Neurodegenerative diseases are linked to the process of neurodegeneration. This can be caused by several mechanisms, including inflammation and accumulation of reactive oxygen species. Despite their high incidence, there is still no effective treatment or cure for these diseases. Cyanobacteria have been seen as a possible source for new compounds with anti-inflammatory and antioxidant potential, such as polysaccharides (sacran), phycobiliproteins (phycocyanin) and lipopeptides (honaucins and malyngamides), which can be interesting to combat neurodegeneration. As a promising case of success, Arthrospira (formerly Spirulina) has revealed a high potential for preventing neurodegeneration. Additionally, advantageous culture conditions and sustainable production of cyanobacteria, which are allied to the development of genetic, metabolic, and biochemical engineering, are promising. The aim of this review is to compile and highlight research on the anti-inflammatory and antioxidant potential of cyanobacteria with focus on the application as neuroprotective agents. Also, a major goal is to address essential features that brand cyanobacteria as an ecoefficient and economically viable option, linking health to sustainability.

The Blue Biotechnology and Ecotoxicology Culture Collection (LEGE-CC) holds a vast number of cyanobacteria whose chemical richness is still largely unknown. To expedite its bioactivity screening we developed a natural products library. Sixty strains and four environmental samples were chromatographed, using a semiautomatic HPLC system, yielding 512 fractions that were tested for their cytotoxic activity against 2D and 3D models of human colon carcinoma (HCT 116), and non-cancerous cell line hCMEC/D3. Six fractions showed high cytotoxicity against 2D and 3D cell models (group A), and six other fractions were selected by their effects on 3D cells (group B). The metabolome of each group was organized and characterized using the MolNetEnhancer workflow, and its processing with MetaboAnalyst allowed discrimination of the mass features with the highest fold change, and thus the ones that might be bioactive. Of those, mass features without precedented identification were mostly found in group A, indicating seven possible novel bioactive molecules, alongside in silico putative annotation of five cytotoxic compounds. Manual dereplication of group B tentatively identified nine pheophytin and pheophorbide derivatives. Our approach enabled the selection of 7 out of 60 cyanobacterial strains for anticancer drug discovery, providing new data concerning the chemical composition of these cyanobacteria.

Neurodegenerative diseases (NDs) are characterized by progressive and irreversible neuronal loss, accompanied by a range of pathological pathways, including aberrant protein aggregation, altered energy metabolism, excitotoxicity, inflammation, and oxidative stress. Some of the most common NDs include Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and Huntington’s Disease (HD). There are currently no available cures; there are only therapeutic approaches that ameliorate the progression of symptoms, which makes the search for new drugs and therapeutic targets a constant battle. Cyanobacteria are ancient prokaryotic oxygenic phototrophs whose long evolutionary history has resulted in the production of a plethora of biomedically relevant compounds with anti-inflammatory, antioxidant, immunomodulatory, and neuroprotective properties, that can be valuable in this field. This review summarizes the major NDs and their pathophysiology, with a focus on the anti-neurodegenerative properties of cyanobacterial compounds and their main effects.

Cancer has a tremendous negative socio-economic impact on our society. Thus, the discovery of new and more effective anticancer drugs is of utmost importance. To address this societal challenge, the main goal of the CYANCAN project was the discovery of anticancer compounds from cyanobacteria. These photosynthetic bacteria are considered among the most promising groups capable of producing metabolites with pharmaceutical applications. A valuable and underexplored natural resource that can underpin the discovery of promising compounds can be found in the Blue Biotechnology and Ecotoxicology Culture Collection (LEGE-CC) at CIIMAR (Interdisciplinary Centre of Marine and Environmental Research), comprising more than 700 different cyanobacterial strains. Herein, we present the recent advances implemented for finding robust anticancer lead compounds from LEGE-CC cyanobacteria. For this purpose, we developed a natural product library. Sixty cyanobacterial strains, representative of LEGE-CC biodiversity, were chromatographed to yield 480 fractions that were tested for their cytotoxic activity against 2D and 3D models of human colon carcinoma (HCT 116). The conjugation of monolayer assays and 3D cancer spheroids led to the selection of 11 active fractions, of which the chemical space was studied using an untargeted metabolomics approach. The putative annotation and identification of several compounds led to the selection of two marine strains for compound isolation: Leptothoe sp. and Lusitaniella coriacea. The isolation of the compounds was guided through bioactivity assays and mass spectrometry. These molecules were purified from the crudes by employing several chromatography methods, and the chemical structures were determined by means of NMR (nuclear magnetic resonance) and MS/MS (tandem mass spectrometry) experiments. Thus, a novel macrolide-type compound was isolated from Leptothoe sp., which presented a highly cytotoxic activity against our cancer cell models. Its effects on cancer vascularization and metastasis were studied using the zebrafish model. Moreover, from L. coriacea, five unprecedented salicyl-capped thiazol(in)e NRPs-PKs (nonribosomal peptides-polyketides) compounds were isolated. These compounds showed the potential to act as reversers of P-glycoprotein efflux activity.

Cyanobacteria are microorganisms who produce secondary metabolites potentially bioactive against multiple activities, such as anticancer. Considered the second biggest cause of world mortality, treatment of cancer aims for more and more diverse therapeutics. Hence, the usage of these organisms is of major interest for marine biotechnology, as a source of new natural drugs. This work focusses on the isolation of natural compounds from cyanobacteria with potential anticancer activity. For that, we followed a bioassay-guided fractionation of cyanobacteria biomass extracts, from multiple strains of the LEGE Cyanobacteria Culture Collection. The obtained crude extract was fractionated through vacuum liquid chromatography, resulting in fractions from less to more polar, who were tested on 2D cell culture of MG-63 cell line through MTT assays and on 3D cell culture of HCT-116 cell line using fluorescence microscopy. The 3D cell model mimics solid tumour in vitro and therefore is a physiologically more relevant model than monolayer cultures. Our results showed that different fractions have activity in 2D than in 3D cultures, unveiling selectivity for cell lines and possible differences in chemical properties of bioactive compounds. We will continue the fractionation of biologically active fractions, through column chromatography and HPLC, to obtain an isolated compound and to elucidate its chemical structure using methods such as LC-MS and NMR spectroscopy, proving the interest of these microorganisms as a potential source of new drugs.

Essential trace metals are vital for cellular processes such as respiration, DNA replication, and photosynthesis. Cyanobacteria must tightly regulate metal homeostasis to prevent deficiency or toxicity, yet their metallophores remain overlooked. Here, we report lusichelins A-E (1-5), new metallophores isolated from the marine cyanobacterium Lusitaniella coriacea LEGE 07167. Their structures and configurational assignments were determined using NMR, mass spectrometry, TD-DFT calculations, and retrobiosynthetic insights. Lusichelins feature a unique structural arrangement with thiazoline/thiazole rings connected by a vinyl group, an aliphatic carbon chain, or directly, enabling potential for hexadentate metal coordination. Genomic analysis identified a hybrid PKS/NRPS biosynthetic gene cluster consistent with the structure of lusichelins and bearing traits characterisitic of metallophore biosynthesis. Notably, lusichelin production was influenced by salt composition in the culture medium rather than iron availability, suggesting an atypical regulatory mechanism. Functionally, lusichelins acted as copper detoxifiers, and lusichelin B (2) exhibited cytotoxicity against colon carcinoma cells while reversing multidrug resistance via ABCB1 efflux pump modulation. These findings expand the understanding of cyanobacterial metallophores in microbial metal homeostatis and highlight their potential in biological applications