Exposure to zinc induces lysosomal-mitochondrial axis-mediated apoptosis in PK-15 cells

Yang, Qingwen; Fang, Yudong; Zhang, Chuanshi; Liu, Xuesong; Wu, Yuehua; Zhang, Yi; Yang, Junjie; Yong, Kang

doi:10.1016/j.ecoenv.2022.113716

Cited by 17 publications

(10 citation statements)

References 40 publications

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“…Lysosomes are important targets in heavy metal damage, and cathepsins released from lysosomes can cause cell damage in various ways. 26 CA074 has been demonstrated to specifically disrupt cathepsin B activity. 27,28 Because the methylated form of CA074 (CA074-Me) has high membrane permeability and can transform rapidly into its unmethylated form, it is suitable and reasonable to use CA074-Me for cathepsin B suppression.…”

Section: Resultsmentioning

confidence: 99%

“…Tao et al discovered that arsenic causes damage to hepatic stellate cells (HSCs) cell through the autophagic-CTSB-NLRP3 inflammasome pathway. 43,44 Yang et al 26 revealed that excess zinc increases the levels of cathepsin B/D in PK-15 cells. Herein, we confirmed that the increased cathepsin B could destroy lysosomes and connect the lysosome-mitochondrial pathway by observing LMP after using a cathepsin inhibitor (CA074-Me).…”

Section: Discussionmentioning

confidence: 99%

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Cathepsin B mediates the lysosomal-mitochondrial apoptosis pathway in arsenic-induced microglial cell injury

Zhang

Jiang

et al. 2023

Hum Exp Toxicol

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Arsenic is a prevalent environmental pollutant that targets the nervous system of living beings. Recent studies indicated that microglial injury could contribute to neuroinflammation and is associated with neuronal damage. Nevertheless, the neurotoxic mechanism underlying the arsenic-induced microglial injury requires additional research. This study explores whether cathepsin B promotes microglia cell damage caused by NaAsO2. Through CCK-8 assay and Annexin V-FITC and PI staining, we discovered that NaAsO2 induced apoptosis in BV2 cells (a microglia cell line). NaAsO2 was verified to increase mitochondrial membrane permeabilization (MMP) and promote the generation of reactive oxygen species (ROS) through JC-1 staining and DCFDA assay, respectively. Mechanically, NaAsO2 was indicated to increase the expression of cathepsin B, which could stimulate pro-apoptotic molecule Bid into the activated form, tBid, and increase lysosomal membrane permeabilization by Immunofluorescence and Western blot assessment. Subsequently, apoptotic signaling downstream of increased mitochondrial membrane permeabilization was activated, promoting caspase activation and microglial apoptosis. Cathepsin B inhibitor CA074-Me could mitigate the damage of microglial. In general, we found that NaAsO2 induced microglia apoptosis and depended on the role of the cathepsin B-mediated lysosomal-mitochondrial apoptosis pathway. Our findings provided new insight into NaAsO2-induced neurological damage.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cathepsin B mediates the lysosomal-mitochondrial apoptosis pathway in arsenic-induced microglial cell injury

Zhang

Jiang

et al. 2023

Hum Exp Toxicol

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“…High intracellular levels of zinc are known to be damaging and pro-apoptotic in many cell types [ 44 , 45 , 46 ]. Several signaling pathways activated in response to venom are linked to alterations in intracellular zinc.…”

Section: Discussionmentioning

confidence: 99%

Intracellular Zinc Trafficking during Crotalus atrox Venom Wound Development

Albrecht

Carter

Garbar

et al. 2023

IJMS

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In this study, we examined zinc trafficking in human umbilical vein endothelial cells (HUVEC) stimulated with Crotalus atrox (CA venom) snake venom. We utilized MTS cytotoxicity assays to monitor the cytotoxic range of CA venom. HUVEC monolayers stimulated with 10 µg/mL CA venom for 3 h displayed cellular retraction, which coincided with 53.0 ± 6.5 percent viability. In contrast, venom concentrations of 100 µg/mL produced a complete disruption of cellular adherence and viability decreased to 36.6 ± 1.0. The zinc probe Fluozin-3AM was used to detect intracellular zinc in non-stimulated controls, HUVEC stimulated with 10 µg/mL CA venom or HUVEC preincubated with TPEN for 2 h then stimulated with 10 µg/mL CA venom. Fluorescent intensity analysis returned values of 1434.3 ± 197.4 for CA venom demonstrating an increase of about two orders of magnitude in labile zinc compared to non-stimulated controls. Endothelial response to CA venom induced a 96.1 ± 3.0- and 4.4 ± 0.41-fold increase in metallothionein 1X (MT1X) and metallothionein 2A (MT2A) gene expression. Zinc chelation during CA venom stimulation significantly increased cell viability, suggesting that the maintenance of zinc homeostasis during envenomation injury improves cell survival.

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“…In PK-15 cells, zinc sulfate supplementation in media from 50 µM onward exhibited toxicity. [ 1 ] Nobody should doubt that zinc is a toxic metal in high doses, but it also has several physiological functions. [ 2 ] Consequently, toxic dose determination of zinc preparations is a matter of considerable current interest.…”

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confidence: 99%

“…[ 3 ] Based on this, it appears that within the chosen experimental conditions, zinc sulfate acted as the culprit, not the zinc alone. [ 1 ] It is essential to reproduce such results, particularly with nontoxic zinc formulations like zinc histidinate. [ 3 ] Further, at 50 µM concentration, the zinc sulfate is toxic to PK-15 cells.…”

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confidence: 99%