bims-metalz 2024-05-12 papers

bims-metalz

Biomed News

on Metabolic causes of Alzheimer’s disease

Issue of 2024–05–12
seven papers selected by
Mikaila Chetty, Goa University

Copper Homeostasis in the Model Organism C. elegans.
Flavin-containing monooxygenase (FMO): Beyond xenobiotics.
2-Butoxytetrahydrofuran, Isolated from Holothuria scabra, Attenuates Aggregative and Oxidative Properties of α-Synuclein and Alleviates Its Toxicity in a Transgenic Caenorhabditis elegans Model of Parkinson's Disease.
Effects of dissolved organic matter on the environmental behavior and toxicity of metal nanomaterials: A review.
Barley Protein LFBEP-C1 from Lactiplantibacillus plantarum dy-1 Fermented Barley Extracts by Inhibiting Lipid Accumulation in a Caenorhabditis elegans Model.
Epigenetic modifications of DNA and RNA in Alzheimer's disease.
Rosmarinic acid ameliorated oxidative stress, neuronal injuries, and mitochondrial dysfunctions mediated by polyglutamine and ɑ-synuclein in Caenorhabditis elegans models.

Cells. 2024 Apr 23. pii: 727. [Epub ahead of print]13(9):

Copper Homeostasis in the Model Organism C. elegans.

Verena Alexia Ohse, Lars-Oliver Klotz, Josephine Priebs.

  Cellular and organismic copper (Cu) homeostasis is regulated by Cu transporters and Cu chaperones to ensure the controlled uptake, distribution and export of Cu ions. Many of these processes have been extensively investigated in mammalian cell culture, as well as in humans and in mammalian model organisms. Most of the human genes encoding proteins involved in Cu homeostasis have orthologs in the model organism, Caenorhabditis elegans (C. elegans). Starting with a compilation of human Cu proteins and their orthologs, this review presents an overview of Cu homeostasis in C. elegans, comparing it to the human system, thereby establishing the basis for an assessment of the suitability of C. elegans as a model to answer mechanistic questions relating to human Cu homeostasis.

Keywords:  C. elegans; copper deficiency; copper toxicity; copper transport; reactive oxygen species

DOI:  https://doi.org/10.3390/cells13090727
Bioessays. 2024 May 07. e2400029

Flavin-containing monooxygenase (FMO): Beyond xenobiotics.

Ajay Bhat, Faith R Carranza, Angela M Tuckowski, Scott F Leiser.

Flavin-containing monooxygenases (FMOs), traditionally known for detoxifying xenobiotics, are now recognized for their involvement in endogenous metabolism. We recently discovered that an isoform of FMO, fmo-2 in Caenorhabditis elegans, alters endogenous metabolism to impact longevity and stress tolerance. Increased expression of fmo-2 in C. elegans modifies the flux through the key pathway known as One Carbon Metabolism (OCM). This modified flux results in a decrease in the ratio of S-adenosyl-methionine (SAM) to S-adenosyl-homocysteine (SAH), consequently diminishing methylation capacity. Here we discuss how FMO-2-mediated formate production during tryptophan metabolism may serve as a trigger for changing the flux in OCM. We suggest formate bridges tryptophan and OCM, altering metabolic flux away from methylation during fmo-2 overexpression. Additionally, we highlight how these metabolic results intersect with the mTOR and AMPK pathways, in addition to mitochondrial metabolism. In conclusion, the goal of this essay is to bring attention to the central role of FMO enzymes but lack of understanding of their mechanisms. We justify a call for a deeper understanding of FMO enzyme's role in metabolic rewiring through tryptophan/formate or other yet unidentified substrates. Additionally, we emphasize the identification of novel drugs and microbes to induce FMO activity and extend lifespan.

DOI: https://doi.org/10.1002/bies.202400029
ACS Chem Neurosci. 2024 May 10.

2-Butoxytetrahydrofuran, Isolated from Holothuria scabra, Attenuates Aggregative and Oxidative Properties of α-Synuclein and Alleviates Its Toxicity in a Transgenic Caenorhabditis elegans Model of Parkinson's Disease.

Sukrit Promtang, Tanatcha Sanguanphun, Pawanrat Chalorak, Laurence S Pe, Nakorn Niamnont, Prasert Sobhon, Krai Meemon.

  Aggregative α-synuclein and incurring oxidative stress are pivotal cascading events, leading to dopaminergic (DAergic) neuronal loss and contributing to clinical manifestations of Parkinson's disease (PD). Our previous study demonstrated that 2-butoxytetrahydrofuran (2-BTHF), isolated from Holothuria scabra (H. scabra), could inhibit amyloid-β aggregation and its ensuing toxicity, which leads to Alzheimer's disease. In the present study, we found that 2-BTHF also attenuated the aggregative and oxidative activities of α-synuclein and lessened its toxicity in a transgenic Caenorhabditis elegans (C. elegans) PD model. Such worms treated with 100 μM of 2-BTHF showed substantial reductions in α-synuclein accumulation and DAergic neurodegeneration. Mechanistically, 2-BTHF, at this concentration, significantly decreased aggregation of monomeric α-synuclein and restored locomotion and dopamine-dependent behaviors. Molecular docking exhibited potential bindings of 2-BTHF to HSF-1 and DAF-16 transcription factors. Additionally, 2-BTHF significantly increased the mRNA transcripts of genes encoding proteins involved in proteostasis, including the molecular chaperones hsp-16.2 and hsp-16.49, the ubiquitination/SUMOylation-related ubc-9 gene, and the autophagy-related genes atg-7 and lgg-1. Transcriptomic profiling revealed an additional mechanism of 2-BTHF in α-synuclein-expressing worms, which showed upregulation of PPAR signaling cascades that mediated fatty acid metabolism. 2-BTHF significantly restored lipid deposition, upregulated the fat-7 gene, and enhanced gcs-1-mediated glutathione synthesis in the C. elegans PD model. Taken together, this study demonstrated that 2-BTHF could abrogate aggregative and oxidative properties of α-synuclein and attenuate its toxicity, thus providing a possible therapeutic application for the treatment of α-synuclein-induced PD.

Keywords:  2-butoxytetrahydrofuran; C. elegans; Holothuria scabra; antiaggregation; antioxidation; α-synuclein toxicity

DOI:  https://doi.org/10.1021/acschemneuro.4c00008
Chemosphere. 2024 May 02. pii: S0045-6535(24)01101-9. [Epub ahead of print]358 142208

Effects of dissolved organic matter on the environmental behavior and toxicity of metal nanomaterials: A review.

Xiaoqing Yang, Zhangjia Wang, Jiake Xu, Cheng Zhang, Peng Gao, Lusheng Zhu.

  Metal nanomaterials (MNMs) have been released into the environment during their usage in various products, and their environmental behaviors directly impact their toxicity. Numerous environmental factors potentially affect the behaviors and toxicity of MNMs with dissolved organic matter (DOM) playing the most essential role. Abundant facts showing contradictory results about the effects of DOM on MNMs, herein the occurrence of DOM on the environmental process change of MNMs such as dissolution, dispersion, aggregation, and surface transformation were summarized. We also reviewed the effects of MNMs on organisms and their mechanisms in the environment such as acute toxicity, oxidative stress, oxidative damage, growth inhibition, photosynthesis, reproductive toxicity, and malformation. The presence of DOM had the potential to reduce or enhance the toxicity of MNMs by altering the reactive oxygen species (ROS) generation, dissolution, stability, and electrostatic repulsion of MNMs. Furthermore, we summarized the factors that affected different toxicity including specific organisms, DOM concentration, DOM types, light conditions, detection time, and production methods of MNMs. However, the more detailed mechanism of interaction between DOM and MNMs needs further investigation.

Keywords:  Adsorption; Dissolution; Environmental behavior; Metal ions; Oxidative stress

DOI:  https://doi.org/10.1016/j.chemosphere.2024.142208
Biomed Environ Sci. 2024 Apr 20. 37(4): 377-386

Barley Protein LFBEP-C1 from Lactiplantibacillus plantarum dy-1 Fermented Barley Extracts by Inhibiting Lipid Accumulation in a Caenorhabditis elegans Model.

Jia Yan Zhang, Meng Ting Liu, Yu Hao Liu, Huan Deng, Juan Bai, Jian Hua Xie, Xiang Xiao.

   Objective: This study aimed to investigate the lipid-lowering activity of LFBEP-C1 in high glucose-fed Caenorhabditis elegans (C. elegans).
Methods: In this study, the fermented barley protein LFBEP-C1 was prepared and tested for its potential anti-obesity effects on C. elegans. The worms were fed Escherichia coli OP50 ( E. coli OP50), glucose, and different concentrations of LFBEP-C1. Body size, lifespan, movement, triglyceride content, and gene expression were analyzed. The results were analyzed using ANOVA and Tukey's multiple comparison test.
Results: Compared with the model group, the head-swing frequency of C. elegans in the group of LFBEP-C1 at 20 μg/mL increased by 33.88%, and the body-bending frequency increased by 27.09%. This indicated that LFBEP-C1 improved the locomotive ability of C. elegans. The average lifespan of C. elegans reached 13.55 days, and the body length and width of the C. elegans decreased after LFBEP-C1 intake. Additionally, LFBEP-C1 reduced the content of lipid accumulation and triglyceride levels. The expression levels of sbp-1, daf-2, and mdt-15 significantly decreased, while those of daf-16, tph-1, mod-1, and ser-4 significantly increased after LFBEP-C1 intake. Changes in these genes explain the signaling pathways that regulate lipid metabolism.
Conclusion: LFBEP-C1 significantly reduced lipid deposition in C. elegans fed a high-glucose diet and alleviated the adverse effects of a high-glucose diet on the development, lifespan, and exercise behavior of C. elegans. In addition, LFBEP-C1 regulated lipid metabolism mainly by mediating the expression of genes in the sterol regulatory element-binding protein, insulin, and 5-hydroxytryptamine signaling pathways.

Keywords:  Caenorhabditis elegans; Fermentation; LFBEP-C1; Lipid accumulation; Protein; Signaling pathway

DOI:  https://doi.org/10.3967/bes2024.042
Front Mol Neurosci. 2024 ;17 1398026

Epigenetic modifications of DNA and RNA in Alzheimer's disease.

Paula Martinez-Feduchi, Peng Jin, Bing Yao.

  Alzheimer's disease (AD) is a complex neurodegenerative disorder and the most common form of dementia. There are two main types of AD: familial and sporadic. Familial AD is linked to mutations in amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2). On the other hand, sporadic AD is the more common form of the disease and has genetic, epigenetic, and environmental components that influence disease onset and progression. Investigating the epigenetic mechanisms associated with AD is essential for increasing understanding of pathology and identifying biomarkers for diagnosis and treatment. Chemical covalent modifications on DNA and RNA can epigenetically regulate gene expression at transcriptional and post-transcriptional levels and play protective or pathological roles in AD and other neurodegenerative diseases.

Keywords:  Alzheimer’s disease; DNA methylation; RNA modifications; circRNAs; epigenetics; lncRNAs; miRNAs; non-coding RNAs

DOI:  https://doi.org/10.3389/fnmol.2024.1398026
Mol Neurobiol. 2024 May 04.

Rosmarinic acid ameliorated oxidative stress, neuronal injuries, and mitochondrial dysfunctions mediated by polyglutamine and ɑ-synuclein in Caenorhabditis elegans models.

Yun Chen, Ruina Xu, Qiaoxing Liu, Yanting Zeng, Weitian Chen, Yongfa Liu, Yong Cao, Guo Liu, Yunjiao Chen.

  Numerous natural antioxidants have been developed into agents for neurodegenerative diseases (NDs) treatment. Rosmarinic acid (RA), an excellent antioxidant, exhibits neuroprotective activity, but its anti-NDs efficacy remains puzzling. Here, Caenorhabditis elegans models were employed to systematically reveal RA-mediated mechanisms in delaying NDs from diverse facets, including oxidative stress, the homeostasis of neural and protein, and mitochondrial disorders. Firstly, RA significantly inhibited reactive oxygen species accumulation, reduced peroxide malonaldehyde production, and strengthened the antioxidant defense system via increasing superoxide dismutase activity. Besides, RA reduced neuronal loss and ameliorated polyglutamine and ɑ-synuclein-mediated dyskinesia in NDs models. Further, in combination with the data and molecular docking results, RA may bind specifically to Huntington protein and ɑ-synuclein to prevent toxic protein aggregation and thus enhance proteostasis. Finally, RA ameliorated mitochondrial dysfunction including increasing adenosine triphosphate and mitochondrial membrane potential levels and rescuing mitochondrial membrane proteins' expressions and mitochondrial structural abnormalities via regulating mitochondrial dynamics genes and improving the mitochondrial kinetic homeostasis. Thus, this study systematically revealed the RA-mediated neuroprotective mechanism and promoted RA as a promising nutritional intervention strategy to prevent NDs.

Keywords:   Caenorhabditis elegans ; Mitochondrial dysfunctions; Neuron damages; Oxidative stress; Proteostasis network; Rosmarinic acid

DOI:  https://doi.org/10.1007/s12035-024-04206-4