Excessive oxidative stress drives lipid peroxidation and contributes to skeletal muscle atrophy in a range of musculoskeletal diseases. Polyunsaturated fatty acids (PUFAs) are essential components of muscle cell membrane phospholipids and are especially susceptible to peroxidation due to the presence of double bonds. Currently, therapeutic options targeting lipid peroxidation to prevent muscle wasting are limited. Substituting the hydrogen atom at the bis-allylic position with deuterium could conceivably limit lipid peroxidation while retaining enzymatic PUFA metabolism. Here we investigated the potential role of deuterated PUFAs (D-PUFAs) in protecting against muscle cell dysfunction under conditions of elevated oxidative stress. Both native (H-) and deuterated (D-) forms of long chain PUFAs including arachidonic acid (ARA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) stimulated in vitro muscle cell growth and development in the absence of oxidative stress. D-ARA, D-EPA, D-DPA, and D-DHA each protected cultured myotubes against the deleterious effects of direct exposure to reactive oxygen species (ROS) by limiting lipid peroxidation. In contrast, H-ARA, H-EPA, H-DPA, and H-DHA each increased sensitivity to ROS-induced lipid peroxidation and exacerbated oxidative stress-induced muscle cell dysfunction. Deuterated 18-carbon linoleic acid (D-LA), alpha linolenic acid (D-ALA), as well as D-ARA and D-EPA (but not D-DPA or D-DHA) also protected against the deleterious effects of ferroptosis inducer erastin on myogenic differentiation. Finally, D-PUFAs modulated local expression of endogenous antioxidant enzymes, muscle-specific protein ligases, and key enzymes involved in mitochondrial energy metabolism. Overall, our study suggests a promising role of D-PUFAs as novel therapeutics to protect against skeletal muscle dysfunction induced by oxidative stress.

2025-12-01·Alzheimers & Dementia

Lipid‐Based Modulation of Neurogenesis: DHA‐H and HPA Promote Proliferation and Differentiation in Alzheimer's Models

Article

作者: Torres, Manuel ; Castroflorio, Enrico ; Fernández‐García, Paula ; Cabot, Joan ; Escriba, Pablo V. ; Suau, Margalida ; Lladó, Victoria

Abstract:

Background:

Lipids are fundamental to neuronal function, and disruptions in lipid homeostasis are increasingly recognized as key contributors to neurodegenerative diseases such as Alzheimer's disesase. While lipid dysregulation is known to alter protein function, the therapeutic potential of lipid‐based interventions remains largely unexplored.

Methods:

Neurospheres culture, immunocytochemistry, immunohistochemistry, inmunofluorescence labeling, confocal microscopy, western‐blot, qPCR.

Results:

Here, using 5xFAD mice and primary neurospheres, we investigate the effects of a hydroxylated derivative of docosahexaenoic acid (DHA‐H) and its metabolite heneicosapentaenoic acid (HPA) on neuronal proliferation and differentiation. We show that DHA‐H and HPA enhance proliferation, as evidenced by increased expression of Ki‐67, Sox2, and Nestin, alongside BrdU incorporation in vitro. Confocal microscopy and Western blot analyses further reveal upregulation of neuronal differentiation markers, including Doublecortin, NeuroD1, and PSA‐NCAM. In vivo, treatment of WT and 5xFAD mice promotes neuronal progenitor cell proliferation in the dentate gyrus, as indicated by elevated staining of phospho‐Histone H3 levels. Moreover, we identify GPR37 as a potential receptor mediating these effects, with its expression upregulated following treatment. This is accompanied by alterations in MAPK and mTOR signaling pathways, uncovering key mechanisms underlying neuroproliferation and differentiation in Alzheimer's disease models.

Conclusion:

These findings highlight the potential of lipid‐based interventions in restoring neurogenesis and neuronal maturation in neurodegenerative conditions.

2025-07-01·JOURNAL OF BIOLOGICAL CHEMISTRY

The hematin-dihydroartemisinin adduct mobilizes a potent mechanism to suppress β-hematin crystallization

Article

作者: Sullivan, David J ; Rimer, Jeffrey D ; Lee, Huan-Jui ; Vekilov, Peter G ; Azargoshasb, Hamidreza

Malaria remains a significant public health challenge in equatorial regions of the world, largely owing to the parasite's emerging resistance to the recently introduced drugs of the artemisinin (ART) family. In the human body, most ART-derivative drugs are metabolized to dihydroartemisinin (DHA), which, in the parasite, after activation by heme, can form a hematin-dihydroartemisinin adduct (H-DHA). Here we test whether and how H-DHA inhibits hematin crystallization, the main constituent of the heme detoxification pathway of malaria parasites. We find that H-DHA is a poor inhibitor of classical crystal growth-it weakly blocks the growth sites on crystal surfaces-and, counterproductively, a promoter of β-hematin nucleation, driven by a boost in the formation of precursors. We establish that at elevated hematin concentrations, H-DHA activates two nonclassical pathways that transform it into a potent β-hematin growth inhibitor. First, β-hematin crystallites, whose nucleation is promoted by H-DHA, incorporate into large β-hematin crystals and suppress their growth, likely by straining the crystal lattice. A second consequence of H-DHA is the generation of macrosteps on β-hematin crystal surfaces that hinder growth. Importantly, the induced growth suppression is irreversible and persists even in the absence of H-DHA. Our findings suggest that a partial resistance mechanism to artemisinin-class drugs in trophozoite-stage parasites may be due to the reduced concentrations of hematin and H-DHA, which deactivate the dual nonclassical mode of action of the adduct in the delayed-clearance parasite strains.

100 项与 Hydroxy-docosahexaenoic acid 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
阿尔茨海默症	临床前	西班牙	University of The Balearic Islands	2023-06-16
阿尔茨海默症	临床前	西班牙	Laminar Pharmaceuticals SA (Spain)	2023-06-16