β-Amyloid (Aβ) can form aggregates through self-assembly and produce neurotoxicity in the early stage of Alzheimer's disease (AD). Therefore, the inhibition of Aβ assembly is considered as the primary target for AD therapy. In this study, we reported that fucoxanthin, a marine carotenoid, potently reduced the formation of Aβ fibrils and oligomers. Moreover, the fucoxanthin-triggered modification significantly reduced the neurotoxicity of Aβ oligomers in vitro. Molecular dynamics simulation analysis further revealed a hydrophobic interaction between fucoxanthin and Aβ peptide, which might prevent the conformational transition and self-assembly of Aβ. Most importantly, fucoxanthin could attenuate cognitive impairments in Aβ oligomer-injected mice. In addition, fucoxanthin significantly inhibited oxidative stress, enhanced the expression of brain-derived neurotrophic factor, and increased ChAT-positive regions in the hippocampus of mice. On the basis of these novel findings, we anticipated that fucoxanthin might ameliorate AD via inhibiting Aβ assembly and attenuating Aβ neurotoxicity.

Five new stilbene oligomers, laetevirenol A-E (4-8), were isolated from Parthenocissus laetevirens, together with three known stilbene oligomers (2, 3, and 9). The structures of the new compounds were elucidated by spectroscopic analysis, including 1D and 2D NMR experiments. Afterward the absolute configurations were determined. Biomimetic transformations revealed a possible biogenetic route, where stilbene trimers were enzymatically synthesized for the first time. In addition, their antioxidant activities were evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. The results showed that stilbene oligomers with an unusual phenanthrene moiety exhibited much stronger antioxidant activities. Thus, the photocatalyzed cyclization of stilbenes was supposed to be an antioxidant activity promoting transformation, which was hypothesized to play a role in the antioxidative defense system of the plant.

Methanobactins (Mbns) are a family of copper-binding peptides involved in copper uptake by methanotrophs, and are potential therapeutic agents for treating diseases characterized by disordered copper accumulation. Mbns are produced via modification of MbnA precursor peptides at cysteine residues catalyzed by the core biosynthetic machinery containing MbnB, an iron-dependent enzyme, and MbnC. However, mechanistic details underlying the catalysis of the MbnBC holoenzyme remain unclear. Here, we present crystal structures of MbnABC complexes from two distinct species, revealing that the leader peptide of the substrate MbnA binds MbnC for recruitment of the MbnBC holoenzyme, while the core peptide of MbnA resides in the catalytic cavity created by the MbnB–MbnC interaction which harbors a unique tri-iron cluster. Ligation of the substrate sulfhydryl group to the tri-iron center achieves a dioxygen-dependent reaction for oxazolone-thioamide installation. Structural analysis of the MbnABC complexes together with functional investigation of MbnB variants identified a conserved catalytic aspartate residue as a general base required for MbnBC-mediated MbnA modification. Together, our study reveals the similar architecture and function of MbnBC complexes from different species, demonstrating an evolutionarily conserved catalytic mechanism of the MbnBC holoenzymes.

Fucoxanthin, a natural carotenoid abundant in edible brown seaweeds, has been shown to possess anti-cancer, anti-oxidant, anti-obesity and anti-diabetic effects. In this study, we report for the first time that fucoxanthin effectively protects against scopolamine-induced cognitive impairments in mice. In addition, fucoxanthin significantly reversed the scopolamine-induced increase of acetylcholinesterase (AChE) activity and decreased both choline acetyltransferase activity and brain-derived neurotrophic factor (BDNF) expression. Using an in vitro AChE activity assay, we discovered that fucoxanthin directly inhibits AChE with an IC50 value of 81.2 μM. Molecular docking analysis suggests that fucoxanthin likely interacts with the peripheral anionic site within AChE, which is in accordance with enzymatic activity results showing that fucoxanthin inhibits AChE in a non-competitive manner. Based on our current findings, we anticipate that fucoxanthin might exhibit great therapeutic efficacy for the treatment of Alzheimer’s disease by acting on multiple targets, including inhibiting AChE and increasing BDNF expression.

Marine cyanobacteria are significant sources of structurally diverse marine natural products with broad biological activities. In the past 10 years, excellent progress has been made in the discovery of marine cyanobacteria-derived peptides with diverse chemical structures. Most of these peptides exhibit strong pharmacological activities, such as neurotoxicity and cytotoxicity. In the present review, we summarized peptides isolated from marine cyanobacteria since 2007.

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Resveratrol, a star natural product from red wine, has attracted increasing attention around the world. In recent years, resveratrol derivatives (including its oligomers) have shown amazing chemical diversity and biological activities. They have been emerging to be promising new sources of natural antioxidant. This review summarizes recent finding on antioxidant activities of resveratrol derivatives and the structure-activity relationship for the first time. Scientific evidences have highlighted their potential as therapeutic agents for cerebral and cardiovascular diseases. In our opinion, more effort should be devoted to the synthesis of resveratrol oligomers. Based on the structure-activity relationship, screening for resveratrol derivatives with higher antioxidant activity than trans-resveratrol is warranted, and these molecules may have greater therapeutic potential in future investigations.

Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by neurofibrillary tangles, synaptic impairments, and loss of neurons. Oligomers of β-amyloid (Aβ) are widely accepted as the main neurotoxins to induce oxidative stress and neuronal loss in AD. In this study, we discovered that fucoxanthin, a marine carotenoid with antioxidative stress properties, concentration dependently prevented Aβ oligomer-induced increase of neuronal apoptosis and intracellular reactive oxygen species in SH-SY5Y cells. Aβ oligomers inhibited the prosurvival phosphoinositide 3-kinase (PI3K)/Akt cascade and activated the proapoptotic extracellular signal-regulated kinase (ERK) pathway. Moreover, inhibitors of glycogen synthase kinase 3β (GSK3β) and mitogen-activated protein kinase (MEK) synergistically prevented Aβ oligomer-induced neuronal death, suggesting that the PI3K/Akt and ERK pathways might be involved in Aβ oligomer-induced neurotoxicity. Pretreatment with fucoxanthin significantly prevented Aβ oligomer-induced alteration of the PI3K/Akt and ERK pathways. Furthermore, LY294002 and wortmannin, two PI3K inhibitors, abolished the neuroprotective effects of fucoxanthin against Aβ oligomer-induced neurotoxicity. These results suggested that fucoxanthin might prevent Aβ oligomer-induced neuronal loss and oxidative stress via the activation of the PI3K/Akt cascade as well as inhibition of the ERK pathway, indicating that further studies of fucoxanthin and related compounds might lead to a useful treatment of AD.