Defective mitochondria and autophagy, as well as accumulation of lipid and iron in WDR45 mutant fibroblasts, is related to beta-propeller protein-associated neurodegeneration (BPAN). In this study, we found that enlarged lysosomes in cells derived from patients with BPAN had low enzyme activity, and most of the enlarged lysosomes had an accumulation of iron and oxidized lipid. Cryo-electron tomography revealed elongated lipid accumulation, and spectrometry-based elemental analysis showed that lysosomal iron and oxygen accumulation superimposed with lipid aggregates. Lysosomal lipid aggregates superimposed with autofluorescence as free radical generator, lipofuscin. To eliminate free radical stress by iron accumulation in cells derived from patients with BPAN, we investigated the effects of the iron chelator, 2,2'-bipyridine (bipyridyl, BIP). To study whether the defects in patient-derived cells can be rescued by an iron chelator BIP, we tested whether the level of iron and reactive oxygen species (ROS) in the cells and genes related to oxidative stress were rescued BIP treatment. Although BIP treatment decreased some iron accumulation in the cytoplasm and mitochondria, the accumulation of iron in the lysosomes and levels of cellular ROS were unaffected. In addition, the change of specific RNA levels related to free radical stress in patient fibroblasts was not rescued by BIP. To alleviate free radical stress, we investigated whether l-serine can regulate abnormal structures in cells derived from patients with BPAN through the regulation of free radical stress. l-serine treatment alleviated increase of enlarged lysosomes and iron accumulation and rescued impaired lysosomal activity by reducing oxidized lipid accumulation in the lysosomes of the cells. Lamellated lipids in the lysosomes of the cells were identified as lipofuscin through correlative light and electron microscopy, and l-serine treatment reduced the increase of lipofuscin. These data suggest that l-serine reduces oxidative stress-mediated lysosomal lipid oxidation and iron accumulation by rescuing lysosomal activity.

01 Mar 2024·Science of The Total Environment

New insights into estimation of bioavailable inorganic phosphorus in natural coastal seawater

Article

Author: Liang, Yan ; Wei, Hong ; Pan, Dawei ; Gai, Guowei ; Fan, Xia

Considering the impact of the high salinity and high turbidity of coastal seawater on phosphorus forms, a new method was proposed to determine bioavailable inorganic phosphorus (BIP). The phosphorus most relevant to eutrophication is BIP, and traditional analysis methods may underestimate the degree of eutrophication. In this study, a microelectrode of multigold (AuμE) was fabricated for direct voltammetric determination of BIP without filtration, and BIP environmental characteristics including distribution and correlation relationships with environmental factors in typical coastal seawater of Northern China were analyzed. The proposed AuμE showed a low detection limit of 0.03 μM. The surface and bottom BIP concentrations ranged from 1.00 to 2.13 and from 0.88 to 2.05 μM, respectively. BIP dominated the total P (TP) accounting for 48.5-67.5 % in the surface layer samples, and 32.6-92.7 % in the bottom layer samples, respectively. The concentrations of BIP were obviously higher than those of DIP, indicating that DIP may underestimate the probability of eutrophication occurring. And BIP was positively correlated with dissolved oxygen (DO) (P < 0.05). BIP may be a promising indicator of eutrophication potential in coastal areas with high salinity and high turbidity. The proposed reliable voltammetry method provides a new indicator for environmental assessment and represents a significant step in the comprehensive analysis of P species.

01 Nov 2023·Free Radical Biology and Medicine

Azoramide prevents MPP+-induced dopaminergic neuronal death via upregulating ER chaperone BiP expression

Article

Author: Yuan, Mingzhe ; Qu, Shuhui ; Ai, Nana ; Ge, Wei ; Su, Huanxing ; Vong, Chi Teng ; Chong, Cheong-Meng ; Wang, Danni

Progressive death of dopaminergic (DA) neurons is the main cause of Parkinson's disease (PD). The discovery of drug candidates to prevent DA neuronal death is required to address the pathological aspects and alter the process of PD. Azoramide is a new small molecule compound targeting ER stress, which was originally developed for the treatment of diabetes. In this study, pre-treatment with Azoramide was found to suppress mitochondria-targeting neurotoxin MPP⁺-induced DA neuronal death and locomotor defects in zebrafish larvae. Further study showed that pre-treatment with Azoramide significantly attenuated MPP⁺-induced SH-SY5Y cell death by reducing aberrant changes in nuclear morphology, mitochondrial membrane potential, intracellular reactive oxygen species, and apoptotic biomarkers. The mechanistic study revealed that Azoramide was able to up-regulate the expression of ER chaperone BiP and thereby prevented MPP⁺-induced BiP decrease. Furthermore, pre-treatment with Azoramide failed to suppress MPP⁺-induced cytotoxicity in the presence of the BiP inhibitor HA15. Taken together, these results suggested that Azoramide is a potential neuroprotectant with pro-survival effects against MPP⁺-induced cell death through up-regulating BiP expression.

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