitochondrial damage and confirms that the regulation of pyroptosis is helpful in maintaining normal mitochondrial function.
研究领域:
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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DOI
PubMed
高影响因子
POULTRY SCIENCE
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2025
·
IF 4.2
Shanxin Li,Gaohui Nie,Xueyan Dai,Jiamei Zhu,Li Xiao,Sunan Wang,Jirong Chen,Jianrong Ren,Caiying Zhang
Excessive molybdenum (Mo) and cadmium (Cd) exert negative influences on organism. Our prior experiments attested that Mo and Cd brought liver damage in ShaoXing ducks ( Anas platyrhyncha ); this injury mechanism has not yet been fully clarified. Hence, the hepatotoxicity mechanisms of Mo and Cd were roundly analyzed by network toxicology in the study, the analysis confirmed that Mo and Cd primarily induce liver injury through lipid metabolism dysregulation, oxidative stress, and mitochondrial dysfunction. Further validation demonstrated that Mo and/or Cd upregulated fatty acid synthesis, reduced PPARβ/δ-mediated fatty acid β-oxidation, promoted free fatty acids (FFA) content and mitochondrial reactive oxygen species (mtROS) level, impaired integrality of mitochondrial membrane and mitochondrial function, thereby causing fatty acid metabolism disarray and mitochondrial dysfunction. Both PPARβ/δ activator GW0742 and mtROS inhibitor ROS-IN-1 could alleviate the changes of above these indexes. Collectively, findings from this research showed that Cd and Mo additively caused crosstalk between fatty acid metabolism disarray and mitochondrial dysfunction, thus inducing liver injury in ducks.
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高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2023
·
IF 5
Changsheng Zhong,Yilin Xie,Huifang Wang,Wenxian Chen,Zhenbo Yang,Lei Zhang,Qin Deng,Ting Cheng,Mengyang Li,Jin Ju,Yanyan Liu,Haihai Liang
Diabetes cardiomyopathy (DCM) refers to myocardial dysfunction and disorganization resulting from diabetes. In this study, we investigated the effects of berberine on cardiac function in male db/db mice with metformin as a positive control. After treatment for 8 weeks, significant improvements in cardiac function and a reduction in collagen deposition were observed in db/db mice. Furthermore, inflammation and pyroptosis were seen to decrease in these mice, as evidenced by decreased expressions of p-mTOR, NOD-like receptor thermal protein domain associated protein 3 (NLRP3), IL-1β, IL-18, caspase-1, and gasdermin D (GSDMD). In vitro experiments on H9C2 cells showed that glucose exposure at 33 mmol/L induced pyroptosis, whereas berberine treatment reduced the expression of p-mTOR and NLRP3 inflammasome components. Moreover, berberine treatment was seen to inhibit the generation of mitochondrial reactive oxygen species (mtROS) and effectively improve cell damage in high glucose-induced H9C2 cells. The mTOR inhibitor, Torin-1, showed a therapeutic effect similar to that of berberine, by reducing the expression of NLRP3 inflammasome components and inhibiting mtROS generation. However, the activation of mTOR by MHY1485 partially nullified berberine's protective effects during high glucose stress. Collectively, our study reveals the mechanism that berberine regulates the mTOR/mtROS axis to inhibit pyroptosis induced by NLRP3 inflammasome activation, thereby alleviating DCM.
研究领域:
药理学
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心脏病学
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糖尿病
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细胞生物学
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炎症
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DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2024
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IF 3.3
Li Tao,Yu-Feng Xue,Fei-Fei Sun,Xue He,Hong-Qian Wang,Cheng-Cheng Tong,Cheng Zhang,De-Xiang Xu,Xi Chen
Ferroptosis has been shown to be involved in carbon tetrachloride (CCl 4 )-induced acute liver injury (ALI). The mitochondrion-targeted antioxidant MitoQ can eliminate the production of mitochondrial reactive oxygen species (mtROS). This study investigated the role of MitoQ in CCl 4 -induced hepatocytic ferroptosis and ALI. MDA and 4HNE were elevated in CCl 4 -induced mice. In vitro, CCl 4 exposure elevated the levels of oxidized lipids in HepG2 cells. Alterations in the mitochondrial ultrastructure of hepatocytes were observed in the livers of CCl 4 -evoked mice. Ferrostatin-1 (Fer-1) attenuated CCl 4 -induced hepatic lipid peroxidation, mitochondrial ultrastructure alterations and ALI. Mechanistically, acyl-CoA synthetase long-chain family member 4 (ACSL4) was upregulated in CCl 4 -exposed human hepatocytes and mouse livers. The ACSL4 inhibitor rosiglitazone alleviated CCl 4 -induced hepatic lipid peroxidation and ALI. ACSL4 knockdown inhibited oxidized lipids in CCl 4 -exposed human hepatocytes. Moreover, CCl 4 exposure decreased the mitochondrial membrane potential and OXPHOS subunit levels and increased the mtROS level in HepG2 cells. Correspondingly, MitoQ pretreatment inhibited the upregulation of ACSL4 in CCl 4 -evoked mouse livers and HepG2 cells. MitoQ attenuated lipid peroxidation in vivo and in vitro after CCl 4 exposure. Finally, MitoQ pretreatment alleviated CCl 4 -induced hepatocytic ferroptosis and ALI. These findings suggest that MitoQ protects against hepatocyte ferroptosis in CCl 4 -induced ALI via the mtROS-ACSL4 pathway.
研究领域:
医学
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生物化学
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DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
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2024
·
IF 4.2
Bendong Shi,Qiaohan Liu,Chenchen Xu,Ziwei Zhang,Jingzeng Cai
Chlorantraniliprole (CAP) is a bis-amide pesticide used for pest control mainly in agricultural production activities and rice-fish co-culture systems. CAP residues cause liver damage in non-target organism freshwater fish. However, it is unclear whether CAP-exposure-induced liver injury in fish is associated with mitochondrial dysfunction-mediated mitophagy, ferroptosis, and cytokines. Therefore, we established grass carp hepatocyte models exposed to different concentrations of CAP (20, 40, and 80 μM) in vitro. MitoSOX probe, JC-1 staining, immunofluorescence double staining, Fe 2+ staining, lipid peroxidation staining, qRT-PCR, and Western blot were used to verify the physiological regulatory mechanism of CAP induced liver injury. In the present study, the CAP-treated groups exhibited down-regulation of antioxidant-related enzyme activities and accumulation of peroxides. CAP treatment induced an increase in mitochondrial reactive oxygen species (mtROS) levels and altered expression of mitochondrial fission/fusion (Drp1, Fis1, Mfn1, Mfn2, and Opa1) genes in grass carp hepatocytes. In addition, mitophagy (Parkin, Pink1, p62, LC3II/I, and Beclin-1), ferroptosis (GPX4, COX2, ACSL4, FTH, and NCOA4), and cytokine (IFN-γ, IL-18, IL-17, IL-6, IL-10, IL-1β, IL-2, and TNF-α)-related gene expression was significantly altered. Collectively, these findings suggest that CAP exposure drives mitophagy activation, ferroptosis occurrence, and cytokine homeostasis imbalance in grass carp hepatocytes by triggering mitochondrial dysfunction mediated by the mtROS-mitochondrial fission/fusion axis. This study partly explained the physiological regulation mechanism of grass carp hepatocyte injury induced by insecticide CAP from the physiological and biochemical point of view and provided a basis for evaluating the safety of CAP environmental residues to non-target organisms.
研究领域:
毒理学
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环境科学
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细胞生物学
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水生生物学
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DOI
PubMed
高影响因子
Exploration
·
2025
·
IF 22.5
Xiaojing Shi,Shuya Wang,Tingli Xiong,Ruishi Li,Wenxuan Zheng,Wensheng Chen,Tianjiao Zhao,Yongqi Yang,Xiaohong Ying,Weimin Qi,Yingci Xia,Jue Wang,Yuqi Zhang,Qiong Huang,Yayun Nan,Kelong Ai
Protecting neuronal mitochondria by eliminating the mitochondrial ROS (mtROS) storm is crucial to abrogate the neuronal damage cascade of ischemic stroke ischemia reperfusion (ISIR), which is a long-standing challenge in the field of ischemic stroke (IS). Existing blood-brain barrier (BBB) penetration methods are usually unable to distinguish between healthy brain tissue and cerebral infarction tissue, and BBB targeting is not compatible with mitochondrial targeting, resulting in a huge barrier to the specific elimination of mtROS in neuronal mitochondria in ISIR. This study introduces an elegantly designed tannic acid, polydopamine, and Mo-based heteropolyacid ternary composite nanomedicine (TPM), which not only has a superb ability to eliminate multiple ROS thanks to the introduction of polydopamine, but also can actively recognize the injured BBB site, specifically enter the neurons in the cerebral infarction area, and then highly specifically target the mitochondria of neurons to efficiently eliminate mtROS. TPM could significantly inhibit neuronal apoptosis by protecting mitochondria and eliminate inflammation by inhibiting activation of the STING pathway, thereby significantly reducing the size of cerebral infarction. This sequential targeting of TPM from the injured BBB to neuronal mitochondria provides a promising strategy to treat ISIR in the clinical setting.
研究领域:
纳米医学
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神经病学
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脑卒中治疗
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活性氧清除
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药物递送
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产品关联
DOI
PubMed
高影响因子
FISH & SHELLFISH IMMUNOLOGY
·
2023
·
IF 4.7
Lei Diao,Wenjie Liu,Yawei Xu,Bin Zhang,Lingnan Meng,Rui Yin,Huijie Chen
Deoxynivalenol (DON) is one of the most common sources of fungal toxins in fish feed, posing a significant risk to the immune and reproductive systems of fish. Microalgal astaxanthin (MIA), a potent antioxidant derived from microalgae , confers multifarious advantages upon piscine organisms, notably encompassing its anti-inflammatory and antioxidant prowess. Herein, we investigated the potential of MIA in ameliorating the immunotoxicity of DON on carp (Cyprinus carpio L.) based on spleen lymphocytes treated with DON (1.5 ng/ml) and/or MIA (96 μM). Firstly, CCK8 results showed that DON resulted in excessive death of spleen lymphocytes. Secondly, spleen lymphocytes treated with DON had a higher proportion of pyroptosis , and the mRNA and protein levels of pyroptosis (NLRP3, IL-1β and ASC) in spleen lymphocytes were increased. Thirdly, the relative red fluorescence intensity of JC-1 and DCFH-DA showed decreased mitochondrial membrane potential and increased ROS in spleen lymphocytes treated with DON. Mitochondrial ATP, DNA and NADPH/NADP + analysis revealed decreased mitochondrial ATP, DNA and NADPH/NADP + levels in DON-treated lymphocytes, corroborating the association between DON exposure and elevated intracellular ATP, DNA and NADPH/NADP + in lymphocytes. DON exposure resulted in the downregulation of mitophagy-related genes and proteins (PINK1, Parkin and LC3) in lymphocytes. Notably, these effects were counteracted by treatment with MIA. Furthermore, DON led to the elevated secretion of inflammatory factors (TNF-α, IL-4 and IFN-γ), thereby inducing immune dysfunction in spleen lymphocytes. Encouragingly, MIA treatment effectively mitigated the immunotoxic effects induced by DON, demonstrating its potential in ameliorating pyroptosis, mitochondrial dysfunction and mitophagy impairment via regulating the mtROS-NF-κB axis in lymphocytes. This study sheds light on safeguarding farmed fish against agrobiological threats posed by DON, highlighting the valuable applications of MIA in aquaculture.
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高影响因子
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