Trichloroethylene and trichloroethanol induce skin sensitization with focal hepatic necrosis in guinea pigs

Zhao, Na; Song, Xiaolu; Naito, Hisao; Li, Hongling; Huang, Yifei; Liu, Huan; Lu, Fengrong; Cai, Tingfeng; Ito, Yuki; Kamijima, Michihiro; Huang, Hanlin; Nakajima, Tamie; Wang, Hailan

doi:10.1002/1348-9585.12142

Cited by 16 publications

(8 citation statements)

References 24 publications

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“…Skin allergy test of EK1 was performed on a guinea pig model as described. 44 Briefly, forty guinea pigs were randomly divided into vehicle control group, DNCB-treatment group, and EK1-treated group (4.0 mg/kg). Sensitization was carried out on the depilated area of left back three times on the 0th, 7th, and 14th day.…”

Section: Methodsmentioning

confidence: 99%

Structural and functional basis for pan-CoV fusion inhibitors against SARS-CoV-2 and its variants with preclinical evaluation

Xia

Lan

Zhu

et al. 2021

Sig Transduct Target Ther

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The COVID-19 pandemic poses a global threat to public health and economy. The continuously emerging SARS-CoV-2 variants present a major challenge to the development of antiviral agents and vaccines. In this study, we identified that EK1 and cholesterol-coupled derivative of EK1, EK1C4, as pan-CoV fusion inhibitors, exhibit potent antiviral activity against SARS-CoV-2 infection in both lung- and intestine-derived cell lines (Calu-3 and Caco2, respectively). They are also effective against infection of pseudotyped SARS-CoV-2 variants B.1.1.7 (Alpha) and B.1.1.248 (Gamma) as well as those with mutations in S protein, including N417T, E484K, N501Y, and D614G, which are common in South African and Brazilian variants. Crystal structure revealed that EK1 targets the HR1 domain in the SARS-CoV-2 S protein to block virus-cell fusion and provide mechanistic insights into its broad and effective antiviral activity. Nasal administration of EK1 peptides to hACE2 transgenic mice significantly reduced viral titers in lung and intestinal tissues. EK1 showed good safety profiles in various animal models, supporting further clinical development of EK1-based pan-CoV fusion inhibitors against SARS-CoV-2 and its variants.

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Section: Methodsmentioning

confidence: 99%

Structural and functional basis for pan-CoV fusion inhibitors against SARS-CoV-2 and its variants with preclinical evaluation

Xia

Lan

Zhu

et al. 2021

Sig Transduct Target Ther

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“…TCE was used primarily as an industrial solvent for the cleaning and degreasing of metals due to its good skim and decontamination properties (Dumas et al, 2018), which induced OMDT in partial occupational workers. The vast majority of OMDT patients present liver injury (Zhao et al, 2020) and animal experiments also reveal that TCE causes liver damage in mice. Liver macrophages play an important role in the liver pathophysiology, previous studies demonstrated that liver inflammation is linked to metabolic signals such as TNF‐α that induce cellular stress responses in liver macrophages including polarization and autophagy (Sun et al, 2020; Wang, Che, et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Macrophage autophagy contributes to immune liver injury in trichloroethylene sensitized mice: Critical role of TNF‐α mediating mTOR pathway

Ding

Zhou

Wang

et al. 2023

Journal Cellular Physiology

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Trichloroethylene (TCE) induces occupational medicamentosa‐like dermatitis due to TCE (OMDT) with immune liver injury, and TNF‐α plays an important role in macrophage polarization and liver injury. However, TNF‐α regulating macrophage polarization in liver injury induced by TCE is still unknown. Thus, on the basis of our previous research, we established the TCE‐sensitized BALB/c mouse model with R7050, a specific inhibitor of TNFR1. Then, we observed significant decreases in autophagy related protein and gene levels in M1 macrophage in TCE positive group, and R7050 can relieve M1 macrophage autophagy. We also found the phosphorylated form of mammalian target of Rapamycin (mTOR) was activated and the expression of p‐mTOR protein increased induce by TCE. In vitro, we found TNFR1 and CD11c were increased in RAW264.7 cell line with TNF‐α. And then we use Zafirlukast (Zaf), an TNFR1 antagonist, CD11c and TNFR1 reduced significantly, we also found p‐mTOR expression increased after TNF‐α treatment, but decreased in TNF‐α + Zaf group. Further, we used Rapamycin (RAP), a mTOR‐specific inhibitor, to establish a TCE‐sensitized mice model and found the expression levels of p62 and p‐mTOR proteins increased and LC3B decreased in the TCE positive group, while RAP treatment reversed the trends of all of these proteins. Rapamycin prevented the TNF‐α‐induced p‐mTOR increase and dramatically downregulated IL‐1β expression in the RAW264.7 cell line with TNF‐α treatment. The results uncover a novel role for TNF‐α/TNFR1, which promotes M1 polarization of macrophage and suppresses macrophage autophagy via the mTOR pathway.

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“…Patients who survive after high-dose glucocorticoid treatment are also often accompanied by multiple complications, such as hyperlipidemia, infection, and femoral head necrosis, and they can easily relapse. Due to its severity, OMDT has become one of the critical but unresolved issues in the field of dermatology and occupational health ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

IP3R-dependent mitochondrial dysfunction mediates C5b-9-induced ferroptosis in trichloroethylene-caused immune kidney injury

Liu

Zuo

et al. 2023

Front. Immunol.

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Patients with occupational medicamentose-like dermatitis due to trichloroethylene often suffer from immune kidney injury. Our previous study reveals that C5b-9-dependent cytosolic Ca2+ overload-induced ferroptosis is involved in trichloroethylene sensitized kidney injury. However, how C5b-9 causes cytosolic Ca2+ rise and the specific mechanism whereby overloaded Ca2+ induces ferroptosis remain unknown. The purpose of our study was to explore the role of IP3R-dependent mitochondrial dysfunction in C5b-9 mediated ferroptosis in trichloroethylene sensitized kidney. Our results showed that IP3R was activated, and mitochondrial membrane potential was decreased in the renal epithelial cells of trichloroethylene-sensitized mice, and these changes were antagonized by CD59, a C5b-9 inhibitory protein. Moreover, this phenomenon was reproduced in a C5b-9-attacked HK-2 cell model. Further investigation showed that RNA interference with IP3R not only alleviated C5b-9-induced cytosolic Ca2+ overload and mitochondrial membrane potential loss but also attenuated C5b-9-induced ferroptosis in HK-2 cells. Mechanistically, IP3R-dependent cytosolic Ca2+ overload activated the mitochondrial permeability transition pore, resulting in the loss of mitochondrial membrane potential and ferroptosis of HK-2 cells. Finally, cyclosporin A, a mitochondrial permeability transition pore inhibitor, not only ameliorated IP3R-dependent mitochondrial dysfunction but also blocked C5b-9-induced ferroptosis. Taken together, these results suggest that IP3R-dependent mitochondrial dysfunction plays an important role in trichloroethylene sensitized renal tubular ferroptosis.

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Trichloroethylene and trichloroethanol induce skin sensitization with focal hepatic necrosis in guinea pigs

Cited by 16 publications

References 24 publications

Structural and functional basis for pan-CoV fusion inhibitors against SARS-CoV-2 and its variants with preclinical evaluation

Structural and functional basis for pan-CoV fusion inhibitors against SARS-CoV-2 and its variants with preclinical evaluation

Macrophage autophagy contributes to immune liver injury in trichloroethylene sensitized mice: Critical role of TNF‐α mediating mTOR pathway

IP3R-dependent mitochondrial dysfunction mediates C5b-9-induced ferroptosis in trichloroethylene-caused immune kidney injury

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