Cellular mechanisms of copper neurotoxicity in human, differentiated neurons DOI Creative Commons
Barbara Witt, Sharleen Friese, Valentin Walther

et al.

Archives of Toxicology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

Abstract Copper (Cu) is an essential trace element involved in fundamental physiological processes the human body. Even slight disturbances Cu homeostasis are associated with manifestation of neurodegenerative diseases. While suggesting a crucial role pathogenesis, exact mechanisms neurotoxicity onset and progression neurological diseases far from understood. This study focuses on molecular cellular Cu-mediated brain cells. First, cytotoxic potential was studied fully differentiated, neurons (LUHMES cells). Lysosomal integrity considerably affected following incubation 420 µM CuSO 4 for 48 h. Further mechanistic studies revealed mitochondria neuronal network as most susceptible target organelles (already at 100 , h), while generation reactive oxygen species turned out to be rather later consequence toxicity. Besides Cu, other elements might likely contribute pathology disorders. also effects levels magnesium, calcium, iron, manganese were observed neurons, presumably aggravating consequences neurotoxicity. In conclusion, insights underlying mode action will foster development treatment strategies against Particularly, interplay provide powerful diagnostic tool used therapeutic approach.

Language: Английский

Zinc Toxicity: Understanding the Limits DOI Creative Commons

Hannah Schoofs,

Joyce Schmit,

Lothar Rink

et al.

Molecules, Journal Year: 2024, Volume and Issue: 29(13), P. 3130 - 3130

Published: July 1, 2024

Zinc, a vital trace element, holds significant importance in numerous physiological processes within the body. It participates over 300 enzymatic reactions, metabolic functions, regulation of gene expression, apoptosis and immune modulation, thereby demonstrating its essential role maintaining overall health well-being. While zinc deficiency is associated with risks, an excess this element can also lead to harmful effects. According World Health Organization (WHO), 6.7 15 mg per day are referred be dietary reference value. An recommended daily intake may result symptoms such as anemia, neutropenia zinc-induced copper deficiency. The European Food Safety Authority (EFSA) defines tolerable upper level (UL) 25 day, whereas Drug Administration (FDA) allows 40 day. This review will summarize current knowledge regarding calculation UL other risks zinc. For example, not limited oral consumption; routes, inhalation or topical application, pose intoxication.

Language: Английский

Citations

36
Impact of perfluorooctanoic acid (PFOA) and perfluorobutanoic acid (PFBA) on oxidative stress and metabolic biomarkers in human neuronal cells (SH-SY5Y) DOI Creative Commons

Precious Obiako,

Solomon Ayisire,

Christie M. Sayes

et al.

Environment International, Journal Year: 2024, Volume and Issue: 190, P. 108864 - 108864

Published: July 2, 2024

Perfluorinated alkyl substances (PFAS) are pervasive environmental contaminants that have attracted considerable attention due to their widespread utilization, resilient characteristics, adverse health implications, and regulatory scrutiny. Despite documented toxicity in living organisms, the precise molecular mechanisms governing induced effects remain unclear. This study aims elucidate of toxic action by collecting empirical data sets along oxidative stress metabolic disruption pathways. We investigated impact long-chain PFAS (perfluorooctanoic acid (PFOA)) its short-chain analog (perfluorobutanoic (PFBA)) on human neuronal cells (SH-SY5Y). The functionalities enzymes associated with (catalase glutathione reductase) cellular metabolism (lactate dehydrogenase pyruvate dehydrogenase) were also characterized. Our results reveal a 24-hour exposure PFOA PFBA generated significant levels reactive oxygen species. Correspondingly, there was notable decline catalase reductase activities, demonstrating more pronounced effect. High concentrations reduced activity. Lactate activity only impacted high concentration PFBA, while decreased increased exposure. findings from this contribute knowledge cell interactions potential underlying PFAS-induced toxicity.

Language: Английский

Citations

5
Mechanisms of Copper-Induced Autophagy and Links with Human Diseases DOI Creative Commons
Yuanyuan Fu, Shuyan Zeng, Zhenlin Wang

et al.

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(1), P. 99 - 99

Published: Jan. 15, 2025

As a structural and catalytic cofactor, copper is involved in many biological pathways required for the biochemistry of all living organisms. However, excess intracellular can induce cell death due to its potential catalyze generation reactive oxygen species, thus homeostasis strictly regulated. And deficiency or accumulation connected with various pathological conditions. Since success platinum-based compounds clinical treatment types neoplasias, metal-based drugs have shown encouraging perspectives drug development. Compared platinum, an essential trace element that may better prospects development than platinum. Recently, therapeutic role copper-induced autophagy chronic diseases such as Parkinson’s, Wilson’s, cardiovascular disease has already been demonstrated. In brief, ions, numerous complexes, copper-based nano-preparations could autophagy, lysosome-dependent process plays important human diseases. this review, we not only focus on current advances elucidating mechanisms compounds/preparations regulation but also outline association between

Language: Английский

Citations

0
Manganese Exposure Enhances the Release of Misfolded α-Synuclein via Exosomes by Impairing Endosomal Trafficking and Protein Degradation Mechanisms DOI Open Access
Dharmin Rokad, Dilshan S. Harischandra, Manikandan Samidurai

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(22), P. 12207 - 12207

Published: Nov. 14, 2024

Excessive exposure to manganese (Mn) increases the risk of chronic neurological diseases, including Parkinson's disease (PD) and other related Parkinsonisms. Aggregated α-synuclein (αSyn), a hallmark PD, can spread neighboring cells by exosomal release from neurons. We previously discovered that Mn enhances its spread, triggering neuroinflammatory neurodegenerative processes. To better understand Mn-induced αSyn, we examined effect on endosomal trafficking misfolded protein degradation. Exposing MN9D dopaminergic neuronal stably expressing human wild-type (WT) αSyn 300 μM for 24 h significantly suppressed mRNA expression Rab11a, thereby downregulating recycling, forcing late endosomes mature into multivesicular bodies (MVBs). Ectopic WT Rab11a mitigated exosome release, whereas ectopic mutant (S25N) increased it. Our in vitro vivo studies reveal upregulated (1) levels Rab27a, which mediates fusion MVBs with plasma membrane; (2) autophagosomal markers Beclin-1 p62, but downregulated lysosomal marker LAMP2, impairing autophagolysosome formation as confirmed LysoTracker, cathepsin, acridine orange assays. novel findings demonstrate promotes

Language: Английский

Citations

1
Cellular mechanisms of copper neurotoxicity in human, differentiated neurons DOI Creative Commons
Barbara Witt, Sharleen Friese, Valentin Walther

et al.

Archives of Toxicology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

Abstract Copper (Cu) is an essential trace element involved in fundamental physiological processes the human body. Even slight disturbances Cu homeostasis are associated with manifestation of neurodegenerative diseases. While suggesting a crucial role pathogenesis, exact mechanisms neurotoxicity onset and progression neurological diseases far from understood. This study focuses on molecular cellular Cu-mediated brain cells. First, cytotoxic potential was studied fully differentiated, neurons (LUHMES cells). Lysosomal integrity considerably affected following incubation 420 µM CuSO 4 for 48 h. Further mechanistic studies revealed mitochondria neuronal network as most susceptible target organelles (already at 100 , h), while generation reactive oxygen species turned out to be rather later consequence toxicity. Besides Cu, other elements might likely contribute pathology disorders. also effects levels magnesium, calcium, iron, manganese were observed neurons, presumably aggravating consequences neurotoxicity. In conclusion, insights underlying mode action will foster development treatment strategies against Particularly, interplay provide powerful diagnostic tool used therapeutic approach.

Language: Английский

Citations

0